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Supramolecular assembly of rifampicin and PEGylated PAMAM dendrimer as a novel conjugate for tuberculosis
Abstract
Introduction
The study aimed to develop and explore the efficiency of a surface-modified 4.0 G PAMAM dendrimer as a novel delivery system for the anti-tuberculosis (TB) drug, rifampicin.
Methods
The 4.0 G PAMAM dendrimer having various concentrations of polyethylene glycol (PEG) 2 kDa content was synthesized using 4-nitrophenyl chloroformate as an activator, and characterized using Fourier-transform infrared (FTIR) and proton nuclear magnetic resonance (¹H NMR) analysis. Thereafter, rifampicin was loaded into dendrimers via simple dissolution solvent evaporation method, and characterized using different analytical techniques. The polymer encapsulation efficiency (EE%) was determined directly using a validated HPLC method. In vitro drug release was studied at pH 7.4. The MTT technique was used to assess the cytotoxicity of the dendrimer formulations against raw 264.7 cell lines.
Results
The percentage coverage of 4.0 G PAMAM dendrimer peripheral with PEG was achieved in a range of 38%–100%. The EE% of the native dendrimer was 7.5% (w/w), and for PEGylated dendrimers was >60% (w/w). The dynamic light scattering (DLS) verified the nanosize of dendrimer formulations, and the zeta potential was positive with values greater than 12 mV. Scanning electron microscopy (SEM) images of dendrimer confirmed the spherical or semi-spherical shape of the nanoparticles, and differential scanning calorimetry (DSC) data verified drug entrapment. The PEGylated dendrimers showed a slower release rate compared to the native/unmodified formulation and free drug. The toxicity of dendrimer was significantly improved after dendrimer PEGylation, and negligible toxicity was detected for formulations with 100% functionalization.
Conclusions
The developed PEGylated G4 PAMAM dendrimers are suggested as a suitable drug carrier with negligible cytotoxicity, high loading potential, and prolonged-release behaviour for rifampicin.
... These two substances play a critical role in tuberculosis therapy and have garnered significant interest in studies aimed at enhancing their effectiveness and delivery via dendrimer encapsulation. Kumar et al. [47], Rajabnezhad et al. [48], and Ahmed et al. [49] reported on the prolonged release of rifampicin from poly(amidoamine) Pegylated dendrimers (PA-MAM). Concurrently, Bellini et al. [50] demonstrated the remarkable stability of the rifampicin-PAMAM complex under physiological pH conditions and the rapid release of rifampicin in acidic environments, resembling the acidic niches within macrophages where M. tuberculosis resides. ...
... These two substances play a critical role in tuberculosis therapy and have garnered significant interest in studies aimed at enhancing their effectiveness and delivery via dendrimer encapsulation. Kumar et al. [47], Rajabnezhad et al. [48], and Ahmed et al. [49] reported on the prolonged release of rifampicin from poly(amidoamine) Pegylated dendrimers (PAMAM). Concurrently, Bellini et al. [50] demonstrated the remarkable stability of the rifampicin-PAMAM complex under physiological pH conditions and the rapid release of rifampicin in acidic environments, resembling the acidic niches within macrophages where M. tuberculosis resides. ...
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages.
... Once deposited in the lungs, and with the adhesion of lung lining fluid, the matrix of the PNAPs degrades and rapidly releases the dendrimer nanoparticles, which act on the targets. Ahmed et al. (2021) [90] prepared rifampicin-encapsulating PEGylated PAMAM dendrimers for the treatment of TB. The dendrimer PEGylation increased the nanoparticles' EE and DL percent, because PEG chains give an extra surface for interaction. ...
... Once deposited in the lungs, and with the adhesion of lung lining fluid, the matrix of the PNAPs degrades and rapidly releases the dendrimer nanoparticles, which act on the targets. Ahmed et al. (2021) [90] prepared rifampicin-encapsulating PEGylated PAMAM dendrimers for the treatment of TB. The dendrimer PEGylation increased the nanoparticles' EE and DL percent, because PEG chains give an extra surface for interaction. ...
Tuberculosis (TB), one of the deadliest contagious diseases, is a major concern worldwide. Long-term treatment, a high pill burden, limited compliance, and strict administration schedules are all variables that contribute to the development of MDR and XDR tuberculosis patients. The rise of multidrug-resistant strains and a scarcity of anti-TB medications pose a threat to TB control in the future. As a result, a strong and effective system is required to overcome technological limitations and improve the efficacy of therapeutic medications, which is still a huge problem for pharmacological technology. Nanotechnology offers an interesting opportunity for accurate identification of mycobacterial strains and improved medication treatment possibilities for tuberculosis. Nanomedicine in tuberculosis is an emerging research field that provides the possibility of efficient medication delivery using nanoparticles and a decrease in drug dosages and adverse effects to boost patient compliance with therapy and recovery. Due to their fascinating characteristics, this strategy is useful in overcoming the abnormalities associated with traditional therapy and leads to some optimization of the therapeutic impact. It also decreases the dosing frequency and eliminates the problem of low compliance. To develop modern diagnosis techniques, upgraded treatment, and possible prevention of tuberculosis , the nanoparticle-based tests have demonstrated considerable advances. The literature search was conducted using Scopus, PubMed, Google Scholar, and Elsevier databases only. This article examines the possibility of employing nanotechnology for TB diagnosis, nanotechnology-based medicine delivery systems, and prevention for the successful elimination of TB illnesses.
... Figure 2 showed the FT-IR spectrum of mPEG-NPC, G3.0 and G3.0@mPEG. In the spectra of mPEG-NPC, the peak at 2888 cm −1 was C-H stretching vibration, the peak at 1114 cm −1 was the C-O asymmetric stretch and the peak at 1768 cm −1 indicated vibration of C=O stretch of carbonate group [35,36]. In spectra of G3.0, the appearance of peak at 3415-3265 cm −1 was attributed to secondary amine group (-NH-). ...
... The strong peak at 1645 cm −1 was C=O stretch of amide group, and the one at 1556 cm −1 was N-H bending vibration. In the spectra of G3.0@mPEG, there were peaks of G3.0 at 3345-3356 cm −1 (N-H) and 1641 cm −1 (C=O of amide); and peak of PEG at 1112 cm −1 (C-O) [35,37]. Besides, the disappearance of peak at 1768 cm −1 was due to the replacement of carbonate group by carbamate group, which demonstrate that PEG was conjugated with G3.0 [36]. ...
Polyamidoamine dendrimer (PAMAM) with its unique characteristics emerges as a potential drug delivery system which can prolong releasing time, reduce the side effects but still retaining treatment efficiency. In this study, methoxy polyethylene glycol modified PAMAM generation 3.0 (G3.0@mPEG) is prepared and characterized via 1H-NMR, FT-IR, and TEM. Subsequently, two antiretroviral agents (ARV) including lamivudine (3TC) and zidovudine (AZT) are individually encapsulated into G3.0@mPEG. The drug-loading efficiency, drug release profile, cytotoxicity and anti-HIV activity are then evaluated. The results illustrate that G3.0@mPEG particles are spherical with a size of 34.5 ± 0.2 nm and a drug loading content of about 9%. Both G3.0@mPEG and ARV@G3.0@mPEG show no cytotoxicity on BJ cells, and G3.0@mPEG loading 3TC and AZT performs sustained drug release behavior which is best fitted with the Korsmeyer–Peppas model. Finally, the anti-HIV activity of ARV via Enzymatic Assay of Pepsin is retained after being loaded into the G3.0@mPEG, in which about 36% of pepsin activity was inhibited by AZT at the concentration of 0.226 mM. Overall, PAMAM G3.0@mPEG is a promising nanocarrier system for loading ARV in HIV treatment and prevention.
... The PEG-modified dendrimer nanoparticles showed less toxicity to human cells due to their reduced zeta potential. The PEG-modified G4 PAMAM dendrimer nanoparticles executed a slow release of encapsulated rifampicin; hence, the developed nanosystem can be suggested as a suitable drug carrier for antimicrobial drugs [40]. Liu et al. showed the in vivo effectiveness of PAMAM dendrimer nanoparticles by encapsulating platensimycin (PTM), a potent inhibitor of FabB and FabF for bacterial fatty acid biosynthesis. ...
