Polymer based drug delivery systems for mycobacterial infections

In the last decade, polymer based technologies have found wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide or PLG) or natural (e.g. alginate, chitosan etc.), have the property of encapsulating a diverse range of molecules of biological interest and bear distinct therapeutic advantages such as controlled release of drugs, protection against the premature degradation of drugs and reduction in drug toxicity. These are important considerations in the long-duration treatment of chronic infectious diseases such as tuberculosis in which patient non-compliance is the major obstacle to successful chemotherapy. Antitubercular drugs, singly or in combination, have been encapsulated in polymers to provide controlled drug release and the system also offers the flexibility of selecting various routes of administration such as oral, subcutaneous and aerosol. The present review highlights the approaches towards the preparation of polymeric antitubercular drug delivery systems, emphasizing how the route of administration may influence drug bioavailability as well as the chemotherapeutic efficacy. In addition, the pros and cons of the various delivery systems are also discussed.     

Inhalable, bioresponsive microparticles for targeted drug delivery in the lungs

Objective There is a growing interest in developing bioresponsive drug delivery systems to achieve greater control over drug release than can be achieved with the conventional diffusion controlled polymeric delivery systems. While a number of such systems have been studied for oral or parenteral delivery, little or no work has been done on bioresponsive delivery systems for inhalation. Using the raised elastase levels present at sites of lung inflammation as a proof‐of‐concept model, we endeavoured to develop a prototype of inhalable elastase sensitive microparticles (ESMs). Methods Microparticles degradable by the enzyme elastase were formed by crosslinking the polymer alginate in the presence of an elastase substrate, elastin, using Ca⁺² ions and subsequent spray drying. Key findings The bioresponsive release of a protein cargo in the presence of elastase demonstrated the enzyme‐specific degradability of the particles. The microparticles showed favorable properties such as high drug encapsulation and good powder dispersibility. Potential polymer toxicity in the lungs was assessed by impinging the microparticles on Calu‐3 cell monolayers and assessing changes in transepithelial permeability and induction of cytokine release. The microparticles displayed no toxic or immunogenic effects. Conclusions With a manufacturing method that is amenable to scale‐up, the ability to be aerosolised efficiently from a first‐generation inhaler device, enzyme‐specific degradability and lack of toxicity, the ESMs show significant promise as pulmonary drug carriers.     

Controlled delivery of biotechnological products

Peptides, proteins, and nucleotides or DNA fragments are the new generation of drugs. They are becoming attractive owing to the fast development of biotechnology. The admnistration of such molecules, however, may be a problem as sensitivity to temperature, instability at some physiological pH values, short plasma half-life, and high molecular dimension, which hinders the diffusive transport, make, at the moment, parenteral route the only possible way of administration of such molecules. Controlled drug delivery that comprises the development of new administration routes could be the answer to the problems for administration of biotechnological molecules. The rational of drug delivery is to change the pharmacokinetic and pharmacodynamic of drugs by controlling their absorption and distribution. Rate and time of drug release at absorption site could be programmed using a so called delivery system. Different technologies, such as chemical (pro-drugs), biological, polymers, lipids (liposomes, LDL), have been proposed to obtain controlled drug release. Also the use of new administration routes is part of controlled drug delivery. In fact, it could increase the drug absorption and reduce the effects of the active ingredient in those districts not interested in the therapy. Drug delivery systems allowing for an effective release in vivo of new biotechnological molecules, such as recombinant antiidiotypic antibodies with antibiotic activity, devoted to the treatment of pulmonary (tuberculosis and pneumocystosis) and mucosal (candidiasis) diseases are discussed under that perspective.     

Functionalized Micellar Systems for Cancer Targeted Drug Delivery

Abstract Polymer micelles are rapidly becoming a powerful nanomedicine platform for cancer therapeutic applications due to their small size (10–100 nm), in vivo stability, ability to solubilize water insoluble anticancer drugs, and prolonged blood circulation times. Recent data from clinical trials with three micelle formulations have highlighted these and other pharmacokinetic advantages with reduced systemic toxicity and patient morbidity compared to conventional drug formulation. While the initial anti-tumor efficacy of these systems seems promising, a strong research impetus has been placed on micelle functionalization in order to achieve tumor targeting and site-specific drug release, with the hope of reaching a more pronounced tumor response. Hence, the purpose of this review is to draw attention to the new developments of multi-functional polymer micelles for cancer therapy with special focus on tumor targeting and controlled drug release strategies.     

