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Freeze-drying of Silica Nanoparticles: Redispersibility Toward Nanomedicine Applications
Abstract
Aim:
To study freeze-drying of silica nanoparticles (SiO2NPs) in order to find suitable conditions to produce lyophilized powders with no aggregation after resuspension and storage.
Methods:
SiO2NPs were synthesized using a Stöber-based procedure, and characterized by scanning electron microscopy, dynamic light scattering and nitrogen adsorption/desorption isotherms. SiO2NPs hydrodynamic diameters were compared prior and after freeze-drying in the presence/absence of carbohydrate protectants.
Results:
Glucose was found to be the most suitable protectant against the detrimental effects of lyophilization. The minimum concentration of carbohydrate required to effectively protect SiO2NPs from aggregation during freeze-drying is influenced by the nanoparticle's size and texture. Negligible aggregation was observed during storage.
Conclusion:
Carbohydrates can be used during SiO2NPs freeze-drying process to obtain redispersable solids that maintain original sizes without residual aggregation.
... The concentration of nanoparticles (g L −1 ) in the purified dispersions was determined by weighing the remaining solid (n = 5) after evaporation of water in an oven (Blue M) at 110°C for 2.0 h. 50 DLS Malvern Zetasizer Ultra was the first technique used to investigate the size, homogeneity, and eventual aggregation of the formed SiO 2 NPs through the determination of their average hydrodynamic diameters (D H ) and polydispersity indexes (PDI) as well. The nanoparticle concentration (C NP ) was also reached by DLS, as detailed in the Supporting Information. ...
... Using the DLS equipment, we also measured the ζ-potential and conductivity of the SiO 2 NPs in the dispersions. 50 More details on the prior analyses and AFM tests are available in the Supporting Information. ...
... Since SSA GEO < SSA BET , SiO 2 NPs can be considered as microporous structures. 50,77 According to Bogush's theory, 24 the formation of microporous silica nanoparticles is due to the aggregation of particles or nuclei, thus forming gradually larger and porous nanoparticles until the synthesis kinetics is stabilized. ...
... carbohydrates) are often used as additives in nanoformulations to protect nanoparticles from freezing and drying stresses, ultimately preventing their aggregation and improving their redispersibility upon reconstitution. 8,12 Although aggregation can affect biodistribution and bioavailability, nanoparticle toxicity can result in unfeasible medical applications. 3,6,13 Nanoparticle toxicity is usually correlated with various properties, including size, shape, chemical composition and surface chemistry. ...
... SNPs were produced according to the Stöber method 26,27 with small modifications. 12 Briefly, 6 mL of ammonia solution (28-30 wt%) was added to 120 mL of ethanol and the resultant solution ( pH around 10) was stirred for 30 minutes. Then, under continuous stirring, two aliquots of TEOS (2.7 mL) were added with a 3 h interval between them. ...
... 11,30 During the freezing step, ice crystals are formed and solutes are excluded from these solids, leading to cryo-concentrated solutions (or suspensions for colloids). 9,12 The mechanical stress generated from the liquid solidification and the increased concentration of nanoparticles can lead to irreversible nanoparticle aggregation. Moreover, during the drying step, the ice-water phase is first sublimated ( primary drying) and then the 'bound' water on the cryo-concentrated nanoparticle suspension is removed (secondary drying). ...
Freeze-drying of nanoparticle suspensions is capable of generating stable nanoformulations with improved storage times and easier transportation. Nonetheless, nanoparticle aggregation is likely induced during freeze-drying, which reduces its redispersibility upon reconstitution and leads to undesirable effects such as non-specific toxicity and impaired efficacy. In this work, bovine serum albumin (BSA) is described as a suitable protectant for silica nanoparticles (SNPs), which result in solid structures with excellent redispersibility and negligible signs of aggregation even when longer storage times are considered. We experimentally demonstrated that massive system aggregation can be prevented when a saturated BSA corona around the nanoparticle is formed before the lyophilization process. Furthermore, the BSA corona is able to suppress non-specific interactions between these nanoparticles and biological systems, as evidenced by the lack of residual cytotoxicity, hemolytic activity and opsonin adsorption. Hence, BSA can be seriously considered for industry as an additive for nanoparticle freeze-drying since it generates solid and redispersible nanoformulations with improved biocompatibility.
... [9][10][11] Because they cannot be preserved in aqueous media without losing their properties as NP forms, they are subjected to freeze drying. [12][13][14][15] Freeze drying or lyophilization, a dehydration process, consists of three stages: i) freezing, ii) primary drying, and iii) secondary drying. [15,16] In the first stage of lyophilization, the NP formulation is cooled, and ice crystals are formed. ...
... [18,19] If the aqueous phase is not removed from the NPs, some physical and chemical instabilities may occur, such as particle aggregation, hydrolysis of the polymeric material, release of the drug from the NP, and the decreased activity of the drug. [14,15] The solid NPs obtained after lyophilization can be redispersed by adding water if necessary. [17,20] However, the lyophilization of NPs alone does not ensure the dimensional stability of NPs when they are redispersed after long-term storage. ...
Sugars, as cryoprotectants, can be added to NP formulations before lyophilization to ensure that NPs retain their size during long‐term storage. In this study, mannitol, glucose, and sucrose were used at different concentrations to extend the storage time of doxorubicin (DOX)‐loaded PLGA‐NPs prepared using two different copolymer ratios (75 : 25 and 50 : 50) at different storage temperatures (−20, +4, and +25 °C). After lyophilization, a glucose or sucrose concentration of only 5 % for DOX‐PLGA‐75 : 25‐NP and a glucose concentration of 10 % for DOX‐PLGA‐50 : 50‐NP were found to prevent agglomeration for up to 4 months at −20 °C. It is noteworthy that after storage at 4 °C for up to 4 months, agglomeration was prevented using 5 % sucrose and 10 % glucose in DOX‐PLGA‐50 : 50‐NP and 10 % sucrose content in both NP types. On the other hand, as expected, no sugar type or concentration could prevent agglomeration during long‐term storage of NPs at 25 °C. The sizes and encapsulation efficiencies (EE%) before lyophilization were 221.8±2.20 and 45.4 % for DOX‐PLGA‐50 : 50‐NP and 221.5±1.31 and 48.7 % for DOX‐PLGA‐75 : 25‐NP, respectively. Furthermore, the release profiles and encapsulation of DOX in both NPs were investigated by UV‐Vis analyses. DSC analysis revealed that DOX was present in the free form and amorphous in the NPs. Consequently, PLGA copolymer ratios were found to have an impact on the long‐term stability of DOX loaded PLGA lyophilizates, and DOX‐loaded NPs prepared with PLGA 75 : 25 or PLGA 50 : 50 can be stored at −20 and +4 °C for up to 4 months when combined with appropriate sugar contents and concentrations, demonstrating the versatility of these materials.
... SiO2 synthesis was adapted from procedures already described in the literature. [35][36][37] In summary, 3.5 mL of NH4OH was added to 120 mL of ethanol under magnetic stirring. Two aliquots of 2.5 mL of tetraethyl orthosilicate (TEOS) were then added to the pre-formed mixture after 0.5 and 3 h of stirring. ...
... In this work, silica nanoparticles (SiO2) were obtained by the sol-gel method through a one-step synthesis approach 35,36,37 and purified by dialysis. TEM was used to investigate the shape, size, and size distribution of the synthesized particles. ...
Protein corona formation and nanoparticle aggregation have been heavily discussed over the last years since the lack of fine-mapping of these two combined effects has hindered the targeted delivery evolution and the personalized nanomedicine development. We present a multi-technique approach that combines Dynamic Light and Small-Angle X-ray Scattering techniques with cryo-Transmission Electron Microscopy in a given fashion that efficiently distinguishes protein corona from aggregates formation. This methodology was tested using 25-nm model silica nanoparticles incubated with either model proteins or biologically relevant proteomes (such as fetal bovine serum and human plasma) in buffers of low and high ionic strengths to precisely tune particle-to-protein interactions. In this work, we were able to differentiate protein corona, small aggregates formation, and massive aggregation, as well as obtain fractal information of the aggregates reliably and straightforwardly. The strategy presented here can be expanded to other particle-to-protein mixtures and might be employed as a quality control platform for samples that undergo biological tests.
... SiO2 synthesis was adapted from procedures already described in the literature. [35][36][37] In summary, 3.5 mL of NH4OH was added to 120 mL of ethanol under magnetic stirring. Two aliquots of 2.5 mL of tetraethyl orthosilicate (TEOS) were then added to the pre-formed mixture after 0.5 and 3 h of stirring. ...
... In this work, silica nanoparticles (SiO2) were obtained by the sol-gel method through a one-step synthesis approach 35,36,37 and purified by dialysis. TEM was used to investigate the shape, size, and size distribution of the synthesized particles. ...
Protein corona formation and nanoparticles' aggregation have been heavily discussed over the last years since the lack of fine-mapping of these two combined effects has hindered the targeted delivery evolution and the personalized nanomedicine development. We present a multi-technique approach that combines Dynamic Light and Small-Angle X-ray Scattering techniques with cryo-Transmission Electron Microscopy in a given fashion that efficiently distinguishes protein corona from aggregates formation. This methodology was tested using ~ 25-nm model silica nanoparticles incubated with either model proteins or biologically relevant proteomes (such as fetal bovine serum and human plasma) in buffers of low and high ionic strengths to precisely tune particle-to-protein interactions. In this work, we were able to differentiate protein corona, small aggregates formation, and massive aggregation, as well as obtain fractal information of the aggregates reliably and straightforwardly. The strategy presented here can be expanded to other particle-to-protein mixtures and might be employed as a quality control platform for samples that undergo biological tests.
... It is also worth mentioning that NPs purification procedure and storage (liquid suspension vs. dry powder) before the transference to the testing media can profoundly influence the colloidal behavior. In particular, silica NP dried powders are difficult to redisperse due to the formation of interparticle siloxane bonds that result in irreversible aggregates [150,151]. In this case, any further evaluation of the NP colloidal behavior will be heavily biased by this original aggregation. ...
... For instance, this situation is frequently observed in MSNs produced following procedures implying calcination for organic template removal or pyrogenic non-porous silica NPs, but not restricted to these examples [104]. Despite this, silica NP powders with good redispersability in relevant media and showing reduced to negligible aggregation attributed to the dry state can be produced by freeze-drying in the presence of proper protectants such as simple carbohydrates [151] or albumin [22,50]. ...