The escalating selective pressure generated by the overuse and misuse of anti-microbials has generated a situation of antimicrobial resistance (AMR). Due to this circumstance , there is an intensified focus on the development of innovative strategies and the implementation of advanced techniques to enhance the administration and effectiveness of antimicrobial medications. The application of nanotechnology through the utilization of nanocarriers has garnered significant interest in the realm of antimicrobial therapy owing to its potential to enhance the delivery and effectiveness of antimicrobial drugs. Nanocarriers have been instrumental in the encapsulation and transportation of antimicrobial drugs, peptides, or other active substances to the infection site, thereby augmenting their therapeutic efficacy while mitigating adverse effects. In addition, nano-carriers can be tailored via material engineering to achieve desired physicochemical properties. The present chapter provides an overview of diverse categories of nanocar-riers, including polymeric, lipidic, dendrimers, metallic, organic, inorganic, and other types, which are employed for the purpose of delivering antimicrobial agents or directing drug target determinants, such as efflux pumps, cell membrane permeability, bio-films, and quorum sensing in drug-resistant microorganisms. Furthermore, the chapter also sheds light on the clinical trials and applications of these nanocarriers.
... The PEG-modified dendrimer nanoparticles showed less toxicity to human cells due to their reduced zeta potential. The PEG-modified G4 PAMAM dendrimer nanoparticles executed a slow release of encapsulated rifampicin; hence, the developed nanosystem can be suggested as a suitable drug carrier for antimicrobial drugs [40]. Liu et al. showed the in vivo effectiveness of PAMAM dendrimer nanoparticles by encapsulating platensimycin (PTM), a potent inhibitor of FabB and FabF for bacterial fatty acid biosynthesis. ...
The escalating selective pressure generated by the overuse and misuse of anti-microbials has generated a situation of antimicrobial resistance (AMR). Due to this circumstance , there is an intensified focus on the development of innovative strategies and the implementation of advanced techniques to enhance the administration and effectiveness of antimicrobial medications. The application of nanotechnology through the utilization of nanocarriers has garnered significant interest in the realm of antimicrobial therapy owing to its potential to enhance the delivery and effectiveness of antimicrobial drugs. Nanocarriers have been instrumental in the encapsulation and transportation of antimicrobial drugs, peptides, or other active substances to the infection site, thereby augmenting their therapeutic efficacy while mitigating adverse effects. In addition, nano-carriers can be tailored via material engineering to achieve desired physicochemical properties. The present chapter provides an overview of diverse categories of nanocar-riers, including polymeric, lipidic, dendrimers, metallic, organic, inorganic, and other types, which are employed for the purpose of delivering antimicrobial agents or directing drug target determinants, such as efflux pumps, cell membrane permeability, bio-films, and quorum sensing in drug-resistant microorganisms. Furthermore, the chapter also sheds light on the clinical trials and applications of these nanocarriers.
... The findings indicated that the surface of the dendrimer was coated with PEG at a level of 38-100%, leading to a slower release rate of rifampicin compared to the non-PEGylated formulation and the unencapsulated drug. The study found that the fully functionalized dendrimer exhibited reduced toxicity towards raw 264.7 cell lines [113]. Likewise, Alfei et al. (2020) created a new biodegradable fifth-generation dendrimer based on polyester and featuring a free carboxylic group. ...
Nanosized Janus and dendrimer particles have emerged as promising nanocarriers for the target-specific delivery and improved bioavailability of pharmaceuticals. Janus particles, with two distinct regions exhibiting different physical and chemical properties, provide a unique platform for the simultaneous delivery of multiple drugs or tissue-specific targeting. Conversely, dendrimers are branched, nanoscale polymers with well-defined surface functionalities that can be designed for improved drug targeting and release. Both Janus particles and dendrimers have demonstrated their potential to improve the solubility and stability of poorly water-soluble drugs, increase the intracellular uptake of drugs, and reduce their toxicity by controlling the release rate. The surface functionalities of these nanocarriers can be tailored to specific targets, such as overexpressed receptors on cancer cells, leading to enhanced drug efficacy The design of these nanocarriers can be optimized by tuning the size, shape, and surface functionalities, among other parameters. The incorporation of Janus and dendrimer particles into composite materials to create hybrid systems for enhancing drug delivery, leveraging the unique properties and functionalities of both materials, can offer promising outcomes. Nanosized Janus and dendrimer particles hold great promise for the delivery and improved bioavailability of pharmaceuticals. Further research is required to optimize these nanocarriers and bring them to the clinical setting to treat various diseases. This article discusses various nanosized Janus and dendrimer particles for target-specific delivery and bioavailability of pharmaceuticals. In addition, the development of Janus-dendrimer hybrid nanoparticles to address some limitations of standalone nanosized Janus and dendrimer particles is discussed.
... Pharmaceutics 2023, 15, 512 ...
The present work describes the development of a hybrid and pH-responsive system for rifampicin using the clay mineral ‘montmorillonite’ as a nanocarrier. The influence of operational variables on the drug incorporation process was evaluated using 24 factorial designs. Under optimized conditions, the experiment allowed an incorporated drug dose equivalent to 98.60 ± 1.21 mg/g. Hybrid systems were characterized by different characterization techniques (FTIR, XRD, TGA, DSC, and SEM) to elucidate the mechanism of interaction between the compounds used. Through in vitro release studies, it was possible to verify the efficacy of the pH-dependent system obtained, with approximately 70% of the drug released after sixteen hours in simulated intestinal fluid. The adjustment of the experimental release data to the theoretical model of Higuchi and Korsmeyer–Peppas indicated that the release of rifampicin occurs in a prolonged form from montmorillonite. Elucidation of the interactions between the drug and this raw clay reinforces its viability as a novel carrier to develop an anti-TB/clay hybrid system with good physical and chemical stability.
... Translating these modified EVs into clinics, as discussed above, has major challenges, and more research is needed as they have a long way to go to achieve their full therapeutic potential. The synthetic DDSs, such as NPs [136][137][138], liposomes [139][140][141][142], dendrimers [143][144][145], micelles [146][147][148], nanocapsules [149][150][151], nanosponges [152,153], peptide-based nanoparticles [154], etc., have good drug encapsulation efficiency (EE), drug loading (DL) capacity, flexibility in functionalization, easy/robust production, and theragnostic functions. However, conjugation of a PEG polymer, peptide, antibody, etc. may develop drug tolerance [54,127] and even cause allergy [48]. ...
The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders the distribution of the most therapeutic molecules into the brain. Therefore, scientists have been striving to develop safe and effective technologies to advance drug penetration into the CNS with higher targeting properties and lower off-targeting side effects. This review will discuss the limitation of artificial nanomedicine in CNS drug delivery and the use of natural extracellular vesicles (EVs), as therapeutic vehicles to achieve targeted delivery to the CNS. Information on clinical trials regarding CNS targeted drug delivery using EVs is very limited. Thus, this review will also briefly highlight the recent clinical studies on targeted drug delivery in the peripheral nervous system to shed light on potential strategies for CNS drug delivery. Different technologies engaged in pre-and post-isolation have been implemented to further utilize and optimize the natural property of EVs. EVs from various sources have also been applied in the engineering of EVs for CNS targeted drug delivery in vitro and in vivo. Here, the future feasibility of those studies in clinic will be discussed.
... The PEGylation of a dendrimer showed negligible toxicity for formulation with 100% functionalization. Thus, formulated PEGylated 4.0 G PAMAM dendrimers are proven to be the choice of drug carrier with high loading, negligible toxicity, and extended-release pattern for rifampicin (Ahmed et al., 2021). ...
Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis’s current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.
Tuberculosis is an airborne disease caused by the pathogen, Mycobacterium tuberculosis, which predominantly affects the lungs. World Health Organization (WHO) has reported that about 85% of TB patients are cured with the existing 6-month antibiotic regimen. However, the lengthy oral administration of high-dose anti-TB drugs is associated with significant side effects and leads to drug resistance cases. Alternatively, reformulating existing anti-tubercular drugs into inhalable nanoparticulate systems is a promising strategy to overcome the challenges associated with oral treatment as they could enhance drug retention in the pulmonary region to achieve an optimal drug concentration in the infected lungs. Hence, this review provides an overview of the literature on inhalable nano-formulations for the delivery of anti-TB drugs, including their formulation techniques and preclinical evaluations between the years 2000 and 2020, gathered from electronic journals via online search engines such as Google Scholar and PubMed. Previous in vitro and in vivo studies highlighted that the nano-size, low toxicity, and high efficacy were among the factors influencing the fate of nanoparticulate system upon deposition in the lungs. Although many preclinical studies have shown that inhalable nanoparticles increased therapeutic efficacy and minimised adverse drug reactions when delivered through the pulmonary route, none of them has progressed into clinical trials to date. This could be attributed to the high cost of inhaled regimes due to the expensive production and characterisation of the nanoparticles as well as the need for an inhalation device as compared to the oral treatment. Another barrier could be the lack of medical acceptance due to insufficient number of trained staff to educate the patients on the correct usage of the inhalation device. Hence, these barriers should be addressed satisfactorily to make the inhaled nanoparticles regimen a reality for the treatment of TB.