Investigation of the Size Distribution for Diffusion-Controlled Drug Release From Drug Delivery Systems of Various Geometries

Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.     

Biodegradable scleral plugs for vitreoretinal drug delivery.

Intraocular controlled drug release is one way to facilitate drug efficacy and decrease side effects that occur with systemic administration. Vitreoretinal drug delivery with the biodegradable scleral plug has been investigated. The scleral plug, which is made of biodegradable polymers and drugs, can be implanted at the pars plana using a simple procedure, and it gradually releases effective doses of drugs with polymer biodegradation for several months. The release profiles of the drugs were dependent on the kind of polymers used, their molecular weights, and the amount of drug in the plug. The plugs are effective for treating vitreoretinal diseases such as proliferative vitreoretinopathy. The implantation site was replaced with connective tissue. Electroretinography and histologic studies revealed little retinal toxicity. This implantable scleral plug was supposed to be advantageous for diseases such as cytomegalovirus retinitis that respond to repeated intravitreal injections and for vitreoretinal disorders that require vitrectomy.     

Research progress of polyamidoamine dendrimer in targeting drug delivery system

Targeting drug delivery system (TDDS) is one of the most concerned research fields in cancer treatment because it can bind selectively and react with the target diseased sites at the cellular or sub-cellular level, making distribution and release of drugs in a controlled manner, thus enhance therapeutic effects and reduce toxic and side-effects on normal cells. Polyamidoamine dendrimer (PAMAMD) is a kind of newly developed polymer in nanometer degree. Hyper-branched, monodispersity, three-dimensional structure and host-guest entrapment ability make it used as drug carrier, gene delivery system and imaging agent. Various targeting ligands, which have high affinity to specific organs, tissues or cells in human body, can be linked to surface functional groups of PAMAMD. And drugs and theoretical gene are carried by encapsulation or chemical conjugation. Finally, PAMAMD targeting drug delivery system can carry drugs and theoretical gene to diseased sites and then release them for targeted therapy. The PAMAMD-based conjugates have small size, ligh permeability and retention effect (EPR), low toxicity and so on. The research progress of PAMAMD modified by different ligands in targeting drug delivery system is reviewed, and research direction of the PAMAMD targeting delivery system in the future is also suggested.     

Development of L-carnosine functionalized iron oxide nanoparticles loaded with dexamethasone for simultaneous therapeutic potential of blood brain barrier crossing and ischemic stroke treatment

The development of suitable drug delivery carriers is significant in biomedical applications to improve the therapeutic efficiency. Recent progress in nanotechnological fields, paved the way for the formulation of variety of drug carriers. The brain disorders such as ischemic stroke, brain cancer, and CNS disorders were poorly treated due to the presence of blood brain barrier that hinders the passage of drugs to the brain. Hence, the formulated drugs should have the ability to cross the blood-brain barrier (BBB) for ischemic stroke treatment. In the present work, we have synthesized PLGA functionalized magnetic Fe₃O₄ nanoparticle (MNP) with L-carnosine peptide (LMNP) composite loaded with dexamethasone (dm@LMNP) and demonstrated as efficient drug delivery platform for simultaneous BBB crossing and treatment of ischemic stroke. The surface morphology, particles size and zeta potential of the prepared material was studied from SEM, PSD, PDI and TEM analyses. The drug loading of dexamethasone in LMNP (dm@LMNP) vesicles was found to be 95.6 ± 0.2%. The in vitro drug release kinetics displayed that prepared composited LMNP material provides controlled and sustainable releasing efficiency at pH 7.4 and 5.8 when compared to the PLGA NPs and free dexamethasone drug molecules. The cytotoxicity and the biocompatibility test results were found to be satisfactory. The L-carnosine loaded nano-formulation has been greatly leads to effective BBB crossing to access the brain tissues. These results showed that the Fe₃O₄ nanoparticles/PLGA polymer can be used as an effective drug carrier for the treatment of stroke and simultaneous blood brain barrier crossing.     