This review shows the most common and promising strategies to generate colloidally stable silica nanoparticles (NPs) in simulated biological fluids and sheds light on the latest advances in producing degradable silica-based structures. Silica NPs can be synthesized in a wide variety of morphologies, porosity levels, and sizes. This versatility makes silica NPs one of the most promising nano-platforms for imaging and disease treatment. Nonetheless, biological barriers can decrease the success of translating them for therapeutic applications since the media composition can induce their colloidal stability loss. It can, consequently, lead to the NPs aggregation and affect their degradation profile. The interplay between NPs aggregation and degradation has been scarcely explored in the literature when biological fluids are seriously taken into account. Herein we discuss the theory behind the colloidal stability of silica NPs, the processes leading to their aggregation, and some strategies to overcome this issue (mainly focused on NPs surface functionalization). Furthermore, we addressed the main issues that affect the degradability of NPs in biological fluids, and explored some strategies, such as chemical surface modification, which are able to tune these degradation-driven profiles. Thus, the understanding of the silica NPs behavior in body fluids is essential for the approval of nanomedicines and, therefore, more investigations concerning the dynamics, thermodynamics, biological response, and structural parameters of silica-based NPs are of utmost importance.
... The method has been extensively used in pharmaceuticals and the food industry. Lyophilization improves the stability of nanoderived therapeutic agents and improves the shelf life of encapsulated actives [162]. Major limitations of nanodervied therapeutic are aggregation of colloidal mass, and formation complex may diminish the therapeutic potential of loaded actives. ...
Background
Process intensification is a major hurdle in pharmaceutical process scale-up. Solvent removal strategies have limited the effectiveness of the overall stability of pharmaceutical formulations. The main aim of present review article is to focus on the use of the freeze-drying process in pharmaceuticals, biopharmaceuticals and nanoderived therapeutics and their translation into commercial viable products. Unwavering efforts of scientists in the process intensification of lyophilization promote unique features of products for commercialization. Regulatory agencies are promoting the utilization of a quality-by-design approach to improve product characteristics. Among 300 FDA-approved pharmaceutical industries, 50% of products are freeze-dried. The freeze-drying process is costlier and requires more time than other drying methodologies. Unstable pharmaceutical dispersions and solutions can be preferably stabilized by using the freeze-drying method.
Main text
This review highlights the utilization of critical quality attributes and process parameters for the freeze-drying process, which helps to improve the integrity and stability of the formulation. The quality-by-design approach possibly cuts the cost of the process and saves money, time, and laborious work. The present review focuses preliminarily on the applications of freeze-drying in the development of biopharmaceuticals, including vaccines, proteins and peptides, and injectable products. In addition, a separate section demonstrating the potential of freeze-drying in nanoderived therapeutics has been illustrated briefly. The present clinical scenario of freeze-dried pharmaceuticals and biopharmaceuticals has also been described in later sections of the review.
Conclusions
This review underscores the value of integrating Quality by Design into the development of lyophilization processes for pharmaceutical and biopharmaceutical products. By identifying critical process parameters, delineating a design space, and leveraging advanced monitoring techniques, manufacturers can effectively address the intricacies of lyophilization. This approach empowers them to produce stable, superior quality products with confidence and consistency.
Graphical abstract
... Freeze-drying, or lyophilization, is a common method for stabilizing nanoparticles for long-term storage, through sublimation of frozen suspension solvent and desorption in vacuo [5,6]. However, this process can cause aggregation, mechanical stress, and surface dehydration without protectants or surfactants [7][8][9]. ...
Cellulose nanocrystals (CNCs) have garnered significant attention in recent years due to their potential applications in coating, reinforcement, and packaging technologies. The present study focuses on the development of an efficient, low-cost, and scalable drying process for CNCs, adapted 2 from the electrospray technique. CNCs were dispersed in various concentrations of tert-butanol (t-BuOH) prior to electrospray drying. The resulting morphologies and micro-rheological behaviors were compared to those obtained through conventional air drying, oven drying, freeze-drying, and air-spray drying methods. The electrospray-dried CNCs derived from an 85 % t-BuOH suspension exhibited superior physico-chemical properties and thermal stability, characterized by highly ordered crystals that self-assembled into thin lamellar structures. Furthermore, the relatively low re-suspension ability of these dried CNCs is advantageous for coating and thin film fabrication, providing high controllability over the morphology. Notably, this rapid drying process (≤ 35 minutes) can be extended to other nanomaterials, provided that their suspensions can be electrically charged to spread and dry uniformly on substrates.
... The physicochemical properties of loaded uncross-linked and crosslinked NGs were compared. Picco et al. method was employed to compute the PS, zeta potential, and PDI of the NGs under investigation [26]. To recapitulate, fresh samples of each synthesized NG were diluted (1:1 v/v) with DW, sonicated for 10 min to generate homogenized dispersions, and measured at 25 ± 0.1 • C using a Malvern Zetasizer (NanoZlS/ZEN3600 Zetasizer Malvern Instruments Ltd., UK). ...
In response to the pressing demand for functional nanomaterials synthesis and applications, two polyelectrolyte complexes (PECs) [electrostatic and cross-linked nanogels (NGs)] loaded individually with caffeic acid (CafA) and eugenol (Eug) demonstrating multifunctionalities were proposed for the first time. Curdlan (Curd) and glucomannan (GM) were carboxymethylated (CMCurd and CMGM) successfully and polymeric ratios of 1:1 and 4:1 (v/v) for chitosan (Cs): CMCurd and lactoferrin (Lf): CMGM were selected for the synthesis of Cs/CMCurd and Lf/CMGM NGs. Due to the use of EDC/NHS, Cs/CMCurd/CafA and Lf/CMGM/Eug NGs possessed very uniform particles sizes of 177 ± 18 and 230 ± 17 nm with marked encapsulation efficiencies (EEs) of 76 ± 4 and 88 ± 3 %, respectively. The formation of a carbonyl-amide linkage in both cross-linked NGs was confirmed by FTIR. It should be noted, the self-assembly was not reliable in retaining enough of the encapsulated compounds. Owing to the excellent physicochemical characteristics of the loaded cross-linked NGs, they were prioritized over the electrostatic ones. Both Cs/CMCurd/CafA and Lf/CMGM/Eug NGs exhibited high colloidal stability over 12 weeks, elevated hemocompatibility, and in vitro serum stability. The generated NGs were also tailored to possess controlled release profiles for CafA and Eug over 72 h. Cs/CMCurd/CafA and Lf/CMGM/Eug NGs had promising antioxidant efficacies and could remarkably inhibit 4 bacterial pathogens at low 2-16 μg/mL concentration of encapsulated NGs compared to their unencapsulated counterparts. Interestingly, the respective NGs could significantly decline the IC50 against colorectal cancer HCT-116 than conventional drugs. Based on these data, it was conferred that the investigated NGs could be promising candidates for functional foods and pharmaceutics.
... Drying methods: In general, many particle properties and applications are investigated in the solid state. Thus, there are various approaches to drive it to powder form and maintain its properties [77,78]. For each system and application, it is necessary to investigate the best strategy. ...
Some characteristics of silica-based materials, such as the control/adjustment of their physical and chemical properties, compatibility, and friendly-use synthesis methods, have held the attention of several scientific groups over the years. This condition of prominence becomes even more evident when we seek these characteristics at the micro- and/or nanoscale. Among existing methods to obtain these micro/nanomaterials, the Stöber method is the focus of this review. This method is known to enable the production of silica micro- or nanoparticles from reagents of medium-easy manipulation under mild conditions using equipment that is common in most laboratories. However, this method has many nuances that must be considered to guarantee accurate results, either in size or distribution, and to ensure result reproducibility. Thus, in this review, we discuss the effects of the primary components used in the synthesis of these materials (i.e., TEOS, ammonia, and water), as well as those of other reaction conditions, such as solvent, temperature, and ionic strength. Therefore, we discuss studies involving the synthesis and characterization of micro- and nanoparticles over the years to establish discussions between their experimental observations and proposed models. This review provides experimental observations about the synthesis of these materials, as well as discussions according to complementary and/or contradictory evidence found over the years. This review seeks to help those who intend to work with this method and provide certain key points that, in our experience, can be important to obtain desired results.
... Indeed, during the freezing of PEC-NG suspensions, the continuous formation of pure ice crystals should lead to a gradual reduction in the volume of the liquid phase, thus, a local increase in particle and counter-ion concentrations, also known as cryoconcentration [10]. This will result in different stresses on PEC-NGs: (i) me-chanical damage or deformation of PEC-NGs caused by growing ice crystals, (ii) structure interference caused by the loss of hydrogen bonds as water molecules are transferred to the ice phase and then sublimated, and (iii) closer approach of particles and weakened electrostatic stabilization by the charge screening effect of counter-ions which facilitate particle aggregation [10,18]. Logically, a higher absolute zeta potential at the beginning would allow a greater electrostatic repulsion to avoid such aggregation and also facilitate disaggregation during the reconstitution, which was also observed by Umerska et al. [11] and Eliyahu et al. [19]. ...
The lyophilization of nanogels is practical not only for their long-term conservation but also for adjusting their concentration and dispersant type during reconstitution for different applications. However, lyophilization strategies must be adapted to each kind of nanoformulation in order to minimize aggregation after reconstitution. In this work, the effects of formulation aspects (i.e., charge ratio, polymer concentration, thermoresponsive grafts, polycation type, cryoprotectant type, and concentration) on particle integrity after lyophilization and reconstitution for different types of polyelectrolyte complex nanogels (PEC-NGs) from hyaluronic acid (HA) were investigated. The main objective was to find the best approach for freeze-drying thermoresponsive PEC-NGs from Jeffamine-M-2005-functionalized HA, which has recently been developed as a potential platform for drug delivery. It was found that freeze-drying PEC-NG suspensions prepared at a relatively low polymer concentration of 0.2 g.L⁻¹ with 0.2% (m/v) trehalose as a cryoprotectant allow the homogeneous redispersion of PEC-NGs when concentrated at 1 g.L⁻¹ upon reconstitution in PBS without important aggregation (i.e., average particle size remaining under 350 nm), which could be applied to concentrate curcumin (CUR)-loaded PEC-NGs for optimizing CUR content. The thermoresponsive release of CUR from such concentrated PEC-NGs was also reverified, which showed a minor effect of freeze-drying on the drug release profile.
... This is highly important from a nanomedicine clinical application perspective, as the NPs have to be stable during manufacturing, storage, and transportation. [187][188][189][190][191] For instance, mercaptoacetic acid-modified Au NPs and succinic-modified SiO 2 and Fe 3 O 4 colloids subjected to freeze-drying avoided aggregation after reconstitution in aqueous solutions. 51,74,192 In this context, COOH groups have shown their importance in the formulation of cryoprotective agents such as carboxylated-poly-Llysine polyampholytes with antifreeze protein properties and ice recrystallization inhibition. ...
