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Drug development process. Abbreviations: BLA, Biologics License Application; FDA, US Food and Drug Administration; NDA, New Drug Application; IND, Investigational New Drug.
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On the cusp of widespread permeation of nanomedicine, academia, industry, and government have invested substantial financial resources in developing new ways to better treat diseases. Materials have unique physical and chemical properties at the nanoscale compared with their bulk or small-molecule analogs. These unique properties have been greatly...
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... process of developing a new drug or a DDS typically pro- ceeds along a relatively predictable sequence. An overview of this process is shown in Figure 1 and shows the progression from bench to bedside. This translation process includes the preclinical (ie, in vitro and in vivo studies) and clinical (ie, clinical trials) development as well as the FDA regulatory and commercialization processes. The complete process can take 10-20 years and requires many hundreds of millions of dollars to get to product launch. 121 There are two major regulatory checkpoints in this process, ie, the Investigational New Drug (IND) submission and eventually the New Drug Application (NDA) submission. The IND is a request from a company or clinical investigator to the FDA for permission to begin human clinical trials with a new drug. The NDA is filed after all nonclinical and clinical studies are complete and is the formal request from the company for approval to begin marketing the new drug. 122 For this discussion, we will provide a high-level overview of the process in getting from development to the point of first in human IND studies and connecting the FDA requisites with the standardized tech- niques included in Table 1. These procedures apply to any material used as a drug, ranging from the most sophisticated polyfunctional nanoparticle to the simplest minor molecular variant "me-too" small-molecule drug. Table 2 Analysis of protein interaction Type of analysis of protein interaction Technique Information acquired Biological and therapeutic outcomes Qualitative 2D PAGe Identification of types of proteins bound to the nanocarrier Improved biodistribution, bioavailability, blood compatibility, and pharmacokinetic aspects of DDS Semiquantitative MALDI-TOF-MS Mass and relative abundance of proteins bound to the nanocarrier Quantitative SPR Real-time monitoring of kinetic rate constants of protein ...
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Nanomaterials have high potential as powerful tools for nanomedicine in a wide range of most promising applications as highly specific devices for diagnosis and therapy. Yet, despite enormous research activities in the design and synthesis of nanomaterials for biomedicine, only a small number of those have made their way to clinical use. The unavoi...
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... One possible explanation for the bioactive molecule's low bioavailability and absorption rate is its poor water solubility or molecular size [145]. Researchers and formulators will have their hands full trying to come up with an effective nano phytomedicine ( Table 2) [146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161]. ...
... Significant entrapment efficiency and drug deposition whilst no erythema was indicated at primary skin irritation index [149] High skin deposition and low primary skin irritation index with complete clearance of parakeratosis in vivo [150] Liposomes Topical Showed acceptable safety profile in the remedy of chronic plaque psoriasis [151] Topical PUVA Multiple fold increase in skin permeation study with reduced psoriasis plaque symptoms [152] Topical High drug penetration and drug retention in vitro and significant psoriasis drug dependent in vivo [153] Niosomes Topical Prominent skin penetration in epidermal and dermal layers in vitro and found stable at low temperature [154] Improved ex vivo permeability [155] Transdermal Higher mean residence time and skin permeation in vivo compared to that of liposomal formulation [156] Ethosomes Topical High permeation rate ex vivo with minimized adverse effects after treatment in clinical studies [157] Nanoemulsions Topical ...