With the advent of the aging society, osteoporosis (OP) risk increases yearly. Currently, the clinical usage of anti-OP drugs is challenged by recurrent side effects and poor patient compliance, regardless of oral, intravenous, or subcutaneous administration. Properly using a drug delivery system or formulation strategy can achieve targeted drug delivery to the bone, diminish side effects, improve bioavailability, and prolong the in vivo residence time, thus effectively curing osteoporosis. This review expounds on the pathogenesis of OP and the clinical medicaments used for OP intervention, proposes the design approach for anti-OP drug delivery, emphatically discusses emerging novel anti-OP drug delivery systems, and enumerates anti-OP preparations under clinical investigation. Our findings may contribute to engineering anti-OP drug delivery and OP-targeting therapy.
The World Health Organization identifies tuberculosis (TB), caused by Mycobacterium tuberculosis, as a leading infectious killer. Although conventional treatments for TB exist, they come with challenges such as a heavy pill regimen, prolonged treatment duration, and a strict schedule, leading to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The rise of MDR strains endangers future TB control. Despite these concerns, the hunt for an efficient treatment continues. One breakthrough has been the use of nanotechnology in medicines, presenting a novel approach for TB treatment. Nanocarriers, such as lipid nanoparticles, nanosuspensions, liposomes, and polymeric micelles, facilitate targeted delivery of anti-TB drugs. The benefits of nanocarriers include reduced drug doses, fewer side effects, improved drug solubility, better bioavailability, and improved patient compliance, speeding up recovery. Additionally, nanocarriers can be made even more targeted by linking them with ligands such as mannose or hyaluronic acid. This review explores these innovative TB treatments, including studies on nanocarriers containing anti-TB drugs and related patents.
Tuberculosis (TB) is a disease caused by a microorganism (Mycobacterium tuberculosis) which invades the lungs and initiates the disease. Currently, treatment with anti-tubercular (anti-TB) drugs becomes the only option available because Bacillus Calmette-Guérin (BCG) vaccination and chemoprophylaxis appear to be unsatisfactory. Currently available treatment is oral medications which are toxic to the patients and especially to the HIV patients leads to death. It was observed that resistant strains, such as multi-drug resistant (MDR-TB) and extensively drug resistant (XDR-TB), to all major anti-TB drugs have the average treatment periods of 6–32 months against TB, MDR-TB, and XDR-TB. Carrier or delivery systems such as liposomes, nanoparticles, microspheres, solid lipid nanoparticles, and dendrimers have been developed for the sustained delivery of anti-TB drugs and have demonstrated better chemotherapeutic efficacy when investigated in animal models. Dendrimer is a drug attachment platform that can bind and release pharmaceuticals via a variety of methods. Due to the tight and globular structure of dendrimers as well as the number of surface functional groups, drug molecules can be encapsulated both inside and linked to the surface groups. Dendrimers have been used to successfully administer drugs directly into target sites, mimic a sustained release formulation, and maintain high efficacy for anti-TB drugs. Most of the current anti-TB drugs are associated with low solubility, limited permeability, and inadequate bio-distribution-associated side effects. Many scientists have suggested the use of dendrimers for the current anti-TB drugs to enhance their efficacy and overcome some of the drawbacks. Various analytical procedures for analyzing the physicochemical characteristics of dendrimers have been mentioned. It includes spectroscopic, rheological, microscopic, chromatographic, calorimetric, and electrophoretic characterization. Hopefully, new drug delivery strategies will improve the future and, in turn, lessen the negative effects associated with the use of dendrimers in therapy of tuberculosis.KeywordsTuberculosisNovel drug deliveryDendrimers
Among all infectious diseases that afflict humans, tuberculosis (TB) remains the deadliest. At present, epidemiologists estimate that one-third of the world population is infected with Mycobacterium tuberculosis, which is responsible for 8–10 million new cases of TB and 3 million deaths annually throughout the world. Over the past 50 years, with medical treatment and standard public health practices, tuberculosis diminished in developed countries and resulted in a loss of interest and funding for research in improving diagnostic and treatment options. In developing countries, efforts including BCG vaccination have failed to control tuberculosis, and the disease continues to spread as the world becomes more globalized. At the same time, multidrug-resistant tuberculosis has emerged, challenging even the most advance treatment centres. Various unique antibodies have been developed to overcome drug resistance, reduce the treatment regimen, and elevate the compliance to treatment. Therefore, we need an effective and robust system to subdue technological drawbacks and improve the effectiveness of therapeutic drugs which still remains a major challenge for pharmaceutical technology. Polymeric nanoparticulate carriers have shown convincing treatment and promising outcomes for chronic infectious diseases. Different types of nanocarriers have been evaluated as promising drug delivery systems for various administration routes. Controlled and sustained release of drugs is one of the advantages of nanoparticle-based antituberculosis drugs over free drug. It also reduces the dosage frequency and resolves the difficulty of low poor compliance. This chapter reviews sodium alginate-based nanotechnology therapies which can be used for the treatment of TB, with a short summary on bibliometric analysis that could provide significant information to researcher about ongoing research.KeywordsMycobacterium tuberculosisTuberculosisSodium alginateNanoparticlesTreatment
Tuberculosis (TB), derived from bacterium named Mycobacterium tuberculosis, has become one of the worst infectious and contagious illnesses in the world after HIV/AIDS. Long-term therapy, a high pill burden, lack of compliance, and strict management regimens are disadvantages which resulted in the extensively drug-resistant (XDR) along with multidrug-resistant (MDR) in the treatment of TB. One of the main thrust areas for the current scenario is the development of innovative intervention tools for early diagnosis and therapeutics towards Mycobacterium tuberculosis (MTB). This review discusses various nanotherapeutic agents that have been developed for MTB diagnostics, anti-TB drugs and vaccine. Undoubtedly, the concept of employing nanoparticles (NPs) has strong potential in this therapy and offers impressive outcomes to conquer the disease. Nanocarriers with different types were designed for drug delivery applications via various administration methods. Controlling and maintaining the drug release might be an example of the benefits of utilizing a drug-loaded NP in TB therapy over conventional drug therapy. Furthermore, the drug-encapsulated NP is able to lessen dosage regimen and can resolve the problems of insufficient compliance. Over the past decade, NPs were developed in both diagnostic and therapeutic methods, while on the other hand, the therapeutic system has increased. These “theranostic” NPs were designed for nuclear imaging, optical imaging, ultrasound, imaging with magnetic resonance and the computed tomography, which includes both single-photon computed tomography and positron emission tomography. More specifically, the current manuscript focuses on the status of therapeutic and diagnostic approaches in the treatment of TB.
Tuberculosis is one of the oldest bacterial infections known to mankind caused by Mycobacterium tuberculosis. The aim of this research is to optimize and formulate a multi-drug loaded eugenol based nanoemulsion system and to evaluate its ability as an antimycobacterial agent and its potential to be a low cost and effective drug delivery system. All the three eugenol based drug loaded nano-emulsion systems were optimized using response surface methodology (RSM)-central composite design (CCD) and were found stable at a ratio of 1 : 5 (oil : surfactant) when ultrasonicated for 8 minutes. The minimum inhibitory concentration (MIC) values against strains of Mycobacterium tuberculosis highly proved that these essential oil-based nano-emulsions showed more promising results and an even improved anti-mycobacterium activity on the addition of a combination of drugs. The absorbance of 1st line anti-tubercular drugs from release kinetics studies showed a controlled and sustained release in body fluids. Thus, we can conclude that this is a much more efficient and desirable method in treating infections caused by Mycobacterium tuberculosis and even its MDR/XDR strains. All these nano-emulsion systems were stable for more than 3 months.