The carboxylic chemical group is a ubiquitous moiety present in amino acids, a ligand for transition metals, a colloidal stabilizer, and a weak acidic ion-exchanger in polymeric resins and given this property, it is attractive for responsive materials or nanopore-based gating applications. As the number of uses increases, subtle requirements are imposed on this molecular group when anchored to various platforms for the functioning of an integrated chemical system. In this context, silica stands as an inert and multipurpose platform that enables the anchoring of multiple chemical entities combined through several orthogonal synthesis methods on the interface. Surface chemical modification relies on the use of organoalkoxysilanes that must meet the demand of tuned chemical properties; this, in turn, urges for innovative approaches for having an improved, but simple, organic toolbox. Starting from commonly available molecular precursors, several approaches have emerged: hydrosilylation, click thiol-ene additions, the use of carbodiimides or the reaction between cyclic anhydrides and anchored amines. In this review, we analyze the importance of the COOH groups in the area of materials science and the commercial availability of COOH-based silanes and present new approaches for obtaining COOH-based organoalkoxide precursors. Undoubtedly, this will attract widespread interest for the ultimate design of highly integrated chemical platforms.
... Picco et al. [37] procedure was used to estimate the mean particle size and zeta potential of the generated NCs. A sample of Quer NCs was diluted (1:1 v/v) with deionized water, sonicated for 10 min to achieve a homogenous solution, and examined at 25 ± 0.1 • C using a Malvern Zetasizer (NanoZlS/ZEN3600 Zetasizer Malvern Instruments Ltd., UK). ...
Despite the high demand for curdlan (Curd), its industrial implementation has not reached a mature stage due to the high cost of simple sugar feed stocks. Herein, Musa sapientum peels hydrolysate (MPH) was proposed for the first time as a sustainable medium for Curd generation and as an ameliorated functional biomaterial for quercetin (Quer) sustained release. In this study, banana peels have been hydrolysed by 3 % NaOH catalyst/ 60 o C, yielding high concentration of glucose 20.5 ± 0.04 and 24.3 ± 0.11 g/L and reducing sugar amount, respectively. Meanwhile, a novel local Rahnella variigena ICRI91 strain was isolated from soil, that was useful for Curd production and identified by 16S rRNA analysis. Furthermore, three-batch fermentation models were carried out using MPH for obtaining a sufficient yield of Curd. R. variigena ICRI91 accumulated a satisfactory Curd concentration; 10.3 ± 0.25 g/L; using 60 g/L MPH. On the other hand, the strain produced an impressive Curd yield; 21.5 ± 0.13 g/L with an attained productivity of 0.179 ± 0.01 g/L/h and a sugar consumption of 68 ± 0.25 % as the MPH content increased to 100 g/L. For the first time, Curd hydrogel was modified by different amount of Xylitol (Xyl), reaching good mechanical performance; 3.1 MPa and 75 % for tensile strength (TS) and elongation at break (EB), respectively. Curd/Xyl (3/5) hydrogel was then integrated with nanometre-sized quercetin nanocrystals (Quer NCs, 83 ± 0.12 nm) with high colloidal stability of-23 ± 0.05 mV. The interconnected H-bonding between Xyl and Curd was confirmed by FTIR and SEM. The generated biomaterial was tailored to exhibit a sustained Quer release over 72 h. It also has improved antibacterial efficacy against four bacterial pathogens compared to that of a free J o u r n a l P r e-p r o o f Journal Pre-proof 2 drug. In recognition of these merits, an edible polymeric nanomaterial has been proposed for the functional food and biomedicine sectors.
... Characterization of KPF-NCs (mean particle size, zeta potential and electronic imaging). The method of Picco et al [28] was employed to determine the particle size and zeta potential of the studied KPF-NCs. Briefly, samples of KPF-NCs were diluted (1:1 v/v) with de-ionized water, sonicated for 10 min to obtain a homogeneous suspension and analyzed at 25°C±0.1°C ...
Despite the major medical advancements in recent decades, treating infected wounds successfully remains a challenge. In this research, a functional blend of Polyhydroxybutyrate (PHB) and Chitosan (Cs) was developed for wound infection mitigation with tailored biological and physicochemical properties. Water insoluble kaempferol (KPF) was pre-formulated to water soluble KPF nanocrystals (KPF-NCs) with fine particle size of 145±11 nm, and high colloidal stability (-31±0.4 mv) to improve its drug transdermal delivery. PHB-Cs-KPF-NCs (1:2 ratio) film owned the best physical properties in terms of high breathability, thermal stability and mechanical strength (33±1 MPa). Besides, XRD and FTIR findings indicated the interaction between Cs, PHB and KPF, reducing the film crystallinity. The scanning electron microscopy (SEM) of the film displayed a highly interconnected porous morphology. KPF-NCs were integrated in PHB-Cs matrix with a marked encapsulation efficiency of 96.6%. The enhanced drug-loading film showed a sustain release pattern of KPF-NCs over 48 hrs. Interestingly, the developed blend possessed an impressive blood clotting capacity within 20 min. Furthermore, we presented a new naturally-sourced mixture of Cs+KPF-NCs with powerful antibacterial effects against MDR Staphylococcus aureus and Acentibacter baumannii at very low concentrations. The membrane evidenced a remarkable antibacterial nature in vitro with almost 100% cell viability reduction against the study strains after 48 hrs. By virtue of these advantages, this green blend is highly proposed for optimal wound care.
... The prepared NPs were pre-frozen for 24 h at −80°C and lyophilized for 24 h at −50°C. The lyophilized NPs were stored at 4°C for further use (Picco et al., 2018). ...
Algae are omnipresent in all seas and oceans, which make thema target for many applications such as bio-fertilizers, fish feeding and removal of heavy metals. In the present study, different algal species were examined as sustainable alternatives substrates for PHA production by Halomonas sp. Several media simulations were utilized to achieve high polymer productivity. The maximum poly(3-hydroxybutyrate) (PHB) concentrations were determined by using Corallina mediterranea hydrolysates as a carbon and nitrogen source. The isolates Halomonas pacifica ASL10 and Halomonas salifodiane ASL11 were found to be able to produce PHA by 67% wt and 63% wt CDW, respectively. PHB nanoparticles (NPs) had high zeta potential values and small particle sizes. These properties make it suitable for several drug delivery and pharmaceutical applications. Interestingly, NPs showed a potent antibacterial activity against several reference strains. The antibacterial efficacy of PHA-NPs has not been previously studied, thus this study opens a promising use of PHA-NPs.
... Cryoprotectant concentration affects the redispersion of the freeze-dried powder dramatically [39]. Redispersibility is the capability of the freeze-dried powder to retain its original particle size upon dilution with aqueous medium [40,41]. In this study, mannitol was used as cryoprotectant at a concentration 3% w/v based on preliminary trials [17]. ...
Background
Clopidogrel (CLP) suffers from extensive first pass metabolism results in a negative impact on its oral systemic bioavailability. Cubosomes are lyotropic liquid crystalline (LLC) nano-systems comprising monoolein, a steric stabilizer and an aqueous system, it considered a promising carrier for different pharmaceutical compounds. Box–Behnken design (BBD) is an efficient tool for process analysis and optimization skipping forceful treatment combinations.
Objective
The study was designed to develop freeze-dried clopidogrel loaded LLC (cubosomes) for enhancement of its oral bioavailability.
Method
A 33 BBD was adopted, the studied independent factors were glyceryl monooleate (GMO lipid phase), Pluronic F127 (PL F127steric stabilizer) and polyvinyl alcohol powder (stabilizer). Particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were set as independent response variables. Seventeen formulae were prepared in accordance with the bottom up approach and in-vitro evaluated regarding PS, PDI and ZP. Statistical analysis and optimization were achieved using design expert software®, then the optimum suggested formula was prepared, in-vitro revaluated, freeze-dried with 3% mannitol (cryoprotectant), solid state characterized and finally packed in hard gelatin capsule for comparative in-vitro release and in-vivo evaluation to Plavix®.
Results
Results of statistical analysis of each individual response revealed a quadratic model for PS and PDI where a linear model for ZP. The optimum suggested formula with desirability factor equal 0.990 consisting of (200 mg GMO, 78.15 mg PL F127 and 2% PVA). LC/MS/MS study confirmed significant higher Cmax, AUC0-24h and AUC0-∞ than that of Plavix®.
Conclusion
The results confirm the capability of developed carrier to overcome the low oral bioavailability.
... This is a key factor for the application of freeze-dried nanoarchitectures in a biological environment since colloidal properties of the carrier affect the behaviors during the application. 38,39 The strategy that we propose here is based on the use of PVP as a protectant to yield one of the smallest PEG/silica nanoarchitectures as a potential nanocarrier for Sorafenib with a simple preparation, high fluorescence brightness, and long-term colloidal stability. 40 The aim of the study was twofold: (i) to evaluate PluS NPs safety on endothelial cells in basal conditions (1% serum) and after stimulation (5% serum) and (ii) to characterize the effect of Sorafenib released by these NPs on endothelial cell morphology, viability, migration, and VEGF-induced angiogenesis-related functions. ...
Silica nanostructures are widely investigated for theranostic applications since relatively mild and easy synthetic methods allow the fabrication of multicompartment nanoparticles (NPs) and fine modulation of their properties. Here, we report the optimization of a synthetic strategy leading to brightly fluorescent silica NPs with a high loading ability, up to 45 molecules per NP, of Sorafenib, a small molecule acting as an antiangiogenic drug. We demonstrate that these NPs can efficiently release the drug and they are able to inhibit endothelial cell proliferation and migration and network formation. Their lyophilization can endow them with long shelf stability, whereas, once in solution, they show a much slower release compared to analogous micellar systems. Interestingly, Sorafenib released from Pluronic silica NPs completely prevented endothelial cell responses and postreceptor mitogen-activated protein kinase signaling ignited by vascular endothelial growth factor, one of the major players of tumor angiogenesis. Our results indicate that these theranostic systems represent a promising structure for anticancer applications since NPs alone have no cytotoxic effect on cultured endothelial cells, a cell type to which drugs and exogenous material are always in contact once delivered.
... SiO 2 NPs were synthesized according to a modified Stöber method as described elsewhere [61][62][63]. Briefly, ammonia solution (NH 4 OH, 7 mL, 28-30 wt%, Sigma Aldrich) was added to ethanol (EtOH, 120 mL, absolute for analysis, J. T. Baker), and the resulting solution was stirred for 30 min. ...
Surface functionalization of silica nanoparticles (SiO2NPs) has been considered as a promising strategy to develop target-specific nanostructures. However, finding a chemical functionalization that can be used as an active targeting moiety while preserving the nanoparticles colloidal stability in biological fluids is still challenging. We present here a dual surface modification strategy for SiO2NPs where a zwitterion (ZW) and a biologically active group (BAG) (amino, mercapto or carboxylic functionalities) are simultaneously grafted on the nanoparticles’ surface. The rationale behind this strategy is to generate colloidally stable nanoparticles and avoid the nonspecific protein adsorption due to ZW groups insertion, while the effective interaction with biosystems is guaranteed by the BAGs presence. The biological efficacy was tested against VERO cells, E. coli bacteria and Zika viruses and a similar trend was observed for all tested particles. The desirable “stealth property” to prevent nonspecific protein adhesion also generated a ZW shielding effect of the BAG functionality hindering their proper interaction and activity in cells, bacteria and viruses.