Psoriasis is an inflammatory and proliferative autoimmune dermatological disorder. It is a skin ailment that is defined by particular, drab-red or peach-pink stiff areas with silvery scales patches. Other typical characteristics include the proliferation of epidermal layer, aberrant keratinization, hyperkeratosis, increased micro capillary vascularization, and infiltration of inflammatory mediator loaded cells. Conventional pharmacotherapies currently available can only provide minor advantages. Nanomedicines based on nanotechnology can potentially improve the efficacy and safety of psoriasis medications. Apoptosis plays an important pathogenetic role in many chronic inflammatory diseases, including those of dermatological interest, in particular, regarding psoriasis. In this regard, treatments with antioxidant properties could be appropriate therapeutic options. We reviewed the available studies on the efficacy of antiapoptotic therapies in psoriasis. We'll look at phytochemicals in this review, which are natural components found in plants with antiapoptotic activity that are frequently used to treat psoriasis. For improved topical treatment, we also take into consideration the advantages of loading phytoconstituents as medicines into lipid based nanocarriers. The utilization of herbal nanomedicines in psoriasis, as well as nano delivery carrier system for phytoconstituents with improved therapeutic profiles and decreased toxicity, are the subjects of this review. The study's purpose is to find more effective herbal nanomedicines for treating psoriasis. In the treatment of psoriasis, phytoconstituents that have shown antipsoriatic potential in recent years, as well as phytoconstituents loaded based nanomedicines, have a lot of promising roles to be explored. Furthermore, very few patents have been found in the field of nanotechnology utilizing lipid-based nanocarrier system for the treatment of psoriasis. Therefore, this review greatly compels the researcher to validate the process development of lipid-based drug delivery system for the patentability of the product. This should be in a view of shifting in the applicability of the drug delivery system for general public health as a potential treatment option in psoriasis.
... Despite the promise of nanomedicine, its implementation and availability to patients has lagged [58,59]. Some of the factors that account for this translational gap include the discrepancy of results between animal and human studies [60] and lack of universal standards [61] and implementation of proper quality control measures in a clinical setting [62]. As the translational gap is addressed, studies continue to show the promise of utilizing nanomedicine to manage a wide range of diseases such as cancer, atherosclerosis, and Alzheimer's disease [62][63][64]. ...
Preterm birth (PTB) is a leading cause of infant morbidity and mortality in the world. In 2020, 1 in 10 infants were born prematurely in the United States. The World Health Organization estimates that a total of 15 million infants are born prematurely every year. Current therapeutic interventions for PTB have had limited replicable success. Recent advancements in the field of nanomedicine have made it possible to utilize the vaginal administration route to effectively and locally deliver drugs to the female reproductive tract. Additionally, studies using murine models have provided important insights about the cervix as a gatekeeper for pregnancy and parturition. With these recent developments, the field of reproductive biology is on the cusp of a paradigm shift in the context of treating PTB. The present review focuses on the complexities associated with treating the condition and novel therapeutics that have produced promising results in preclinical studies.
... Despite the promise of nanomedicine, its implementation and availability to patients has lagged [58,59]. Some of the factors that account for this translational gap include the discrepancy of results between animal and human studies [60] and lack of universal standards [61] and implementation of proper quality control measures in a clinical setting [62]. As the translational gap is addressed, studies continue to show the promise of utilizing nanomedicine to manage a wide range of diseases such as cancer, atherosclerosis, and Alzheimer's disease [62][63][64]. ...
Preterm birth is a leading cause of infant morbidity and mortality in the world. In 2020, 1 in 10 infants were born prematurely in the United States. Globally, the World Health Or-ganization estimates 15 million infants are born prematurely. The efficacy of current ther-apeutic interventions for preterm birth have been called into question due to limited repli-cable success. Recent advancements in the field of nanomedicine have made it possible to utilize the vaginal administration route to effectively and locally deliver drugs to the fe-male reproductive tract. Also, studies using murine models have provided important in-sights about the cervix as a gatekeeper for pregnancy and parturition. It seems plausible that the field of reproductive biology is on the cusp of a paradigm shift in the context of treating preterm birth. The present review focuses on the complexities associated with treating the condition and novel therapeutics that have produced promising results in pre-clinical studies.
... The incorporation of methodologies capable of probing these features to the bionanoconstruct development workflow is imperative, as they too influence the pharmacokinetic profile and behavior of the bionanoconstruct during application. For a comprehensive discussion of the characterization of nanomaterials and their bioconjugates, the reader is referred to reviews prepared by Sapsford et al. 29 and Khorasani et al. 111 4.2. Characterization of the Surface Molecular Architecture's Biological Activity. ...