A boom in respiratory tract infection cases has inflicted a socio-economic burden on the healthcare system worldwide, especially in developing countries. Limited alternative therapeutic options have posed a major threat to human health. Nanotechnology has brought an immense breakthrough in the pharmaceutical industry in a jiffy. The vast applications of nanotechnology ranging from early diagnosis to treatment strategies are employed for respiratory tract infections. The research avenues explored a multitude of nanosystems for effective drug delivery to the target site and combating the issues laid through multidrug resistance and protective niches of the bacteria. In this review a brief introduction to respiratory diseases and multifaceted barriers imposed by bacterial infections are enlightened. The manuscript reviewed different nanosystems, i.e. liposomes, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, nanogels, and metallic (gold and silver) which enhanced bactericidal effects, prevented biofilm formation, improved mucus penetration, and site-specific delivery. Moreover, most of the nanotechnology-based recent research is in a preclinical and clinical experimental stage and safety assessment is still challenging.
In this study, monodispersed silica nanoparticles were synthesized using the Stöber method. The synthesized nanoparticles underwent a range of surface modifications and were converted to nanoparticles with drug release and antibacterial features. For modification, firstly –NH2 groups were created on the silica nanoparticle surface using (3-Aminopropyl)triethoxysilane (APTES). In the second stage, hexachlorocyclotriphosphazene (Phz) molecules were bound to the silica nanoparticle surfaces due to these amino groups. In the final stage of modification, the chloride groups in the hexachlorocyclotriphosphazene structure were modified with trimethoprim (TMP) and nanoparticles with antibacterial properties were obtained. The modified silica nanoparticles were characterized with scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FT-IR), Transmission Electron Microscopy (TEM), and Thermogravimetric analysis (TGA). The silica-based nanoparticles were used for release of rhodamine 6G, chosen as a model drug. As a result of the drug release studies, the modified silica nanoparticles were found to abide by the Korsmeyer–Peppas low power model and non-Fickian release mechanism as release model. Additionally, nanoparticles both loaded and not loaded with the model drug were determined to have antibacterial properties against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus bacteria.
Objective:
To evaluate the impact of PEG content on poly(lactic-co-glycolic acid) (PLGA) NP physicochemical properties, hydrophobic drug release (rifampicin as a model drug) and human serum protein binding.
Methods:
Rifampicin loaded and unloaded nanoparticles with PEG content of 0-17% (w/w) were prepared by an emulsification-evaporation technique. Nanoparticles were characterized for size, zeta potential and morphology. PEGlyation was confirmed using proton nuclear magnetic resonance (1H NMR). Fluorescence spectroscopy and dynamic light scattering were used to determine nanoparticle-protein binding, binding constants and stability of nanoparticles in human serum, respectively. Drug loading and release were determined by UV-VIS spectroscopy and drug release data was mathematically modelled.
Key findings:
A NP PEG content of 17% w/w significantly retarded release of rifampicin from PLGA NPs and altered kinetics of drug release. Stern-Volmer (Ksv) protein binding constants decreased upon PEG incorporation. A 2% w/w PEG was sufficient to significantly reduce protein binding extent to PLGA NPs and maintain particle size distributions.
Conclusion:
The ability to fine tune drug release and formation of protein corona around nanoparticles is crucial to formulation scientists. This study suggests that PLGA NPs with low PEG content might be suitable for extended circulation and rapid drug release and that higher PEG content retards hydrophobic drug release.
The fourth generation (G4) of poly(amidoamine) dendrimer was PEGylated and then physically incorporated with carboplatin to develop the new drug delivery carrier. The proton nuclear magnetic resonance (¹H NMR) and Fourier-transform infrared spectroscopy (FTIR) were utilized to confirm the successful synthesis and incorporation. The PEGylation leads to increase the particle dimension of G4 dendrimer to 4.04 to 30.67 nm that was still in the effective range for killing cancerous cells. The cytotoxicity on L929 fibroblasts demonstrated that the PEGylation of G4 could eliminate the toxic caused by amine surrounding groups of G4. Three cancerous cells including the cervical cancer cell line (HeLa), the adenocarcinomic human alveolar basal epithelial cells (A549), and the human breast cancer cell line (MCF7) were treated with G4-PEG@CAR as a function of CAR concentrations. The results of resazurin test and live/dead assay indicated that the killing effect of G4-PEG@CAR on three representative cells were achieved and increased following the enhancement of CAR concentration. Furthermore, the better effectiveness of G4-PEG@CAR was achieved on Hela.
Introduction
Tuberculosis (TB) is the single largest infectious disease which requires a prolonged treatment regime with multiple drugs. The present treatment for TB includes frequent administration of a combination of four drugs for a duration of 6 months. This leads to patient’s noncompliance, in addition to developing drug-resistant strains which makes treatment more difficult. The formulation of drugs with biodegradable polymeric nanoparticles (NPs) promises to overcome this problem.
Materials and methods
In this study, we focus on two important drugs used for TB treatment – rifampicin (RIF) and isoniazid (INH) – and report a detailed study of RIF-loaded poly lactic-co-glycolic acid (PLGA) NPs and INH modified as INH benz-hydrazone (IH2) which gives the same therapeutic effect as INH but is more stable and enhances the drug loading in PLGA NPs by 15-fold compared to INH. The optimized formulation was characterized using particle size analyzer, scanning electron microscopy and transmission electron microscopy. The drug release from NPs and stability of drug were tested in different pH conditions.
Results
It was found that RIF and IH2 loaded in NPs release in a slow and sustained manner over a period of 1 month and they are more stable in NPs formulation compared to the free form. RIF- and IH2-loaded NPs were tested for antimicrobial susceptibility against Mycobacterium tuberculosis H37Rv strain. RIF loaded in PLGA NPs consistently inhibited the growth at 70% of the minimum inhibitory concentration (MIC) of pure RIF (MIC level 1 µg/mL), and pure IH2 and IH2-loaded NPs showed inhibition at MIC equivalent to the MIC of INH (0.1 µg/mL).
Conclusion
These results show that NP formulations will improve the efficacy of drug delivery for TB treatment.
Aceclofenac is a potent anti-inflammatory analgesic agent indicated for acute and chronic treatment of rheumatoid arthritis, ostio arthritis, and onkylosing spondylytis. Aceclofenac is poorly water soluble and may show dissolution limited absorption. Solid dispersions (SDs) of Aceclofenac in PEG-6000, PVP were prepared by solvent evaporation method. The solid dispersion was characterized for physical appearance, solubility and IR. FTIR study reveled that drug was stable in SDs. Solubility of Aceclofenac from SDs increased in distilled water. The drug content was found to be high and uniformly distributed in the all formulation. Dissolution of drug increased from all the solid dispersion. Dissolution of Aceclofenac increased with increase in the proportion of carriers (1:1, 1:5, and 1:9). Of both the carriers used, dissolution of the drug was more in PEG 6000 based SDs. It is concluded that dissolution of the Aceclofenac could be improved by solid dispersion and PEG 6000 based solid dispersions were more effective in the enhancing the dissolution.
PEGylated PAMAM-G4 dendrimers with substitution percentages of 50% and intermediate size PEG chains (0.55 and 2.0?kDa) were synthesized and evaluated as solubility enhancers and potential supramolecular carriers for the poorly soluble drug Silybin (SIL). Aqueous solubility profiles revealed that the PEGylated system with 2.0?kDa chains induced a five-fold solubility increase for SIL and the largest drug-loading capacity within the systems under study with an average complex stoichiometry of 71:1 according to the Higuchi-Connors formulation for multiple binding sites. The supramolecular interaction between SIL and PEGylated PAMAM-G4 dendrimers was confirmed by 2D-NOESY experiments, which evidenced the simultaneous complexation of the drug in both PAMAM-G4 branches and outermost PEG chains. In vitro release studies showed that 2.0?kDa PEG chains induced a more extended release time compared to 0.5?kDa PEG chains. This result was attributed to the enhancement of PEG-assistance to SIL complexation in systems with longer PEG chains, which are able to self-penetrate into dendrimer cavities and cooperate in the stabilization of SIL complexes, thus delaying the release of SIL from the supramolecular host. These results are valuable for the future design and development of novel PAMAM-based systems for SIL complexation and delivery.