... Recently, lyophilization of nanoparticles has gained considerable interest for pharmacological and nanobiotechnological applications, in order to preserve their chemical and physical integrity [45] (Table 3). For instance, mercaptoacetic functionalized Au nanoparticles have shown exceptional stability in lyophilization procedures [10]. ...
We present the study of the anchoring of carboxylic groups on SiO2 nanoparticles from different approximations based on the photochemical radical thiol-ene addition (PRTEA) reaction: a photografting approach between mercaptosuccinic acid (MSA) and vinyl-modified SiO2 nanoparticles and the post-grafting on the surface of silica colloids of the silane precursor 2-((2-(trimethoxysilyl)ethyl)thio)succinic acid (TMSMSA), obtained from the PRTEA. These synthetic strategies were compared with a widely common derivatization methodology based on the nucleophilic attack of surface-anchored amino groups with succinic anhydride. The successful functionalization of the colloidal silica was confirmed by infrared spectroscopy (FTIR), zeta potential at different pH and contact angle measurements. We found that although these three approaches were valid for −COOH immobilization, they had a noticeable impact on the dispersability and agglomeration of the colloidal suspension at the end of the synthesis. Scanning electron microscopy, dynamic light scattering (DLS) and fluorescence correlation spectroscopy (FCS) measurements indicated that the PRTEA photografting between MSA and vinyl-modified SiO2 resulted in highly dispersed colloidal particles. On the other hand, the presence of surface −COOH groups was highly beneficial for redispersion of the colloidal material after lyophilization or freeze-drying procedures.
... Alternatively, freeze-drying of nanomaterials is often used as an emerging and powerful approach to maintain nanoparticle colloidal stability through converting them into solid mass, which has been proven previously to preserve labile biological systems such as proteins, antibodies, plasma constituents and others in pharmaceutical, food and agricultural industries. Moreover, freeze-drying is an essential step in commercial manufacturing of nanoparticles, which allows practical storage and shipping while preserves the quality attributes of the product (Fonte et al., 2016;Picco et al., 2018;Alkilany et al., 2014;Wang, 2000). ...
Maintaining colloidal stability of nanoparticles in suspensions is a major challenge. Therefore, freeze-drying (lyophilization) is recently proposed to preserve colloidal stability of nanoparticles through maintaining them in a solid state. However, freeze-drying would itself induce nanoparticle aggregation unless proper formulation with a careful selection of cryoprotectants is considered. Herein, we evaluate the colloidal stability of gold nanorods (GNRs) conjugated with a rituximab as a model monoclonal antibody upon freeze-drying in the presence of various cryoprotectants (mannitol, trehalose and sucrose). Aggregation-induced optical responses of GNRs were used as a sensitive tool to follow nanoparticle aggregation. In the absence of cryoprotectants, rituximab-conjugated GNRs aggregate irreversibly while evaluated cryoprotectants exhibit a significant protective effect. Maximal colloidal stability of GNRs is observed in the presence of trehalose while mannitol results in best cake formation in terms of shape and integrity. A combination of trehalose and mannitol produces a lyophilized product with satisfactory GNR colloidal stability and cake shape. Moreover, we show that freeze-dried rituximab-conjugated GNRs in presence of proper cryoprotectants maintain typical binding to lymphoma tissues as confirmed via immunohistochemistry assay.
... Optimization of the micellar formulation Considering 'particle isolation' hypothesis (Allison et al., 2000) and 'water replacement hypothesis (Crowe et al., 1994;Allison et al., 1998;Chen et al., 2010), the protection level against lyophilization process would be depend on properties and concentrations of the excipients and nanoparticle (Picco et al., 2018). To determine the best combination of surfactant and protectants for DTBM-R, the effect of various excipients on micelle reconstitution were checked using polymeric micelle without DTX (blank micelle) by DLS. ...
Docetaxel (DTX)-loaded polymeric micelles (DTBM) were formulated using the triblock copolymer, poly(ethylene glycol)–polylactide–poly(ethylene glycol) (PEG–PLA–PEG), to comprehensively study their pharmaceutical application as anticancer nanomedicine. DTBM showed a stable formulation of anticancer nanomedicine that could be reconstituted after lyophilization (DTBM-R) in the presence of PEG 2000 and D-mannitol (Man) as surfactant and protectant, respectively. DTBM-R showed a particle size less than 150 nm and greater than 90% of DTX recovery after reconstitution. The robustly formed micelles might minimize systemic toxicity due to their sustained drug release and also maximize antitumor efficacy through increased accumulation and release of DTX from the micelles. From the pharmaceutical development point of view, DTBM-R showing successful reconstitution could be considered as a potent nanomedicine for tumor treatment.
... However, several physico-chemical phenomena, such as air adsorption and modiication of nanoparticle surface during the various steps of the process may lead diiculty in redispersion of colloidal carriers in aqueous media for the subsequent administration [6,7]. The addition of inert additives, deined as lyoprotectants or cryoprotectants) at relatively high concentrations (10-30%, but in some instances also up to 50% by weight), could protect the colloidal suspension against stress induced by the freeze-drying process [8][9][10]. ...
In biological systems, nanoparticles interact with biomolecules, which may undergo protein corona formation that can result in noncontrolled aggregation. Therefore, comprehending the behavior and evolution of nanoparticles in the presence of biological fluids is paramount in nanomedicine. However, traditional lab-based colloid methods characterize diluted suspensions in low-complexity media, which hinders in-depth studies in complex biological environments. Here, we apply X-ray photon correlation spectroscopy (XPCS) to investigate silica nanoparticles (SiO 2) in various environments, ranging from low to high complex biological media. Interestingly, SiO 2 revealed Brownian motion behavior, irrespective of the complexity of the chosen media. Moreover, the SiO 2 surface and media composition were tailored to underline the differences between a corona-free system from protein corona and aggregates formation. Our results highlighted XPCS potential for real-time nanoparticle analysis in biological media, surpassing the limitations of conventional techniques and offering deeper insights into colloidal behavior in complex environments.
Objective: To develop paraoxonase1 (PON1) nanoparticles (NPs) and evaluated for their effectiveness in reducing the hepatotoxicity caused by chlorpyrifos (CPF). Methods: The method of solvent evaporation is utilised in the processes of preparing PON1 nanoparticles. The entrapment efficiency (EE), drug content, and drug release of the produced nanoparticles were all characteristics that were analysed. The scanning electron microscopy (SEM) technique was utilised in order to determine the surface morphology. As part of the CPF induced hepatotoxicity method, in vivo studies were conducted on biochemical markers such as acetylcholinesterase (AchE), nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and malondialdehyde (MDA). These markers were tested on an animal model. Results: The images obtained by scanning electron microscopy (SEM) provide evidence that the particles display a smooth texture and a spherical configuration. The values for the zeta potential (mV), mean particle size (nm), PDI, entrapment efficiency (%), and drug content (%) were determined to be -22.86mV, 242.37 ± 37.26 nm, 0.094, 81.13%, and 95.08% correspondingly. Within a period of thirty days, the maximum percentage (i.e.,) of the drug was released. In addition to alleviating hepatic toxicity with enhanced anti-oxidant levels, supplementation with PON1-NPs results in a considerable reduction in liver weight, liver index, and levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and alanine transaminase (ALP). Conclusion: The principal reduction in AchE, inflammatory mediators and elevated levels of anti-oxidant enzymes in hepatic tissue by the PON1 and improved efficacy by PON1 NPs contributed hepatoprotection against CPF induced hepatotoxicity
Lyophilization also known as freeze-drying is a technique that has been employed to enhance the long-term durability of nanoparticles (NPs) that are utilized for drug delivery applications. This method is used to prevent their instability in suspension. However, this dehydration process can cause stress to the NPs, which can be alleviated by the incorporation of excipients like cryoprotectants and lyoprotectants. Nevertheless, the freeze-drying of NPs is often based on empirical principles without considering the physical–chemical properties of the formulations and the engineering principles of freeze-drying. For this reason, it is crucial to optimize the formulations and the freeze-drying cycle to obtain a good lyophilizate and ensure the preservation of NPs stability. Moreover, proper characterization of the lyophilizate and NPs is of utmost importance in achieving these goals. This review aims to update the recent advancements, including innovative formulations and novel approaches, contributing to the progress in this field, to obtain the maximum stability of formulations. Additionally, we critically analyze the limitations of lyophilization and discuss potential future directions. It addresses the challenges faced by researchers and suggests avenues for further research to overcome these limitations. In conclusion, this review is a valuable contribution to the understanding of the parameters involved in the freeze-drying of NPs. It will definitely aid future studies in obtaining lyophilized NPs with good quality and enhanced drug delivery and therapeutic benefits.
Earth crust is rich with different materials and their oxides that traditionally have been utilized in numerous applications since the emergence of life on earth. Metal oxides, being the most abundant material of earth crust, have been pivot to the researcher for their unique qualities such as stability, ease of synthesis, superconductivity, colossal magnetoresistance, and structural variety. The implication of metal oxides in glass formation also results in a unique congregation of characteristics such as smaller phonon energy, high refractive index, and transparency in the middle infrared spectrum. In practical applications, dispersive wavelength, mean dispersion, and refractive index play a vital role. These factors determine the feasibility and sustainability of glass. In this regard, metal oxides promise superior properties that become the main incentive for its growth in this field. There are a few parameters that limit the practical applications of metal oxide glasses. In this regard, the low transmission capability, up to 4 μm only, of these metal oxide glasses in the electromagnetic spectrum is a major contributor. Moreover, the glasses of transition metals must possess very high electronic conductivity, but the addition of conventional formers limits it. Transition metal–based glasses have very small capability to form a glass all alone; therefore, formers such as SiO2 are inserted. The addition of impurities allows the formation of glass, but an overall disordered structure is formed. This disordered structure is characterized by a high degree of cation dispersion that disturbs the electron flow and reduces the capability of electronic conductivity. In this chapter, various other factors that limit its industrial implications will also be elaborated. Furthermore, the fabrication process also limits its utilization as an uncontrolled environment may result in unexpected physical properties. Therefore, this chapter sheds light on various fabrication techniques of metal oxides glass formation and also the physical properties of these glasses in terms of their fabrication. In addition, environmental consequences and future aspects of metal oxide glass will also be elaborated.
The poor aqueous solubility of 1,4-dihydropyridine drugs needs to be solved urgently to improve the bioavailability. Nanotechnology can improve drug solubility and dissolution by reducing particle size, but usually a specific polymer or surfactant is required for stabilization. In this study, Poloxamer-407(P-407) was screened as the optimal stabilize through energy simulation, molecular docking and particle size. morphological study, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, Raman, in vitro dissolution test and molecular simulation of interactions were utilized to explore the formation mechanisms of four 1,4-dihydropyridine drugs/P-407 nanosuspensions. The result shows that the optimized nanosuspensions had the particle size in the nano-size range and maintained the original crystal state. The in vitro dissolution rate of the nanosuspension was 3-4 times higher than the corresponding API and could reduce the restriction of drug dissolution in different pH environments. Raman spectroscopy, FTIR and molecular docking simulations provided strong supporting evidence for the formation mechanism of 1,4-dihydropyridine drugs/P-407 nanosuspensions at the molecular level, which confirmed that the stable intermolecular hydrogen bond adsorption and hydrophobic interaction were formed between the drug and P-407. This research will provide practical concepts and technologies, which are helpful to develop nanosuspensions for the same class of drugs.