The progress achieved over the last three decades in the field of bioconjugation has enabled the preparation of sophisticated nanomaterial-biomolecule conjugates, referred to herein as bionanoconstructs, for a multitude of applications including biosensing, diagnostics, and therapeutics. However, the development of bionanoconstructs for the active targeting of cells and cellular compartments, both in vitro and in vivo, is challenged by the lack of understanding of the mechanisms governing nanoscale recognition. In this review, we highlight fundamental obstacles in designing a successful bionanoconstruct, considering findings in the field of bionanointeractions. We argue that the biological recognition of bionanoconstructs is modulated not only by their molecular composition but also by the collective architecture presented upon their surface, and we discuss fundamental aspects of this surface architecture that are central to successful recognition, such as the mode of biomolecule conjugation and nanomaterial passivation. We also emphasize the need for thorough characterization of engineered bionanoconstructs and highlight the significance of population heterogeneity, which too presents a significant challenge in the interpretation of in vitro and in vivo results. Consideration of such issues together will better define the arena in which bioconjugation, in the future, will deliver functional and clinically relevant bionanoconstructs.
... resulted in 438 studies on various indications including oncology, autoimmune disorders, infectious diseases, cardiology, hormonal impairments, and orthopedics in different stages of clinical trials proving themselves to make a better world tomorrow (Clinicaltrials.gov). However, there is a need to shrink the gap from bench side to industrial production and comfortably reach the clinical applications (Boisseau and Loubaton, 2011;Khorasani et al., 2014;Hua et al., 2018). The literature for this review was largely gathered from different search engines like Google Scholar, Science Direct, PubMed, etc., with relevant search strings. ...
Nanotoxicology is an emerging field employed in the assessment of unintentional hazardous effects produced by nanoparticles (NPs) impacting human health and the environment. The nanotoxicity affects the range between induction of cellular stress and cytotoxicity. The reasons so far reported for these toxicological effects are due to their variable sizes with high surface areas, shape, charge, and physicochemical properties, which upon interaction with the biological components may influence their functioning and result in adverse outcomes (AO). Thus, understanding the risk produced by these materials now is an important safety concern for the development of nanotechnology and nanomedicine. Since the time nanotoxicology has evolved, the methods employed have been majorly relied on in vitro cell-based evaluations, while these simple methods may not predict the complexity involved in preclinical and clinical conditions concerning pharmacokinetics, organ toxicity, and toxicities evidenced through multiple cellular levels. The safety profiles of nanoscale nanomaterials and nanoformulations in the delivery of drugs and therapeutic applications are of considerable concern. In addition, the safety assessment for new nanomedicine formulas lacks regulatory standards. Though the in vivo studies are greatly needed, the end parameters used for risk assessment are not predicting the possible toxic effects produced by various nanoformulations. On the other side, due to increased restrictions on animal usage and demand for the need for high-throughput assays, there is a need for developing and exploring novel methods to evaluate NPs safety concerns. The progress made in molecular biology and the availability of several modern techniques may offer novel and innovative methods to evaluate the toxicological behavior of different NPs by using single cells, cell population, and whole organisms. This review highlights the recent novel methods developed for the evaluation of the safety impacts of NPs and attempts to solve the problems that come with risk assessment. The relevance of investigating adverse outcome pathways (AOPs) in nanotoxicology has been stressed in particular.
... Based on the established concept of multivalent binding, recent advances in theoretical modelling opened the door towards the design of super-selective nanomedicines, that will be discussed more extensively in the following section. In parallel, new quantitative experimental characterization techniques arose in recent years [96]. Single-cell and molecule approaches are necessary for guiding the design of targeted nanomedicines, providing crucial molecular information of both cell receptors and nanoparticle targeting ligands. ...
Although the concept of selective delivery has been postulated over 100 years ago, no targeted nanomedicine has been clinically approved so far. Nanoparticles modified with targeting ligands to promote the selective delivery of therapeutics towards a specific cell population have been extensively reported. However, the rational design of selective particles is still challenging. One of the main reasons for this is the lack of quantitative theoretical and experimental understanding of the interactions involved in cell targeting. In this review, we discuss new theoretical models and experimental methods that provide a quantitative view of targeting. We show the new advancements in multivalency theory enabling the rational design of super-selective nanoparticles. Furthermore, we present the innovative approaches to obtain key targeting parameters at the single-cell and single molecule level and their role in the design of targeting nanoparticles. We believe that the combination of new theoretical multivalent design and experimental methods to quantify receptors and ligands aids in the rational design and clinical translation of targeted nanomedicines.