A drug delivery carrier G4–FA–PEG with PEG and FA modified on the periphery of G4.0 poly(amidoamine) (PAMAM) dendrimer was synthesized, and doxorubicin (DOX) was encapsulated in the interior. The in vitro cytotoxicity and cellular uptake in gliomas cells were both enhanced via a FR-mediated endocytosis pathway.
The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.
This study was carried out to investigate the protective effects of chitosan nanoparticles (CNP) against hydrogen peroxide (H2O2)-induced oxidative damage in murine macrophages RAW264.7 cells. After 24 h pre-incubation with CNP (25-200 μg/mL) and chitosan (CS) (50-200 μg/mL, as controls), the viability loss in RAW264.7 cells induced by H2O2 (500 μM) for 12 h was markedly restored in a concentration-dependent manner as measured by MTT assay (P < 0.05) and decreased in cellular LDH release (P < 0.05). Moreover, CNP also exerted preventive effects on suppressing the production of lipid peroxidation such as malondialdehyde (MDA) (P < 0.05), restoring activities of endogenous antioxidant including superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) (P < 0.05), along with increasing total antioxidant capacity (T-AOC) (P < 0.05). In addition, pre-incubation of CNP with RAW264.7 cells for 24 h resulted in the increase of the gene expression level of endogenous antioxidant enzymes, such as MnSOD and GSH-Px (P < 0.05). At the same concentration, CNP significantly decreased LDH release and MDA (P < 0.05) as well as increased MnSOD, GSH-Px, and T-AOC activities (P < 0.05) as compared to CS. Taken together, our findings suggest that CNP can more effectively protect RAW264.7 cells against oxidative stress by H2O2 as compared to CS, which might be used as a potential natural compound-based antioxidant in the functional food and pharmaceutical industries.
The present investigation was aimed to design polyamidoamine (PAMAM) dendrimer having polyethylene glycol grafts as novel drug carrier. In this study we successfully synthesized and conjugated PEGylated PAMAM dendrimers with anti HIV drug stavudine. Hemolytic toxicity studies were carried out for PEGylated PAMAM dendrimers which showed that haemolysis of cell was very negligible in PEGylated PAMAM dendrimers. Moreover surface were characterization of PEGylated PAMAM dendrimers was carried out TEM micrographs. Further physiochemical and physiological parameter such as UV, DSC, drug entrapment and drug release were carried out for PEGylated and non PEGylated PAMAM dendrimers. Drug loading, drug release and toxicity are better for PEGylated PAMAM dendrimers.
The aim of this study was to assess the in vitro release kinetics of antituberculosis drug-loaded nanoparticles (NPs) using a "modified" cylindrical apparatus fitted with a regenerated cellulose membrane attached to a standard dissolution apparatus (modifiedcylinder method). The model drugs that were used were rifampicin (RIF) and moxifloxacin hydrochloride (MX). Gelatin and polybutyl cyanoacrylate (PBCA) NPs were evaluated as the nanocarriers, respectively. The dissolution and release kinetics of the drugs from loaded NPs were studied in different media using the modified cylinder method and dialysis bag technique was used as the control technique. The results showed that use of the modified cylinder method resulted in different release profiles associated with unique release mechanisms for the nanocarrier systems investigated. The modified cylinder method also permitted discrimination between forced and normal in vitro release of the model drugs from gelatin NPs in the presence or absence of enzymatic degradation. The use of dialysis bag technique resulted in an inability to differentiate between the mechanisms of drug release from the NPs in these cases. This approach offers an effective tool to investigate in vitro release of RIF and MX from NPs, which further indicate that this technique can be used for performance testing of nanosized carrier systems.
Three methods were investigated for their suitability for the activation of poly(ethylene glycol) 2000 mono-methyl ether en route to conjugation with dendrimers, using 4-nitrophenylchloroformate as the activator. The use of acetonitrile as a solvent gave the best results. Poly(ethylene glycol) (PEG) grafted polyamidoamine (PAMAM) dendrimers were synthesized and characterized; the use of acetonitrile as a solvent gave the best result. A series of PEG conjugated PAMAM dendrimers with varying degrees of substitution of the dendrimer surface functional group by PEG were prepared. The encapsulation efficiency and the in vitro release characteristics of these PEG conjugated PAMAM dendrimers were studied. The percentage coverage of PAMAM dendrimer surface with PEG had little effect on the encapsulation efficiency but affected the release of methotrexate. IR spectra showed that many of the encapsulated methotrexate molecules were located within the cavity of the dendrimer.
Background
Multidrug resistant tuberculosis threatens global TB control. The lengthy treatment includes one of the injectable drugs: kanamycin, amikacin, or capreomycin, usually for the first six months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first anti-tuberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report on a Phase I, single dose, dose-escalating study aimed at demonstrating safety and tolerability in normal subjects and measuring PK parameters.Methods and FindingsTwenty healthy adults (n=5 per group) were recruited to self administer a single dose of inhaled dry powder capreomycin (25 mg, 75 mg, 150 mg, or 300 mg nominal dose) using a simple, handheld delivery device. Inhalations were well-tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 minutes. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 μg/mL (MIC for Mycobacterium tuberculosis) following the highest dose; t1/2 was 4.8 ± 1.0 hours.ConclusionsA novel inhaled microparticle dry powder formulation of capreomycin was well-tolerated. A single 300 mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen.
Poly(amidoamine) (PAMAM) dendrimers are the first complete dendrimer family to be synthesized, characterized and commercialized. Based on this extensive activity, they are recognized as a unique new class of synthetic nanostructures. Dendrimers allow the precise control of size, shape and placement of functional groups that is desirable for many life science applications. From this perspective, this review focuses on crucial properties of biomimetic dendrimers that will broaden the potential for their use as macromolecular vectors in novel drug delivery and biomedical applications.
Because of limitations associated with the conventional treatment of various chronic diseases a growing attention has been given to the development of targeted drug delivery systems. Pulmonary route of drug delivery gaining much importance in the present day research field as it enables to target the drug delivery directly to lung both for local and systemic treatment. Over the last 2 decades, the systemic absorption of a broad range of therapeutics after pulmonary application has been demonstrated in animals as well as in humans. This review was prepared with an aim to discuss the technical, physiological, and efficacy aspects of the novel pulmonary route of drug targeting. The review also focuses on the mechanisms of pulmonary drug administration along with compatibility of the excipients employed, devices used, and techniques of particulate dosage production. This review was prepared based on the method of extensive literature survey on the topics covering all the aspects discussed in the present subject. Hence, the better understanding of complexes and challenges facing the development of pulmonary drug delivery system offer an opportunity to the pharmaceutical scientist in minimizing the clinical and technical gaps.
Nanotechnology has offered enormous improvement in field of therapeutics by means of designing of drug delivery systems and opened the possibility of controlling infections at the molecular level. Nanocarriers can cross biological barriers and are able to target cellular reservoirs of Mycobacterium tuberculosis (M. tuberculosis). Nanoparticle-based systems have significant potential for treatment and prevention of tuberculosis (TB). A variety of nanocarriers have been widely evaluated as potential drug delivery systems for various administration routes. Targeting the drugs to certain physiological sites such as the lymph nodes has emerged as a promising strategy in treating TB with improved drug bioavailability and reduction of the dosing frequency. Nanotechnology based rational targeting may improve therapeutic success by limiting adverse drug effects and requiring less frequent administration regimes, ultimately resulting in more patients compliance and thus attain higher adherence levels. The development of nanoparticle based aerosol vaccine is undergoing which could serve as new platform for immunization. Present article compiles the general physiological aspects of the infection along with the relevance nanocarriers used in prevention of tuberculosis.
The antibiotic rifampicin shows polymorphism. Two crystalline forms, an amorphous form and four solvates (S I and S II from water; S III from tetrahydrofuran; S IV from carbon tetachloride) have been isolated and characterized by thermal analysis, infrared and X-ray powder spectroscopy. The functional I.R. bands have been interpreted as indicative of some structural features involved in the polymorphism: the intramolecular H-bonds between C23--OH and O=C--O--C25, C4--OH and O=C11, and C1--OH and O=C15. The relative physical stabilities of the various forms are reported.
In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations.
Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively.
Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions.
As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.