Colloidal drying is a method that is used in many areas but leads to particle agglomeration. In this study, the effects of drying methods on the agglomeration, dispersion, and silanization efficiency of silica nanoparticles (NSp) were investigated using vacuum oven dryer (VOD), rotary evaporator (RE), and freeze-dryer (FD) methods. In addition, dried silica nanoparticles were mechanically ground using a conventional ball mill system, and the relationship between grinding effect and agglomeration was investigated. The results of the SEM analysis showed that the surface energy, which increased with the reduction of the grain size as a result of the prolongation of the grinding time, caused the agglomeration of the grains. BET analysis, it was observed that the surface areas of silica nanoparticles vary depending on the drying method. Contact angle measurement was performed to investigate the silanization ability of silica nanoparticles and it was determined that silica nanoparticles with the low surface area had the lowest contact angle. Therefore, the silanization ability of silica nanoparticles was observed to increase with the reduction of agglomeration. As a result, the VOD technique, which allows the production of low surface area silica nanoparticles, was chosen as the best method for increasing the silanization efficiency.
In the twenty-first century, the RDP (redispersible powder) has become the critical ingredient in various sectors and has numerous applications in day to day life. RDP is a free-flowing, white powder obtained by spray drying of an aqueous dispersion. Commercially available polymeric admixtures are classified into polymer dispersion, redispersible polymer powder (RDPP), water-soluble polymers, and liquid polymers. RDPP is a polymer emulsion that is converted to RDP by high temperature and pressure followed by spray drying and surface treatment to powdered thermoplastic resin material. Today, the demand for RDP is increasing in various fields due to their desirable change in properties after their addition with different products. High-grade RDP is manufactured via the various monomers so that the efficiency of RDP increases for the application purpose. RDPP is synthesized via polymerization and spray drying technique which has applications in concrete–polymer composite/polymer-modified mortar and concrete. The different types of latex-based RDP known are a copolymer of ethylene–vinyl acetate (EVA), a terpolymer of ethylene/vinyl chloride/vinyl laurate (E/VC/VL), terpolymer of vinyl acetate/ethylene/vinyl ester of versatic acid (VAc/E/VeoVa), acrylate copolymer, polyvinyl acetate (PVAc) polymer, styrene–butadiene rubber (SBR), etc. The current paper audits the standards process technology for RDP, the past significant importance and historical backgrounds, recent and future developments and advancement of concrete–polymer composite, and normalization work on concrete–polymer composites. The core–shell morphology of RDP in polymer cement waterproof mortar is also discussed in this paper. In the construction field, polymer-modified cement (hydraulic) mixtures are used due to their unique properties. As new inventions have been done in the area of RDPP, it is investigated that polymer film formation in cement mortars modified with water-soluble RDPP also occurs. The effect of RDPP concentration on the initial and final setting time of cement mortars plays a significant role in this field. Furthermore, the amalgamation of nanotechnology with RDP synthesis has boosted the applications of RDP in various other fields. RDP has played a vital role in the field of medicine, pharmaceuticals, and cosmetics. In the food industry, RDP is used to increase storage ability, durability, and product properties. The review paper covers all the stages in RDP/RDPP synthesis from the year 1999 to 2021. The different techniques for synthesizing high-quality and efficient RDP have been reviewed here. The paper gives a complete overlook of trends in applications of RDP over the period. This paper discusses all the past and future applications, recent trends, development of RDP in the various fields and shows its bright prospective in the upcoming years.
The outreach of nanoparticle-based medical treatments has been severely hampered due to the imbalance between the efforts in designing extremely complex materials and the general lack of studies devoted to understanding their colloidal stability in biological environments. Over the years, the scientific community has neglected the relevance related to the nanoparticles' colloidal state, which consequently resulted in very poor bench-to-clinic translation. In this work, we show how mesoporous silica nanoparticles (MSNs, one of the most promising and tested drug delivery platforms) can be efficiently synthesized and prepared, resulting in a colloidally stable system. We first compared three distinct methods of template removal of MSNs and evaluated their ultimate colloidal stability. Then, we also proposed a simple way to prevent aggregation during the drying step by adsorbing BSA onto MSNs. The surface modification resulted in colloidally stable particles that are successfully redispersed in biologically relevant medium while retaining high hemocompatibility and low cytotoxicity.
In recent years, metal oxide, especially in the form of powders, is extensively studied owing to their unique and novel properties. In this regard, this chapter provides a thorough description of current advances on the synthesis and preparation of metal oxide powders. The chapter begins with the introduction and motivation of the preparation of synthetic metal oxide powders. This is followed by the description of the synthesis and preparation method of metal oxide powders, which can be categorized into chemical methods, physical methods, and biological methods. Several important methods under each category were described with examples. This chapter ends with concluding remarks with views on the recent progress and future challenges of metal oxide powders research.
Nanomedicine is considered a promising alternative to improve cancer diagnosis and treatment. Particularly, the use of nanoparticles (NPs) has enabled the encapsulation of highly toxic anticancer drugs, facilitated ultimate targeting, and allowed tailoring of drug delivery. However, when in biological fluids, these NPs are coated by proteins which hide the targeting moieties and suppress the engineered biological outcome. Herein, how the Ki‐1 monoclonal antibody (mAb) can preserve its targetability through grafting on the surface of zwitterionic‐functionalized nanoparticles, is unveiled. Zwitterions, known for their stealth ability, are used to minimize unspecific NPs protein adsorption and consequently maintain mAb functionality. In this work, Ki‐1 mAb is used as it recognizes TNFRSF8 (CD30⁺) transmembrane protein overexpressed on CD30⁺ lymphoma cells such as L540 cells. While nonfunctionalized NPs show negligible toxic effects toward L540 cells, the Ki‐1‐functionalized structure demonstrates cytotoxicity, since they undergo cellular uptake, suggesting a receptor‐mediated internalization. This dual‐functionalization strategy provides a promising multifunctional nanoplatform toward future personalized medicine applications, minimizing unspecific protein adsorption on NPs and ensuring selective cancer cell targeting.
Silica nanoparticles present an enormous potential as controlled drug delivery systems with high selectivity towards diseased cells. This application is directly related to the phenomenon of protein corona, characterized by the spontaneous adsorption of proteins on the nanoparticle surface, which is not fully understood. Here, we report an investigation on the influence of pH, ionic strength and temperature on the thermodynamics of interaction of bovine serum albumin protein (BSA) with non-functionalized silica nanoparticles (SiO2NPs). Complementary, we also investigated the ability of polyethylene glycol (PEG) and zwitterionic sulfobetaine (SBS) surface-modified nanoparticles to prevent the adsorption of BSA (protein negatively charged at physiological pH) and lysozyme (protein positively charged at physiological pH). We showed that BSA interaction with SiO2NPs is enthalpically governed. On the other hand, functionalization of silica nanoparticles with PEG and SBS completely prevented BSA adsorption. However, these functionalized nanoparticles presented a negative zeta potential and were not able to suppress lysozyme anchoring due to strong nanoparticle-protein electrostatic attraction. Due to the similarity of BSA with Human Serum Albumin, this investigation bears a resemblance to processes involved in the phenomenon of protein corona in human blood, producing information that is relevant for the future biomedical use of functionalized nanoparticles.
Protein coronas form on the surfaces of nanomaterials in biological fluids. This layer of proteins affects the properties of nanomaterials, altering their behavior and masking engineered functionality. The use of non-fouling moieties reduces or prevents corona formation, however these ligands typically complicate functionalization. We present here a surface modification strategy for silica nanoparticles using specific molar ratios of zwitterionic and amine moieties. Through proper balance of ligands, we were able to generate particles that featured reactive ‘handles’, while retaining non-fouling properties, high hemocompatibility and low cytotoxicity.
This review aims to provide an overview of current knowledge on stabilization of proteins by sugars in the solid state in relation to stress conditions commonly encountered during drying and storage. First protein degradation mechanisms in the solid state (i.e. physical and chemical degradation routes) and traditional theories regarding protein stabilization (vitrification and water replacement hypotheses) will be briefly discussed. Secondly, refinements to these theories, such as theories focusing on local mobility and protein-sugar packing density, are reviewed in relationship to the traditional theories and their analogies are discussed. The last section relates these mechanistic insights to the stress conditions against which these sugars are used to provide protection (i.e. drying, temperature, and moisture). In summary sugars should be able to adequately form interactions with the protein during drying, thereby maintaining it in its native conformation and reducing both local and global mobility during storage. Generally smaller sugars (disaccharides) are better at forming these interactions and reducing local mobility as they are less inhibited by steric hindrance, whilst larger sugars can reduce global mobility more efficiently. The principles outlined here can aid in choosing a suitable sugar as stabilizer depending on the protein, formulation and storage condition-specific dominant route of degradation.
Nano/micro-particle-based drug delivery systems for systemic (i.e. intravenous) applications have significant advantages over their non-formulated and free drug counterparts. For example, nanoparticle systems are capable of delivering therapeutics and treating areas of the body that other delivery methods cannot reach. As such, nanoparticle drug delivery and imaging systems are one of the most investigated systems in preclinical and clinical settings. Here we will highlight the diversity of nanoparticle types, the key advantages these systems have over their free drug counterparts, and discuss their overall potential in influencing clinical care. In particular, we will focus on current clinical trials for nanoparticle formulations that have yet to be clinically approved. Additional emphasis will be on clinically approved nanoparticle systems, both for their currently approved indications and their use in active clinical trials. Finally, we will discuss many of the often overlooked biological, technological, and study design challenges that impact the clinical success of nanoparticle delivery systems. This article is protected by copyright. All rights reserved.