... The synthesized nanoparticles are challenging to get entirely characterized by their safety and toxicity (Wei et al., 2012;Kaur et al., 2014;Khorasani et al., 2014). The relationship between the structure and functions of these Nanoparticles are still to be investigated thoroughly. ...
A novel approach of combining nanotechnology to the pharmaceutical and biotechnological field resulted in the formation of nanomedicines. Nanomedicines have progressed to a more considerable extent for curing irremediable diseases such as neurological defects, cardiovascular defects, etc., because of its minute size which assists in increased surface area and hence a remarkable dissolution profile. In addition to the health care sector, modernization of nanotechnology has also been implemented in other industries like cosmetics, electronics, catalysis, and chemical industries. Nanoparticles can be made by using polymers, either lipids or inorganic compounds like metals. They can be prepared by using either top to bottom or bottom to top approach. Interestingly, polymeric nanoparticles have provided an enormous opportunity to alter the surface of the nanoparticles leading to better drug delivery and drug targeting. However, these have the potential to induce toxicity as well. Also, the toxicity profile still has to be investigated. Moreover, characterization of the nanomedicines is always trouble, which has created a gap between conventional drugs and nanomedicines.
... 14 In this review, we focus on the control and characteriza- tion of biomolecule adsorption from a liquid solution to a surface, either bare or functionalized. Thus, we will not address the case of nanoparticles in solution, 15 for which the analytical techniques are different. We are also not pre- senting techniques that are specific to the field of biosens- ing since here we do not aim to quantify the concentration of analytes in a solution but rather quantify the amount of adsorbed biomolecules on a given surface and how they interact with this surface (kinetics, conformational state). ...
The control over the adsorption or grafting of biomolecules from a liquid to a solid interface is of fundamental importance in different fields, such as drug delivery, pharmaceutics, diagnostics, and tissue engineering. It is thus important to understand and characterize how biomolecules interact with surfaces and to quantitatively measure parameters such as adsorbed amount, kinetics of adsorption and desorption, conformation of the adsorbed biomolecules, orientation, and aggregation state. A better understanding of these interfacial phenomena will help optimize the engineering of biofunctional surfaces, preserving the activity of biomolecules and avoiding unwanted side effects. The characterization of molecular adsorption on a solid surface requires the use of analytical techniques, which are able to detect very low quantities of material in a liquid environment without modifying the adsorption process during acquisition. In general, the combination of different techniques will give a more complete characterization of the layers adsorbed onto a substrate. In this review, the authors will introduce the context, then the different factors influencing the adsorption of biomolecules, as well as relevant parameters that characterize their adsorption. They review surface-sensitive techniques which are able to describe different properties of proteins and polymeric films on solid two-dimensional materials and compare these techniques in terms of sensitivity, penetration depth, ease of use, and ability to perform "parallel measurements."
... Over the last years, several regulatory entities such as the European Medicines Agency (EMA, EU), the International Organization for Standardization (ISO), the U.S. Food and Drug Administration (FDA, USA), the Nanotechnology Characterization Laboratory (NCL, USA), the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and the National Institute of Standards and Technology (NIST, USA), etc., have been putting substantial efforts on the regulation of this novel and unique class of materials [18,78,83,[659][660]. These efforts have however to be done by regulators, researchers, and by the regulated community, to ensure that nanomaterials (including nanosimilars and non-biological complex drugs) are evaluated and characterized appropriately, and in order to permit the prediction/correlation of their potential efficacies and/or to determine whether they pose risks to human health or to the environment (during synthesis, processing, application, and even after disposal) [77,658]. ...
... Particularly, the characterization of pharmaceutical nanoparticles/nanocrystals (i.e. amorphous/crystalline pure drug nanoparticles, organic/inorganic excipient nanoparticles and co-precipitated drug nanoparticle formulations) is also crucial for [2,12,18,47,77,80,[658][659]: ...
... Despite of all the advances achieved over the last years on the development of more powerful and precise analytical techniques and equipment (also presenting higher analytical resolutions), the characterization of nanoparticles/nanocrystals still represents a relevant challenge. This occurs mainly because of [2,12,18,47,77,80,[658][659]: ...