A centrifugation method was used to investigate the accumulation of 14C-rifampicin by Staphylococcus aureus and Escherichia coli, and to characterize the mechanism of rifampicin transport into S. aureus. For both species, drug accumulation was rapid with the steady-state concentration (SSC) reached within 40 s of drug exposure. Rifampicin accumulation by S. aureus was temperature and pH dependent; the lower the experimental temperature and the lower the experimental pH, the lower was the concentration of rifampicin accumulated. Accumulation was unaffected by the presence of inhibitors of antibiotic efflux, carbonyl cyanide m-chlorophenylhydrazone (CCCP), dinitrophenol (DNP), or reserpine. Exposure to increasing concentrations of rifampicin suggested that the accumulation process was saturable above a rifampicin concentration of 0.2 mg/L. Michaelis-Menten kinetics gave an apparent Km and Vmax for rifampicin, calculated from a Lineweaver-Burk plot, of 0.05 mg/L (0.06 microM) and 3.8 ng rifampicin per second, respectively. However, calculations suggest that these values reflect those for binding of rifampicin to its target, RNA polymerase.
The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85 +/- 1.60 microg/ml [mean +/- standard deviation; n = 80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25 +/- 3.50 microg/ml) or ACs (2.61 +/- 5.01 microg/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 microg/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 microg/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 microg/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.
The purpose of the investigation was to evaluate the potential of polyamidoamine (PAMAM) dendrimer as nanoscale drug delivery units for controlled release of water insoluble and acidic anti-inflammatory drug. Flurbiprofen (FB) was selected as a model acidic anti-inflammatory drug. The aqueous solutions of 4.0 generation (G) PAMAM dendrimer in different concentrations were prepared and used further for solubilizing FB. Formation of dendrimer complex was characterized by Fourier transform infrared spectroscopy. The effect of pH on the solubility of FB in dendrimer was evaluated. Dendrimer formulations were further evaluated for in vitro release study and hemolytic toxicity. Pharmacokinetic and biodistribution were studied in male albino rats. Efficacy of dendrimer formulation was tested by carrageenan induced paw edema model. It was observed that the loaded drug displayed initial rapid release (more than 40% till 3rd hour) followed by rather slow release. Pharmacodynamic study revealed 75% inhibition at 4th hour that was maintained above 50% till 8th hour. The mean residence time (MRT) and terminal half-life (THF) of the dendritic formulation increased by 2-fold and 3-fold, respectively, compared with free drug. Hence, with dendritic system the drug is retained for longer duration in the biosystem with 5-fold greater distribution. It may be concluded that the drug-loaded dendrimers not only enhanced the solubility but also controlled the delivery of the bioactive with localized action at the site of inflammation.
The present study was aimed at developing and exploring the use of PEGylated poly (propylene imine) dendritic architecture for the delivery of an anti-tuberculosis drug, rifampicin. For this study, PEGylated poly(propylene imine) dendritic architecture was synthesized and loaded with rifampicin. Various physicochemical and physiological parameters UV, IR, NMR, TEM, DSC, drug entrapment, drug release and hemolytic toxicity of both PEGylated and non-PEGylated systems were determined and compared. The PEGylation of the systems was found to have increased their drug-loading capacity, reduced their drug release rate and hemolytic toxicity. The systems were found suitable for prolonged delivery of rifampicin.
Current tuberculosis (TB) treatment is based on a combination of drugs that were developed mostly in the central decades of the last century. Cure rates are high for drug sensitive strains of Mycobacterium tuberculosis (M. tb) when the recommended complex and lengthy treatment protocols are adhered to. However the difficulty in correctly prescribing and adhering to these protocols, the emergence of M tb strains resistant to multiple drugs, and drug-drug interactions that interfere with optimal treatment of HIV and TB coinfected patients have generated a pressing need for improved TB therapies. Together with the ominous global burden of TB, these shortcomings of current treatment have contributed to a renewed interest in the development of improved drugs and protocols for the treatment of tuberculosis. This article highlights hurdles related to the optimized use of existing drugs and challenges related to the development of novel, improved products, focusing in particular on aspects inherent in TB drug clinical development. Concluding comments propose processes for more efficient development of new TB therapies.
Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%), and drug released percentages after 2 hours (Q2h) and 24 hours (Q24h). The results were statistically analyzed and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits; in comparison to Levitra® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q2h (41.45%) and Q24h (74.05%). Compared to Levitra® tablets, the significantly (P< 0.01) delayed Tmax, prolonged MRT(0-∞) and higher relative bioavailability (3.7 folds) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.
Objective: The aim of present study is to develop and explore efficiency of 5.0G EDA PAMAM dendrimers as long-duration drug release carriers for the treatment of tuberculosis. Method: Rifampicin (RIF) was selected as a major drug for incorporation into PAMAM dendrimers based on its anti-tubercular activity and hydrophobic nature. Further polyethylene glycol (PEGylated) PAMAM dendrimers were evaluated for their hemolytic toxicity and in vivo anti-tubercular studies. The 5.0G PAMAM dendrimers are prepared by using initiator core ethylene diamine and methyl acrylate, furthermore the PEGylation was done by polyethylene glycol 2000 using epichlorhydrin as a cross linking agent. Result: The Rifampicin loaded PEGylated 5.0G PAMAM dendrimers were characterized by FTIR, NMR, DSC and SEM analysis. The in vivo study report was ensures that, the suitability of PEGylated dendrimer in the connection of prolonged delivery of Rifampicin, moreover PEGylated system has shown a reduced hemolytic toxicity. Conclusion: The observed results were concluding that, the PEGylated method was a less time consuming, inexpensive, and reproducible and moreover it reduces toxicity.
Current treatment therapeutic approach for tuberculosis is the administration of first line drugs in the form of tablets and capsules for 4-6 months. However, this approach leads to severe adverse effects. Therefore, present study was designed to achieving local and sustained targeting of anti-tubercular drugs in order to reduce dose and frequency. The nanoparticle based dry powder formulation of rifampicin was developed and analyzed with respect to its direct targeting potential of lungs. Rifampicin loaded nanoparticles were formulated by ionic gelation probe sonication method, and characterized with respect to particle size, zeta potential, entrapment and drug loading efficiency. The range of size and entrapment efficiency of prepared nanoparticles was estimated from 124.1 ± 0.2 to 402.3 ± 2.8 nm and 72.00 ± 0.1%, respectively. The freeze-dried powder of nanoparticle formulation was used to carry out in vitro lung deposition studies through Andersen cascade impactor. The cumulative in vitro drug release studies with developed nanoparticle formulation showed sustained release up to 24 hrs. Our in vitro sustained drug release results were corroborated by the extended residence and slow clearance of rifampicin from the lungs. Furthermore, our results suggest the minimum lung distribution of drug in treated rats which confirms the negligible toxicity rendered by nanoparticle dry powder formulation. Moreover, pharmacokinetic and toxicity studies carried out with prepared NPs dry powder inhalation (DPI) formulations and compared with conventional DPI
Statement of significance:
It is well established that dendrimers have demonstrated promising potentials for drug delivery. However, the inherent toxicity poses challenges for its clinical translation. In this regard, PEGylation has helped mitigate some of the toxicity concerns of dendrimers and have paved the way forward for testing its translational potentials. The review is a collection of articles demonstrating the utility of PEGylation of the most studied PAMAM dendrimers. To our knowledge, this is a first such attempt to draw reader's attention, specifically, towards PEGylated PAMAM dendrimers.
Adequate characterization of NPs (nanoparticles) is of paramount importance to develop well defined nanoformulations of therapeutic relevance. Determination of particle size and surface charge of NPs are indispensable for proper characterization of NPs. DLS (dynamic light scattering) and ZP (zeta potential) measurements have gained popularity as simple, easy and reproducible tools to ascertain particle size and surface charge. Unfortunately, on practical grounds plenty of challenges exist regarding these two techniques ranging from inadequate understanding of the operating principles along with critical issues like sample preparation and interpretation of the data. As both DLS and ZP have emerged from the realms of physical colloid chemistry – it is difficult for researchers engaged in nanomedicine research to master these two techniques. However, there is very little literature available in drug delivery research which can offer a simple, concise account on these techniques. This review tries to address this issue while providing the basic principles of the techniques, summarizing the core mathematical principles and offering practical guidelines on tackling commonly encountered problems while running DLS and ZP measurements. Finally, the review tries to analyze the relevance of these two techniques from translatory perspective.