Despite the potential of antibody-coated nanoparticles (Ab-NPs) in many biological applications, there are very few successful, commercially available examples in which the carefully engineered nanomaterial have made it beyond the laboratory bench. Herein we explore the robustness and cost of protein-nanoparticle conjugation. Using multivalent polyamidoamine (PAMAM) dendrimers and dextran as crosslinkers, it was possible to retain colloidal stability during silica NP-linker binding and the subsequent protein conjugation reaction between linker-coated NPs and proteins to generate monodisperse Ab-NPs. The physicochemical properties of the linkers were inherited by the NPs to benefit colloidal stability. Attaching negatively charged carboxyl-terminated PAMAM to the NPs contributed to overall negative charge of particles, and in turn led to high electrostatic attraction between the protein and PAMAM-coated NPs during the reaction conditions. In contrast, using an uncharged version of PAMAM dendrimer led to NP aggregation and lower protein binding efficiency. Dextran as a cost-effective, uncharged macromolecule allowed for steric repulsions between neighbouring particles during protein binding, thus inducing NP stability in solution, and also produced monodisperse Ab-NPs. By freeze drying Ab-NPs from a 1% BSA solution it is possible to reconstitute the solid-form colloid back to a stable state by adding solvent and simply shaking the sample vial by hand. The consequences of the different surface chemistries and freeze-drying stabilizers on the colloidal stability of the NPs were probed by dynamic light scattering. The performance of Ab-NPs prepared by the different conjugation strategies was compared in a simple fluorescence linked immunoassay in whole serum. The signal-to-noise ratio for Ab-NPs decreased in the following order: PAMAMDextran>BSA. We believe this work provides researchers with the tools and strategies for reliably generating Ab-NPs that can be used for a variety of biological applications.
We investigate how the densities of inherent structures, which we refer to as the closest jammed configurations, are distributed for packings of 10(4) frictionless hard spheres. A computational algorithm is introduced to generate closest jammed configurations and determine corresponding densities. Closest jamming densities for monodisperse packings generated with high compression rates using Lubachevsky-Stillinger and force-biased algorithms are distributed in a narrow density range from φ = 0.634-0.636 to φ ≈ 0.64; closest jamming densities for monodisperse packings generated with low compression rates converge to φ ≈ 0.65 and grow rapidly when crystallization starts with very low compression rates. We interpret φ ≈ 0.64 as the random-close packing (RCP) limit and φ ≈ 0.65 as a lower bound of the glass close packing (GCP) limit, whereas φ = 0.634-0.636 is attributed to another characteristic (lowest typical, LT) density φLT. The three characteristic densities φLT, φRCP, and φGCP are determined for polydisperse packings with log-normal sphere radii distributions.
Application of silica nanoparticles as fillers in the preparation of nanocomposite of polymers has drawn much attention, due to the increased demand for new materials with improved thermal, mechanical, physical, and chemical properties. Recent developments in the synthesis of monodispersed, narrow-size distribution of nanoparticles by sol-gel method provide significant boost to development of silica-polymer nanocomposites. This paper is written by emphasizing on the synthesis of silica nanoparticles, characterization on size-dependent properties, and surface modification for the preparation of homogeneous nanocomposites, generally by sol-gel technique. The effect of nanosilica on the properties of various types of silica-polymer composites is also summarized.
The size-dependent physicochemical and optical properties of silica nanoparticles have been studied. Significant increase in the specific surface area (SSA), concentration of silanol groups (δOH) and apparent density (Da) were observed as the particle size reduced from ∼130 to ∼7nm. The decrease in the silanol number (αOH) and Si–O–Si bond angle in smaller particle size suggest that the silica structure, especially the surface has been significantly altered at nanoscale. This finding is supported by the presence of defect sites such as E′ centers and oxygen deficient centers (OCD). The stability of E′ centers (UV–vis analysis) increase linearly with the increase in particle size. The increase in the intensity of blue and green bands (PL analysis) with the decrease in the particle size are attributed to the higher silanol concentration and increased in the number of self-trapped exciton (STE)/OCD, respectively. The green band was blue-shifted with the decrease in the particle size. Overall, the silica nanoparticles have shown distinctive properties relative to the bulk silica.
Silver nanoparticles (AgNPs) are of inter-est due to their antimicrobial attributes, which are derived from their inherent redox instability and subsequent release of silver ions. At the same time, this instability is a substantial challenge for achieving stable long-term storage for on-demand use of AgNPs. In this study, we describe and validate a ''just add water'' approach for achieving suspensions of princi-pally singly dispersed AgNPs. By lyophilizing (freeze drying) the formulated AgNPs into a solid powder, or cake, water is removed thereby eliminating solution-based chemical changes. Storing under inert gas further reduces surface reactions such as oxidation. An example of how to optimize a lyophilization formulation is presented, as well as example formu-lations for three AgNP core sizes. This ''just add water'' approach enables ease of use for the researcher desiring on-demand singly dispersed AgNP suspen-sions from a single master batch. Implementation of this methodology will enable studies to be performed over long periods of time and across different laboratories using particles that are identical chemi-cally and physically and available on-demand. In addition, the approach of freeze drying and on-demand reconstitution by adding water has enabled the devel-opment of AgNP reference materials with the required shelf-life stability, one of the principal objectives of this research.
Nanoparticles are ubiquitous in environment and are potentially important in many environmental processes such as sorption,
coprecipitation, redox reactions, and dissolution. To investigate particle size effects on nanoparticle aggregation and stability,
this study tested aggregation behavior of 12(±2), 32(±3), and 65(±3)nm (hydrated radius) hematite particles under environmental
relevant pH and ionic strength conditions. The results showed that at the same ionic strength and pH conditions, different
particle sizes show different tendency to aggregate. At the same ionic strength, aggregation rates are higher for smaller
particles. The critical coagulation concentration also depends on particle size, and decreases as particle size decreases.
As the particle size decreases, fast aggregation shifted to lower pH. This may be related to a dependence of PZC on particle
size originating from change of structure and surface energy characteristics as particle size decreases. Under the same conditions,
aggregation occurs faster as particle concentration increases. Even though the nanoparticles of different sizes show different
response to the same pH and ionic strength, DLVO theory can be used to qualitatively understand hematite nanoparticle aggregation
behavior.
It has been suggested that stabilization of liposomes and proteins during freeze-drying requires only that they be maintained in a vitrified (glassy) state. In the present paper we show that vitrification is indeed necessary. However, dextran, which exists as a glass at a higher temperature than does trehalose and thus might be expected to stabilize liposomes more effectively, preserves DPPC liposomes only when extremely large quantities of the dextran are added. Dextran does not stabilize egg PC liposomes and, in fact, inhibits the stabilizing effects of trehalose. Dextran also does not depress Tm in the dry phospholipids and shows no interaction with the polar headgroup, as assessed by infrared spectroscopy. Trehalose, by contrast, depresses Tm in dry egg PC by about 60°C and depresses vibrational frequency of the phosphate in the polar headgroup to the frequency seen in the hydrated lipid, an effect we ascribe to hydrogen bonding between the sugar and the polar headgroup. We conclude that while vitrification may be required it is not in itself sufficient to preserve freeze-dried liposomes.
In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.
Mise au point comportant des definitions generales et la terminologie, la methodologie utilisee, les procedes experimentaux, les interpretations des donnees d'adsorption, les determinations de l'aire superficielle, et les donnees sur la mesoporosite et la microporosite
Unique forms of manufactured nanomaterials, nanoparticles, and their suspensions are rapidly being created by manipulating properties such as shape, size, structure, and chemical composition and through incorporation of surface coatings. Although these properties make nanomaterial development interesting for new applications, they also challenge the ability of colloid science to understand nanoparticle aggregation in the environment and the subsequent effects on nanomaterial transport and reactivity. This review briefly covers aggregation theory focusing on Derjaguin-Landau-Verwey-Overbeak (DLVO)-based models most commonly used to describe the thermodynamic interactions between two particles in a suspension. A discussion of the challenges to DLVO posed by the properties of nanomaterials follows, along with examples from the literature. Examples from the literature highlighting the importance ofaggregation effects on transport and reactivity and risk of nanoparticles in the environment are discussed.
Three different silica filler materials were thermally treated in order to effect dehydration, dehydroxylation, and rehydroxylation. Samples were characterized by thermogravimetry (TG), pycnometry, elemental analysis, and scanning electron microscopy (SEM). For all fillers, our results indicate incremental removal of silanol groups at higher heating temperatures and irreversible dehydroxylation at over 673 K. To remove the organic content and maintain adequate silanol density for subsequent silanization on Stöber-type silica, we suggest heating at 673 K followed by overnight boiling in water.
Particle characterization is an important component in product research and development, manufacture, and quality control of particulate materials and an important tool in the frontier of sciences, such as in biotechnology and nanotechnology. This book systematically describes one major branch of modern particle characterization technology - the light scattering methods. This is the first monograph in particle science and technology covering the principles, instrumentation, data interpretation, applications, and latest experimental development in laser diffraction, optical particle counting, photon correlation spectroscopy, and electrophoretic light scattering.
In addition, a summary of all major particle sizing and other characterization methods, basic statistics and sample preparation techniques used in particle characterization, as well as almost 500 latest references are provided.
The book is a must for industrial users of light scattering techniques characterizing a variety of particulate systems and for undergraduate or graduate students who want to learn how to use light scattering to study particular materials, in chemical engineering, material sciences, physical chemistry and other related fields.
Light scattering is a very powerful method to characterize the structure of polymers and nanoparticles in solution. Recent technical developments have strongly enhanced the possible applications of this technique, overcoming previous limitations like sample turbidity or insufficient experimental time scales. However, despite their importance, these new developments have not yet been presented in a comprehensive form. In addition, and maybe even more important to the broad audience, there lacks a simple-to-read textbook for students and non-experts interested in the basic principles and fundamental techniques of light scattering. As part of the Springer Laboratory series, this book tries not only to provide such a simple-to-read and illustrative textbook about the seemingly very complicated topic of light scattering from polymers and nanoparticles in dilute solution, but also intends to cover some of the newest technical developments in experimental light scattering.
The rapidly developing field of nanomaterials has expanded in many commercial areas. More recent studies have begun to provide a foundation for understanding how nanomaterials influence cells and how they also can serve as methodological tools for studies in medicine and cell biology, include research into stem cells. Recent investigations have shown affects of nanomaterials on specific subcellular structures, such as the actin-based brush border network in cells with an increasing emphasis on the barrier function of epithelial tissues. While other studies have shown involvement of nanoparticles in specific cytoplasmic signal transduction events such as the rise in intracellular free calcium, a signaling event known to regulate many changes in cell architecture and function. In parallel, nanomaterials are increasingly used in medicine for drug delivery, treatment of cancer, and an increasing number of new applications. This book investigates these areas and also includes new methods for assessment in cell biology and medicine.
Nanomedicine is defined as the application of nanobiotechnology in clinical medicine, which is currently being used to research the pathomechanism of disease, refine molecular diagnostics, and aid in the discovery, development, and delivery of drugs. In The Handbook of Nanomedicine, Third Edition, Prof. Kewal K. Jain updates, reorganizes, and replaces information in the comprehensive second edition in order to capture the most recent advances in this dynamic field. Important components of nanomedicine such as drug delivery via nanobiotechnology and nanopharmaceuticals as well as nanooncology, where the greatest number of advances are occurring, are covered extensively. As this text is aimed at nonmedical scientists, pharmaceutical personnel, as well as physicians, descriptions of the technology involved and other medical terminology are kept as clear and simple as possible.