Low drug bioavailability, which is mostly a result of poor aqueous drug solubilities and of inadequate drug dissolution rates, is one of the most significant challenges that pharmaceutical companies are currently facing, since this may limit the therapeutic efficacy of marketed drugs, or even result in the discard of potential highly effective drug candidates during developmental stages. Two of the main approaches that have been implemented in recent years to overcome poor drug solubility/dissolution issues have frequently involved drug particle size reduction (i.e., micronization/nanonization) and/or the modification of some of the physicochemical and structural properties of poorly water soluble drugs. A large number of particle engineering methodologies have been developed, tested, and applied in the synthesis and control of particle size/particle-size distributions, crystallinities, and polymorphic purities of drug micro- and nano-particles/crystals. In recent years pharmaceutical processing using supercritical fluids (SCF), in general, and supercritical carbon dioxide (scCO2), in particular, have attracted a great attention from the pharmaceutical industry. This is mostly due to the several well-known advantageous technical features of these processes, as well as to other increasingly important subjects for the pharmaceutical industry, namely their "green", sustainable, safe and "environmentally-friendly" intrinsic characteristics. In this work, it is presented a comprehensive state-of-the-art review on scCO2-based processes focused on the formation and on the control of the physicochemical, structural and morphological properties of amorphous/crystalline pure drug nanoparticles. It is presented and discussed the most relevant scCO2, scCO2-based fluids and drug physicochemical properties that are pertinent for the development of successful pharmaceutical products, namely those that are critical in the selection of an adequate scCO2-based method to produce pure drug nanoparticles/nanocrystals. scCO2-based nanoparticle formation methodologies are classified in three main families, and in terms of the most important role played by scCO2 in particle formation processes: as a solvent; as an antisolvent or a co-antisolvent; and as a "high mobility" additive (a solute, a co-solute, or a co-solvent). Specific particle formation methods belonging to each one of these families are presented, discussed and compared. Some selected amorphous/crystalline drug nanoparticles that were prepared by these methods are compiled and presented, namely those studied in the last 10-15 years. A special emphasis is given to the formation of drug cocrystals. It is also discussed the fundamental knowledge and the main mechanisms in which the scCO2-based particle formation methods rely on, as well as the current status and urgent needs in terms of reliable experimental data and of robust modeling approaches. Other addressed and discussed topics include the currently available and the most adequate physicochemical, morphological and biological characterization methods required for pure drug nanoparticles/nanocrystals, some of the current nanometrology and regulatory issues associated to the use of these methods, as well as some scale-up, post-processing and pharmaceutical regulatory subjects related to the industrial implementation of these scCO2-based processes. Finally, it is also discussed the current status of these techniques, as well as their future major perspectives and opportunities for industrial implementation in the upcoming years.
... Indeed, incomplete or inappropriate characterization of important NMs' parameters were identified as critical points in project failures by actors involved in the development of NMs [12]. The characterization has been pointed out as a hurdle that delays and still hampers the development of projects involving nanomaterials [2,11,[13][14][15][16][17][18][19]. ...
A faithful characterization of nanomedicine (NM) is needed for a better understanding of their in vivo outcomes. Size and surface charge are studied with well-established methods. However, other relevant parameters for the understanding of NM behavior in vivo remain largely inaccessible. For instance, the reactive surface of nanomedicines, which are often grafted with macromolecules to decrease their recognition by the immune system, is excluded from a systematic characterization. Yet, it is known that a subtle modification of NM's surface characteristics (grafting density, molecular architecture and conformation of macromolecules) is at the root of major changes in the presence of biological components. In this work, a method that investigates the steric hindrance properties of the NMs' surface coverage based on its capacity to exclude or allow adsorption of well-defined proteins was developed based on capillary electrophoresis. A series of proteins with different molecular weights (MW) were used as molecular probes to screen their adsorption behavior on nanoparticles bearing different molecular architectures at their surface. This novel strategy evaluating to some degree a functionality of NMs can bring additional information about their shell property and might allow for a better perception of their behavior in the presence of biological components. The developed method could discriminate NM with a high surface coverage excluding high MW proteins from NM with a low surface coverage that allowed high MW proteins to adsorb on their surface. The method has the potential for further standardization and automation for a routine use. It can be applied in quality control of NMs and to investigate interactions between proteins and NM in different situations.