In the recent years, conjugation of polyethylene glycol (PEG) on dendrimer has become an established and highly refined technology for delivery of bioactives. Dendrimers provide an ideal platform for delivery of bioactive as they represent well-defined, highly branched, nanoscale architecture with several modifiable surface groups. However, the actual potential of dendrimers is not realized due to toxicity limitations. PEG molecules are nontoxic, non-immunogenic, and non-antigenic; highly water soluble, FDA approved and is endowed with tremendous potential to impart these properties to other biomolecules through the process of PEGylation. PEGylated dendrimer-mediated drug delivery overcomes the shortcomings of dendrimer reticuloendothelial system (RES) uptake, drug leakage, immunogenicity, hemolytic toxicity, cytotoxicity, hydrophobicity, facilitates the solubilization as well as raises the overall aptitude for DNA transfection, siRNA delivery, transepithelial transport and tumor targeting. This review focuses on various types of PEGylated dendrimer with a detailed note on various modes of PEG usage as well as their influence on various biopharmaceutical properties of dendrimer.
The synthesis of two water soluble dendrimers is described. The formation of water soluble inclusion complexes with a variety of small, hydrophobic guest molecules is also described. Moreover, when these guest molecules are drug moieties, then the resulting drug/dendrimer complexes can be considered ideal candidates for use as novel drug delivery systems.
PEGylated diaminobutane poly(propylene imine) dendrimers were investigated as prospective drug delivery systems. Solubilization and release properties of these dendrimeric derivatives were investigated by fluorescence spectroscopy by employing pyrene as probe. The prospective application of the same dendrimers as drug carriers was first evaluated by incorporating within their interior sufficient concentrations of betamethasone corticosteroids.
Dendrimer, a new class of hyper-branched polymer with predetermined molecular weight, is being received much attention in nano biomedical applications such as anticancer drug delivery, gene therapy, disease diagnosis and etc. In this study, polyamidoamine (PAMAM)-based dendrimer generation 3.0 (G 3.0) was synthesized and subsequently pegylated. Obtained results showed that pegylation degree of the dendrimer was around 31% for its external amine groups. TEM image of the pegylated dendrimer exhibited spherical shape and nano sizes ranging from 30 to 40 nm. The fluorouracil (5-FU)-loaded pegylated dendrimer showed a slow release profile of the drug. In vitro study, at the primary screening concentration of 100 microg/mL, the PAMAM dendrimer presented higher toxicity in MCF-7 cells as compared to its pegylated counterpart. Meanwhile, the (5-FU)-loaded pegylated dendrimer exhibited the antiproliferative activity against the cell line with the IC50 of 9.92 +/- 0.19 microg/mL. In vivo tumor xenograft study, we succeeded in generating MCF-7 cells-derived cancer tumors on mice that was well-confirmed by using flow cytometer assay. The 5-FU encapsulated pegylated dendrimer exhibited a significant decrement in volume of the tumors which was generated by MCF-7 cancer cells.
G4 PAMAM dendrimers grafted with poly(ethylene glycol) (PEG) of different sizes (Mw = 550 and 5000) and grafting densities (12−94% of surface terminals) were simulated using the coarse-grained (CG) force fields previously developed and reparametrized in this work. Simulations are carried out for G4, G5, and G7 un-PEGylated dendrimers that are either unprotonated, terminally protonated, or protonated on both terminals and interior sites, corresponding to pH values of >10, 7, and <5, respectively. As protonation increases, simulations show only a small (6% for G4 and G5) change of dendrimer radius of gyration Rg and show a structural transition from dense-core to dense-shell structure, both of which are in agreement with recent scattering experiments and all-atom simulations. For the PEGylated dendrimers, the Rg of the fully PEG(Mw = 5000)-grafted dendrimer also agrees well with experiment. Longer PEG chains with higher grafting density yield PEG−PEG crowding, which stretches dendrimer terminals toward water more strongly, leading to larger size and a dense-shell structure of the dendrimer. Long PEG chains at high grafting densities also penetrate into the dendrimer core, while short ones do not, which might help explain the reduced encapsulation of hydrophobic compounds seen experimentally in dendrimers that are 75%-grafted with long PEG’s (Mw = 5000). This reduced encapsulation for dendrimers with long grafted PEG’s has previously been attributed to PEG-induced dendrimer aggregation, but this explanation is not consistent with our previous simulations which showed no aggregation even with long PEG’s but is consistent with the new simulations reported here that show PEG penetration into the core of the dendrimer to which the PEG is attached.
The aim of this research was to investigate a novel dry powder formulation of rifampicin (RF) that presents an improved lung deposition profile by means of a polymorphic transformation into a flake-like crystal hydrate. Rifampicin dihydrate (RFDH) was prepared by recrystallization of RF in anhydrous ethanol. A control formulation, amorphous RF (RFAM) was prepared by spray drying. The physicochemical properties of the RFDH and the RFAM were characterized. Aerosol performances of RFDH and RFAM were studied with two dry powder inhalers (DPIs), an Aerolizer and a Handihaler, using a Next Generation Impactor (NGI). The RFDH powder was successfully prepared using simple recrystallization process and had a MMAD of 2.2 μm. The RFDH powders were characterized as having a very thin flaky structure; this unique morphology provided improved aerosolization properties with a decreased device dependency upon aerosolization. The flaky morphology of RFDH resulted in a reduced agglomeration tendency than that of spherical RFAM particles. The maximum fine particle fraction (FPF(TD)) of 68% for the RFDH was achieved with the Aerolizer device. Significant chemical degradation was not observed from the RFDH, while the RFAM showed significant chemical degradation at 9 months. The excipient-free formulation of the RFDH offers the benefit of delivering a maximum potency formulation, of the antibiotic, directly to the site of infection, the lung.
While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, rifampicin and the pro-drug pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems.
Partly PEGylated polyamidoamine (PAMAM) dendrimers were used as the carrier for tumor-selective targeting of the anticancer drug doxorubicin (DOX). Acid-sensitive cis-aconityl linkage or acid-insensitive succinic linkage was introduced between DOX and polymeric carriers to produce PPCD or PPSD conjugates, respectively. DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against murine B16 melanoma cells increased with, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. Confocal laser scanning microscopy confirmed the acid-sensitive release of DOX from PPCD conjugates in the lysosomes and the entrance into nuclei. Pharmacokinetic and biodistribution studies demonstrated that increasing PEGylation degree resulted in reduced liver and splenic accumulation, longer circulation time and more tumor accumulation of the conjugates. Although PPSD conjugates showed more tumor accumulation than PPCD conjugates at the same PEGylation degree, the acid-sensitive DOX release from PPCD conjugates ensured higher concentration of free DOX in tumor and more pronounced antitumor activity. Besides, the antitumor activity of PPCD conjugates increased with increasing PEGylation degree. Overall, PPCD conjugate with the highest PEGylation would be a promising candidate for solid tumor therapy.
To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system.
Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed. Tumor accumulation was also visualized by in vivo fluorescence imaging.
DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree. In vitro cytotoxicity of PPCD conjugates against ovarian cancer (SKOV-3) cells increased, while cellular uptake decreased with increasing PEGylation degree. PPSD conjugates released negligible drug at any tested pH condition and were less cytotoxic. The conjugates were internalized by SKOV-3 cells via clathrin-mediated and adsorptive endocytosis, and were delivered to acidic lysosomes where DOX was released from PPCD conjugates and diffused into the nuclei. PPCD conjugates with highest PEGylation degree showed the highest tumor accumulation in mice inoculated with SKOV-3 cells.
The obtained results suggested that PPCD conjugates with highest PEGylation degree would be a potential candidate for solid tumor treatment.
The nature of the groups that reside on the periphery of dendrimers and have contact with the surrounding media is the primary factor that controls the surface-related physico-chemical characteristics of these macromolecules. Therefore, transformation/tailoring of the peripheral functionalities of dendrimers is an economical way to change the overall behaviour of a particular dendrimer class or to impart new properties. In addition, the yields of the completely modified macromolecules could provide valuable information for the accessibility and the back folding of the moieties placed at the dendritic surfaces. The present article reviews the parent toxicity issues associated with cationic dendrimers like PAMAM and PPI, and examines the possibility of addressing this aspect through surface engineering with conjugation of biocompatible molecules.