In depth and cutting-edge, The Handbook of Nanomedicine, Third Edition informs its readers of the ever-growing field of nanomedicine, destined to play a significant role in the future of healthcare.
Long-term storage of stable nanoparticulate systems is critical to the utilization of nanotechnology in biomedical applications. Freeze-drying or lyophilization is the most commonly used approach to preparing stable injectable nano formulations. A detailed understanding of the freezing stress on nanoparticles is essential to the successful preservation of original particle attributes and to the development of reliable lyophilization processes. However, visualization of the freezing process and the underlying mechanisms that result in particle aggregation remains challenging. Here, we show a clear causal relationship between the freeze-concentration event and particle aggregation by employing correlative imaging techniques, encompassing both real-time dynamic visualization and super-resolution imaging for frozen systems. Direct evidence was obtained to corroborate the particle isolation hypothesis. Moreover, ice-ice, ice-air and ice-container interfaces were identified as hotspots for generating freezing stress on susceptible nanoparticles. In light of these observations, sphere close packing models were explored. Based on the relationship between jammed particles and void fraction within a confined interfacial space, we are able to define the boundary condition of the minimal ‘cryoprotectant to particle ratio’ required for effective design space of particle isolation and cryoprotection. These findings clearly demonstrated the utility of visualization techniques and modeling in elucidating the mechanism of freezing stress and protection, providing guiding tools to the rational design of cryoprotectant containing nano formulations and processes.
Introduction:
Nanomedicine has emerged as a major field of academic research with direct impact on human health. While a first generation of products has been successfully commercialized and has significantly contributed to enhance patient's life, recent advances in material design and the emergence of new therapeutics are contributing to the development of more sophisticated systems. As the field matures, it is important to comprehend the challenges related to nanoparticle commercial development for a more efficient and predictable path to the clinic. Areas covered: The review provides an overview of nanoparticle-based delivery systems currently on the market and in clinical trials, and discuss the principal challenges for their commercial development, both from a manufacturing and regulatory perspective, to help gain understanding of the translational path for these systems. Expert Opinion: Clinical translation of nanoparticle-based delivery systems remains challenging on account of their 3D nanostructure and requires robust nano-manufacturing process along with adequate analytical tools and methodologies. By identifying early enough in the development the product critical attributes and understanding their impact on the therapeutic performance, the developers of nanopharmaceuticals will be better equipped to develop efficient product pipelines. Second-generation products are expected to broaden nanopharmaceutical global market in the upcoming years.
Puzzling aspects of the microporous structure of Stöber silica, including inconsistencies in the BET specific surface area and the long measurement time required for N2 adsorption, hinder further research on and potential applications of this material. In this work, Stöber silica samples prepared using systematic and detailed post-treatment methods were characterized by N2 adsorption, scanning electron microscopy, transmission electron microscopy, inductively coupled plasma optical emission spectrometry, elemental analysis, and Fourier transform infrared spectroscopy. We have found that the often overlooked sample preparation conditions may be the main causes that perplex the gas adsorption characterization results of Stöber silica samples. The pore-blocking processes associated with a variety of sample treatment methods are discussed in detail. Strong evidence for the particle growth model and pore-blocking mechanism involving ethoxyl groups, Si species, and condensation of silanols is provided. A remarkable result is that the measurement time is shortened from 1 month in our previous work to 2‒3 days for samples with large specific surface areas. A suitable post-treatment condition is recommended to obtain microporous Stöber silica with a short measurement time, including water washing, low temperature drying without vacuum, and a short storage time.
Vaccines and therapies are not available for several diseases caused by viruses, thus viral infections result in morbidity and mortality of millions of people every year. Nanoparticles are considered to be potentially effective in inhibiting viral infections. However, critical issues related to their use include their toxicity and their mechanisms of antiviral action, which are not yet completely elucidated. To tackle these problems, we synthesized silica nanoparticles with distinct surface properties and evaluated their biocompatibility and antiviral efficacy. We show that nanoparticles exhibited no significant toxicity to mammalian cells while declines up to 50 % in the viral transduction ability of two distinct recombinant viruses were observed. We designed experiments to address the mechanism of antiviral action of our nanoparticles and found that their hydrophobic/hydrophilic characters play a crucial role. Our results reveal that the use of functionalized silica particles is a promising approach for controlling viral infection and offer promising strategies for viral control.
Lyophilization has been used to improve the long-term stability of polymeric nanoparticles for drug delivery applications, avoiding their instability in suspension. However, this dehydration process may induce stresses to nanoparticles, mitigated by the use of some excipients such as cryo- and lyoprotectants. Still, the lyophilization of polymeric nanoparticles is frequently based in empirical principles, without considering the physical–chemical properties of formulations and the engineering principles of lyophilization. Therefore, the optimization of formulations and the lyophilization cycle is crucial to obtain a good lyophilizate, and guarantee the preservation of nanoparticles stability. The proper characterization of the lyophilizate and nanoparticles has a great importance in achieving these purposes. This review updates the fundaments involved in the optimization procedures for lyophilization of polymeric nanoparticles, with the aim of obtaining the maximum stability of formulations. Different characterization methods to obtain and guarantee a good lyophilized product are also discussed. A special focus is given to encapsulated therapeutic proteins. Overall, this review is a contribution for the understanding of the parameters involved in the lyophilization of polymeric nanoparticles. This may definitely help future works to obtain lyophilized nanoparticles with good quality and with improved therapeutic benefits.
Inorganic nanoparticles are widely used for therapeutic and diagnostic purposes as they offer unique features as compared with their organic and polymeric counterparts. As such, inorganic nanoparticles represent an exciting opportunity to develop drug delivery and imaging systems that are poised to tackle unique challenges which are currently unaddressed in clinical settings. Despite these clear advantages, very few inorganic nanoparticle systems have entered the clinic. Here, we review the current clinical landscape of inorganic nanoparticle systems and their opportunities and challenges, with particular emphasis on gold-, iron-oxide- and silica-based nanoparticle systems. Key examples of inorganic nanoparticles that are currently being investigated in the clinic (e.g., trials which are recruiting or currently active but not completed) are highlighted, along with the preclinical work that these examples have leveraged to transition from the lab to the clinic.
Controversial reports regarding Stöber silica's microporosity and specific surface area remain in the literature despite its decades of widespread applications. In this work, Stöber silica samples prepared with controlled reaction time and post-synthesis washing/drying conditions were characterized by nitrogen adsorption at 77 K, transmission electron microscopy, elemental analysis, Fourier transform infrared spectroscopy, thermal analysis and evolved gas analysis. Our experimental results demonstrated the important but often overlooked effects of reaction time and post-synthesis treatments on Stöber silica's pore characteristics, as evidenced by the strikingly large range of BET specific surface area (11.3~309.7 m2/g). A simple micropore filling and blocking mechanism compatible with an existing Stöber silica growth model incorporating both aggregation and monomer addition steps was proposed to explain all our experimental findings. The carbon and nitrogen contents appear to serve well as the indicative link between our experimental variables and the resulting pore blocking by TEOS and its derivatives. A suitable combination of experimental conditions is recommended in order to make microporous Stöber silica samples with large specific surface area, including a short reaction time, water washing, and drying at moderate temperature preferably under vacuum.
For various applications of gold nanotechnology, long-term nanoparticle stability in solution is a major challenge. Lyophilization (freeze-drying) is a widely used process to convert labile protein and various colloidal systems into powder for improved long-term stability. However, the lyophilization process itself may induce various stresses resulting in nanoparticle aggregation. Despite a plethora of studies evaluating lyophilization of proteins, liposomes, and polymeric nanoparticles, little is known about the stability of gold nanoparticles (GNPs) upon lyophilization. Herein, the effects of lyophilization and freeze-thaw cycles on the stability of two types of GNPs: Citrate-capped GNPs (stabilized via weakly physisorbed citrate ions, Cit-GNPs) and mercaptoacetic acid-capped GNPs (stabilized via strongly chemisorbed mercaptoacetic acid, MAA-GNPs) are investigated. Both types of GNPs have similar core size and effective surface charge as evident from transmission electron microscopy and zeta potential measurements, respectively. Plasmon absorption of GNPs and its dependence on nanoparticle aggregation was employed to follow stability of GNPs in combination with dynamic light scattering analysis. Plasmon peak broadening index (PPBI) is proposed herein for the first time to quantify GNPs aggregation using non-linear Gaussian fitting of GNPs UV-vis spectra. Our results indicate that Cit-GNPs aggregate irreversibly upon freeze-thaw cycles and lyophilization. In contrast, MAA-GNPs exhibits remarkable stability under the same conditions. Cit-GNPs exhibit no significant aggregation in the presence of cryoprotectants (molecules that are typically used to protect labile ingredients during lyophilization) upon freeze-thaw cycles and lyophilization. The effectiveness of the cyroprotectants evaluated was in the order of trehalose or sucrose > sorbitol > mannitol. The ability of cryoprotectants to prevent GNPs aggregation was dependent on their chemical structure and their ability to interact with the GNPs as assessed with zeta potential analysis.
This work aimed to evaluate the influence of a freeze-drying process using different cryoprotectants on the structure of insulin loaded into poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and to assess the stability of these nanoparticles upon 6 months of storage following ICH guidelines. Insulin-loaded PLGA nanoparticles with size around 450 nm were dehydrated using a standard freeze-drying cycle, using trehalose, glucose, sucrose, fructose and sorbitol at 10% (w/v) as cryoprotectants. All formulations, except those non-added of cryoprotectant and added with trehalose, collapsed after freeze-drying. The addition of cryoprotectants increased the nanoparticles stability upon storage. FTIR results showed that insulin maintained its structure after encapsulation in about 88%, decreasing to 71% after freeze-drying. The addition of cryoprotectants prior freeze-drying, increased insulin structural stability in average up to 79%. Formulations collapsed after freeze-drying showed better protein stabilization upon storage, in special sorbitol added formulation, preserving 76%, 80% and 78% of insulin structure at 4ºC, 25ºC/60% RH and 40ºC/75% RH, respectively. Principal component analysis also showed that sorbitol added formulation showed the most similar insulin structural modifications among the tested storage conditions. These findings suggested that regarding nanoparticles stability, cryoprotectant are versatile to be use in a standard freeze-drying, however they present different performances on the stabilization of the loaded protein. Thus, on the freeze-drying of nanoparticles field, this work gives rise to the importance of the process optimization searching for a balance between a good obtainable cake with an optimal structural stabilization of the loaded protein.
Although monodisperse amorphous silica nanoparticles have been widely investigated, their formation mechanism is still a topic of debate. Here, we demonstrate the formation of monodisperse nanoparticles from colloidally stabilized primary particles, which at a critical concentration, undergo a concerted association process, concomitant with a morphological and structural collapse. The formed assemblies grow further by addition of primary particles onto their surface. The presented mechanism, consistent with previously reported observations, reconciles the different theories proposed to date.
Nanomedicine, the use of nanotechnology for biomedical applications, has potential to change the landscape of the diagnosis and therapy of many diseases. In the past several decades, the advancement in nanotechnology and material science has resulted in a large number of organic and inorganic nanomedicine platforms. Silica nanoparticles (NPs), which exhibit many unique properties, offer a promising drug delivery platform to realize the potential of nanomedicine. Mesoporous silica NPs have been extensively reviewed previously. Here we review the current state of the development and application of nonporous silica NPs for drug delivery and molecular imaging.
Nanosuspensions are nanosized colloidal dispersion systems stabilized by surfactants, polymers or a combination of both. Due to nanosizing results in the creation of new interfaces and in a positive Gibbs free energy change, nanosuspension is a thermodynamically unstable system with tendency of agglomeration or crystal growth. Despite the nanosuspensions technology has been extensively investigated, stability issue is still the limitation and shortcoming for its application on pharmaceutical industrial. Furthermore, the knowledge on empirical relationship between the stabilizer efficacy and stability of the nanosuspension is relatively deficiency. This review especially focused on the stability issue of nanosuspensions in drug delivery to retrieve the state art of the nanosuspensions. Therefore, the main contents of present review including the presentation of nanosuspensions instable, the method and guideline for section and optimizing stabilizers, the approaches for enhancing stability, as well as the other influencing factors on the stability of the prepared nanosuspensions. For a given drug candidate having a set of properties, this article could be used as a reference in making educated choice of stabilizer and in optimizing operation parameters for nanosuspensions formulation, rather than a trial and error approach that is being practiced currently.
Using experimentally measured nucleation and ionic strength transients, we confirm that an aggregation model can predict the particle growth profiles of Stöber systems for a range of conditions. In addition, we examine the characteristics of the evolving size distribution. Systems giving the largest particles are characterized, after a short transient, by a size distribution wherein the dominant aggregation event is between the freshly generated nucleus and a large aggregate.
A new, simple, and "green" method was developed for the surface modification of 20nm diameter Stöber silica particles with 3-aminopropyl(diethoxy)methylsilane in ethanol. The bulk polycondensation of the reagent was inhibited and the stability of the sol preserved by adding a small amount of glacial acetic acid after appropriate reaction time. Centrifugation, ultrafiltration, and dialysis were compared in order to choose a convenient purification technique that allows the separation of unreacted silylating agent from the nanoparticles without destabilizing the sol. The exchange of the solvent to acidic water during the purification yielded a stable colloid, as well. Structural and morphological analysis of the obtained aminopropyl silica was performed using transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential measurements, Fourier-transform infrared (FTIR), (13)C and (29)Si MAS nuclear magnetic resonance (NMR) spectroscopies, as well as small angle X-ray scattering (SAXS). Our investigations revealed that the silica nanoparticle surfaces were partially covered with aminopropyl groups, and multilayer adsorption followed by polycondensation of the silylating reagent was successfully avoided. The resulting stable aminopropyl silica sol (ethanolic or aqueous) is suitable for biomedical uses due to its purity.
Five different samples of Stöber silica monodisperse particles show large variations in their swelling ability as well as on their chemical compositions. Nanosized particle diameters were determined under four different conditions, using suitable techniques: photon correlation spectroscopy (PCS) in water and ethanol, AFM at 25 °C under 55% relative humidity, high-resolution scanning electron microscopy and transmission electron microscopy, under 10-6 mbar. The comparison of these results shows that the smaller particles are highly swollen in ethanol, to a greater extent than in water. The swelling coefficients are lower for the larger particles, with a preference for water. Evidence for changes in the chemical composition were obtained by electron energy-loss and infrared absorption spectra: the smaller particles contain detectable amounts of C−H groups, which are not detected by IR in the larger ones, and O energy-loss spectra fine structure changes continuously with particle sizes. The location of carbon constituents in the particles was determined by electron spectroscopy imaging in the transmission electron microscope (ESI-TEM): they are dispersed throughout the finer particles, but they are excluded from the core of the larger particles. The results are interpreted considering the kinetics and extent of TEOS hydrolysis dependence on base concentration and the limiting effect of ethoxy residual groups on the densification of the silica network.
MSNs have attracted increasing interest as drug carriers due to promising in vivo results in small-animal disease models, especially related to cancer therapy. In most cases small hydrophobic drugs have been used, but recent in vitro studies demonstrate that MSNs are highly interesting for gene delivery applications. This review covers recent advances related to the therapeutic use of mesoporous silica nanoparticles (MSNs) administered intravenously, intraperitoneally or locally. We also cover the use of MSNs in alternative modes of therapy such as photodynamic therapy and multidrug therapy. We further discuss the current understanding about the biodistribution and safety of MSNs. Finally, we critically discuss burning questions especially related to experimental design of in vivo studies in order to enable a fast transition to clinical trials of this promising drug delivery platform.
Drug nanoparticles prepared in a liquid medium are commonly freeze-dried for the preparation of an oral dosage in solid dosage form. The freezing rate is known to be a critical parameter for redispersible nanoformulations. However, there has been controversy as to whether a fast or slow freezing rate prevents irreversible aggregation. A systematic investigation is presented herein regarding the effect of both the molecular weight of the cryoprotectant and the freezing rate in order to elucidate the mechanism underlying irreversible aggregation. It was found that irreversible aggregation occurred during drying rather than freezing, although a proper freezing rate is critical. A more homogeneous distribution of the cryoprotectant and drug nanoparticles led to more redispersible powders. Thus, keeping the local concentration distribution of the nanoparticles and cryoprotectant fixed during the freezing step plays a critical role in how the freezing rate affects the redispersibility. The kinetic approach of excluding the tendency of ice crystal growth permitted an explanation of the controversial results. This study will facilitate an in-depth understanding of the aggregation process of nanoparticles or proteins during freeze-drying.
Purpose. To investigate the feasibility of producing freeze-dried poly-(ethylene oxide) (PEO)-surface modified nanoparticles and to study their ability to avoid the mononuclear phagocytic system (MPS), as a function of the PEO chain length and surface density.
Methods. The nanoparticles were produced by the salting-out method using blends of poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid-co-ethylene oxide) (PLA-PEO) copolymers. The nanoparticles were purified by cross-flow filtration and freeze-dried as such or with variable amounts of trehalose as a lyoprotectant. The redispersibility of the particles was determined immediately after freeze-drying and after 12 months of storage at –25 C. The uptake of the nanoparticles by human monocytes was studied in vitro by flow cytometry.
Results. PLA-PEO nanoparticles could be produced from all the polymeric blends used. Particle aggregation after freeze-drying was shown to be directly related to the presence of PEO. Whereas this problem could be circumvented by use of trehalose, subsequent aggregation was shown to occur during storage. These phenomena were possibly related to the specific thermal behaviours of PEO and trehalose. In cell studies, a clear relationship between the PEO content and the decrease of uptake was demonstrated.
Conclusions. The rational design of freeze-dried PEO-surface modified nanoparticles with potential MPS avoidance ability is feasible by using the polymer blends approach combined with appropriate lyoprotection and optimal storage conditions.
An aggregative growth model for the formation of uniform particles is developed and tested with rate and particle size distribution data gathered on spheres precipitated from silicon alkoxides. Smoluchowski population balance equations with a source term are solved for conditions applicable to the precipitation reaction. Size dependent aggregation rate constants are determined from estimates of particle properties and measures of particle surface potentials. Assuming particles grow solely by aggregation, the model provides good estimates of final particle size distribution parameters from silicon alkoxide reaction rates.
Monodispersed silica spheres were obtained by hydrolysis and condensation of a tetraalkoxysilane in concentrated ammonia solutions and their structure was studied. The particle size, in the range 10–730 nm, was observed by transmission electron microscopy. Thermogravimetric analysis and nuclear magnetic resonance reveal a high silanol concentration, close to 5.4 mmol OH g−1, despite a very small specific surface area of most samples, determined by Kr adsorption. This contrast is explained by an ultramicroporous structure of the beads. Pores smaller than 1 nm have been directly observed on transmission electron micrographs of ultramicrotomed slices of these beads. This porosity also explains both the low density measured by decaline picnometry and the vibration mode observed in Raman spectra below 10 cm−1 for particles 10 nm diameter. Some samples of monodispersed silica beads display peculiarities. Type I Kr isotherms, associated with very long equilibrium times and high surface areas up to 210 m2 g−1 with Kr and 385 m2 g−1 with N2, prove their microporosity. The density obtained by picnometry is still smaller than for usual samples. Thermal treatments and reaction with NaOH illustrate various properties of these microporous silica spheres.
The mechanisms behind the formation and growth of silica particles prepared from tetraalkoxysilanes in alcoholic solutions of water and ammonia were investigated. By analyzing the competitive growth of a dispersion of silica spheres with a bimodal distribution, it was established that the growth proceeds through a surface reaction-limited condensation of hydrolyzed monomers of small oligomers. By following the hydrolysis of tetraethoxysilane with 13C liquid NMR and the particle growth with time-resolved static light scattering, it was found that both processes were described by the same first-order rate constants. Therefore, despite the fact that the incorporation of hydrolyzed monomers proceeds through a reaction-limited process, the overall rate of the particle growth is limited by the first-order hydrolysis rate of the alkoxide. It was concluded that the particle formation (or particle nucleation) proceeds through an aggregation process of siloxane substructures that is influenced strongly by the surface potential of the silica particles and the ionic strength of the reaction medium. These conclusions were based on the dependence of the particle stability and final particle size on additions of LiNO3 to the reaction and dispersion medium and the independence of the growth rate on the same additions.
A system of chemical reactions has been developed which permits the controlled growth of spherical silica particles of uniform size by means of hydrolysis of alkyl silicates and subsequent condensation of silicic acid in alcoholic solutions. Ammonia is used as a morphological catalyst. Particle sizes obtained in suspension range from less than 0.05 μ to 2 μ in diameter.
We extend the work of Stober, Fink and Bohn (J. Colloid Interfac Sci. 26 (1968) 62) to establish the ranges of reagent concentrations which result in the precipitation of monodisperse silica particles from ethanol solutions containing ammonia, water, and tetraethyl orthosilica. A correlation is presented which can be used to predict final particle sizes over concentrations of 0.1-0.5 M TEOS, 0.5–17.0 M H2O and 0.5-3 M NH3. The maximum particle size achievable for these conditions at 25°C is ⋍ 800 nm and near the maximum, monodispersity is difficult to maintain. The effects of reaction temperature are studied and particle size distributions are analyzed. A seeded growth technique for preparing larger particles and/or increasing solids mass fraction up to a theoretical limit of ⋍ 24 wt% of silica is described.
As nano-sizing is becoming a more common approach for pharmaceutical product development, researchers are taking advantage of the unique inherent properties of nanoparticles for a wide variety of applications. This article reviews the physical and chemical stability of drug nanoparticles, including their mechanisms and corresponding characterization techniques. A few common strategies to overcome stability issues are also discussed.