The solubility of the hydrophobic drug ibuprofen has been compared in an aqueous solution of polyamidoamine (PAMAM) G4 dendrimer and sodium dodecyl sulphate (SDS). The PAMAM G4 dendrimer solution significantly enhanced the solubility of ibuprofen compared to 2% SDS solution. It was found that the solubility of ibuprofen in dendrimer solution was directly proportional to dendrimer concentration and inversely proportional to temperature. The influence of dendrimer solution pH on the solubility enhancement of ibuprofen suggests that it involves an electrostatic interaction between the carboxyl group of the ibuprofen molecule and the amine groups of the dendrimer molecule.
Polyamidoamine dendrimers having poly(ethylene glycol) grafts were designed as a novel drug carrier which possesses an interior for the encapsulation of drugs and a biocompatible surface. Poly(ethylene glycol) monomethyl ether with the average molecular weight of 550 or 2000 was combined to essentially every chain end of the dendrimer of the third or fourth generation via urethane bond. The poly(ethylene glycol)-attached dendrimers encapsulating anticancer drugs, adriamycin and methotrexate, were prepared by extraction with chloroform from mixtures of the poly(ethylene glycol)-attached dendrimers and varying amounts of the drugs. Their ability to encapsulate these drugs increased with increasing dendrimer generation and chain length of poly(ethylene glycol) grafts. Among the poly(ethylene glycol)-attached dendrimers prepared, the highest ability was achieved by the dendrimer of the fourth generation having the poly(ethylene glycol) grafts with the average molecular weight of 2000, which could retain 6.5 adriamycin molecules or 26 methotrexate molecules/dendrimer molecule. The methotrexate-loaded poly(ethylene glycol)-attached dendrimers released the drug slowly in an aqueous solution of low ionic strength. However, in isotonic solutions, methotrexate and adriamycin were readily released from the poly(ethylene glycol)-attached dendrimers.
Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We determined the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP beta subunit deep within the DNA/RNA channel, but more than 12 A away from the active site. The structure, combined with biochemical results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.
The purpose of this study was to determine if aerosol delivery of drug loaded microparticles to lungs infected withMycobacterium tuberculosis may be achieved by predicting dispersion of dry powders through knowledge of particle surface properties. Particle sizes of rifampicin-loaded poly(lactide-co-glycolide) microparticles (R-PLGA), rifampicin alone, and lactose and maltodextrin carrier particles (bulk and 75-125-μm sieved fractions) were determined by electron microscopy for the projected area diameter (Dp) and laser diffraction for the volume diameter (Dv). Surface energies (Y) of R-PLGA, rifampicin alone, lactose, and maltodextrin were obtained by inverse phase gas chromatography, surface areas (Sa) by N2 adsorption, and cohesive energy densities by calculation. Particle dispersion was evaluated (Andersen nonviable impactor) for 10% blends of R-PLGA and rifampicin alone with bulk and sieved fractions of the carriers. Dp for R-PLGA and rifampicin alone was 3.02 and 2.83 μm, respectively. Dv was 13±1 and 2±1 μm for R-PLGA and rifampicin alone, respectively, indicating that R-PLGA was more aggregated. This was evident in Y of 35±1 and 19±6 mJ/m2 for R-PLGA and rifampicin alone. Dp for lactose and maltodextrin (sieved and bulk) was approximately 40 mm. Bulk maltodextrin (Dv=119±6 mm) was more aggregated than bulk lactose (Dv=54±2 mm). This was a result of the higher Sa for maltodextrin (0.54 m2/g) than for lactose (0.21 m2/g). The Y of bulk lactose and maltodextrin was 40±4 and 60±6 mJ/m2 and of sieved lactose and maltodextrin was 39±1 and 50±1 mJ/m2. Impaction studies yielded higher fine particle fractions of R-PLGA from sieved lactose, 13%±3%, than from sieved maltodextrin, 7%±1%, at 90 L/min. An expression, based on these data, is proposed as a predictor of drug dispersion from carrier particles.
Delivery of dry powder formulations can be achieved by characterizing particle surfaces and predicting impact on dispersion.
Unimolecular dendritic micelles designed as solubility enhancers were obtained by coupling polyethylene glycol (PEG) to Starburst polyamidoamine (PAMAM) dendrimers. Micelles-750, -2000, and -5000 have a generation 3.0 dendrimer core (32 primary amine end groups) and PEG arms with molecular weights of 750, 2000, and 5000, respectively. The conjugate of dendrimer core and PEG was characterized by MALDI-TOF MS and 1H NMR. 1H NMR was also used to estimate the average number of PEG arms on each dendrimer molecule. A typical hydrophobic compound, pyrene, was sonicated in an excess amount together with micelles at 50 degrees C for 6 h to produce its saturated water solution. The change of the solubility of pyrene was monitored at 334 nm, its maximum adsorption wavelength, by UV-VIS spectra. Concentrated micelles tended to dissolve more pyrene. However, there is no obvious linear relationship between micelle type and the amount of pyrene entrapped within micelles. Micelle-2000 could solubilize more pyrene than micelle-750. It is hypothesized that micelle-5000 did not solubilize more pyrene than micelle-2000 because of the PEG shell disruption by adjacent interpenetration of individual micelles when PEG arm length increased.
This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.
Dendrimers are emerging as a relatively new class of polymeric biomaterials with applications in drug delivery, and imaging. Achieving a high drug payload in dendrimers, and understanding the therapeutic effect of the dendrimer-drug conjugates are receiving increasing attention. A high drug payload nanodevice was obtained by covalent conjugation of ibuprofen to a polyamidoamine (PAMAM-G4-OH) dendrimer. Using DCC as a coupling agent, 58 molecules of ibuprofen were covalently conjugated to one molecule of generation 4 PAMAM-OH dendrimer. Cellular entry of the fluoroisothiocynate (FITC)-labeled dendrimer-drug conjugate was evaluated in vitro by using human lung epithelial carcinoma A549 cells by flow cytometry, confocal microscopy and UV/Visible spectroscopy. The pharmacological activity of the dendrimer-ibuprofen conjugate was compared to pure ibuprofen at various time points by measuring the suppression of prostaglandin E2. Significant amounts of the conjugate entered the cells rapidly within 15 min. Suppression of prostaglandin was noted within 30 min for the dendrimer-drug conjugates versus 1 h for the free ibuprofen. The results suggest that dendrimers with high drug payload improve the drug's efficacy by enhanced cellular delivery, and may produce a rapid pharmacological response. These dendrimer-drug conjugates can potentially be further modified by attaching antibodies and ligands for targeted drug delivery.
The field of biomedical dendrimers is still in its infancy, but the explosion of interest in dendrimers and dendronised polymers as inherently active therapeutic agents, as vectors for targeted delivery of drugs, peptides and oligonucleotides, and as permeability enhancers able to promote oral and transdermal drug delivery makes it timely to review current knowledge regarding the toxicology of these dendrimer chemistries (currently under development for biomedical applications). Clinical experience with polymeric excipients, plasma expanders, and most recently the development of more 'classical polymer'-derived therapeutics can be used to guide development of "safe" dendritic polymers. Moreover, in future it will only ever be possible to designate a dendrimer as "safe" when related to a specific application. The so far limited clinical experience using dendrimers make it impossible to designate any particular chemistry intrinsically "safe" or "toxic". Although there is widespread concern as to the safety of nano-sized particles, preclinical and clinical experience gained during the development of polymeric excipients, biomedical polymers and polymer therapeutics shows that judicious development of dendrimer chemistry for each specific application will ensure development of safe and important materials for biomedical and pharmaceutical use.
The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. Incorporating therapeutics with polymeric nanoparticles offers additional degrees of manipulation for delivery systems, providing sustained release and the ability to target specific cells and organs. However, nanoparticle delivery to the lungs has many challenges including formulation instability due to particle-particle interactions and poor delivery efficiency due to exhalation of low-inertia nanoparticles. Thus, novel methods formulating nanoparticles into the form of micron-scale dry powders have been developed. These carrier particles exhibit improved handling and delivery, while releasing nanoparticles upon deposition in the lungs. This review covers the development of nanoparticle formulations for pulmonary delivery as both individual nanoparticles and encapsulated within carrier particles.
Dendrimers: a glimpse of history, current progress, and applications
- Gautam
Dendrimers: a glimpse of history, current progress, and applications
- Sp Gautam
- R Gupta
- Gupta
- Gautam
- Singh
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