Classification of stimuli–responsive polymers as anticancer drug delivery systems

Abstract

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli–responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli–responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.     

纳米载体在非酒精性脂肪肝药物治疗中的研究进展

非酒精性脂肪肝（non-alcohol fatty liver disease，NAFLD）已成为当前全球最常见的肝病之一，临床表现为肝脂肪变性，并逐步恶化为非酒精性脂肪肝炎（nonalcoholic steatohepatitis，NASH）、肝硬化、肝癌等末期肝病。目前治疗NAFLD的药物主要包括保肝药物、胰岛素增敏剂、降脂药、抗氧化剂等，但治疗效果尚未满足要求。纳米载体是纳米医学的重要组成部分，具有增加药物溶解性、控制药物释放、促进口服吸收、提高药物治疗效果和降低药物毒性等优势，在NAFLD药物治疗中具有较大的应用潜力，有待深入研究。     

长春新碱抗肿瘤新剂型的研究进展

长春新碱作为临床一线广谱化疗药物广泛用于实体瘤的治疗,由于存在药物半衰期短、神经系统和胃肠道毒性强等缺点,使其临床应用受到限制。因此,提高长春新碱的肿瘤靶向性、延长体内滞留时间,将其制备成新型给药系统具有重要意义。近十年来国内外关于长春新碱的新剂型研究主要有纳米粒、脂质体、微泡、微球等,这些新剂型提高了长春新碱生物利用度,使其具有良好的缓控释能力或肿瘤靶向能力。针对长春新碱抗肿瘤新型给药系统的研究做一综述,为合理开发长春新碱新剂型提供理论依据。     

Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery

In the last decade, considerable attention has been devoted to the use of biodegradable polymeric materials as potential drug delivery carriers. However, bioavailability and drug release at the disease site remain uncontrollable even with the use of polymeric nanocarriers. To address this issue, successful methodologies have been developed to synthesize polymeric nanocarriers incorporated with regions exhibiting a response to stimuli such as redox potential, temperature, pH, and light. The resultant stimuli-responsive polymeric nanocarriers have shown tremendous promise in drug delivery applications, owing to their ability to enhance the bioavailability of drugs at the disease site. In such systems, drug release is controlled in response to specific stimuli, either exogenous or endogenous. This review reports recent advances in the design of stimuli-responsive nanocarriers for drug delivery in cancer therapy. In particular, the synthetic methodologies investigated to date to introduce different types of stimuli-responsive elements within the biomaterials are described. The sufficient understanding of these stimuli-responsive nanocarriers will allow the development of a better drug delivery system that will allow us to solve the challenges encountered in targeted cancer therapy.     

Formulation and in vitro evaluation of rifampicin loaded porous microspheres

Rifampicin (RIF) is a major component in fixed dose combination therapy for the treatment of tuberculosis. RIF has low solubility and high permeability with high dose and hence it is classified as class II drug in Biopharmaceutical Classification System (BCS). RIF has poor and variable bioavailability because of its poor solubility, acid decomposition and, drug and food interaction. The present investigation was aimed to develop RIF loaded porous microspheres as a controlled release dosage form. Eudragit based porous microspheres of RIF were prepared by emulsion solvent diffusion method. Prepared porous microspheres were evaluated for its entrapment efficacy, morphology, thermal behavior, crystalline nature, in-vitro drug release and stability in simulated gastric fluid. The entrapment efficacy of drug loaded microspheres was found to be in the range of 19.04a74.57%. Surface morphology revealed the porous and spherical structure of microspheres. Differential scanning calorimetric studies confirmed that formulation process altered the crystalline nature of RIF. In vitro drug release studies indicated that drug to polymer ratio of 2:1 showed more than 85% drug release over the period of 3 h. Stability studies in simulated gastric fluid (SGF) indicated that low relative decomposition of 18.5% was achieved with high drug to low polymer ratio of 1:4. The results obtained from the present investigation concluded that RIF loaded porous microspheres are suitable for developing oral controlled release dosage form of RIF that can prevent acid decomposition and provide better biopharmaceutical properties. Further more the microspheres can be evaluated for preventing the interaction with isoniazid, other drugs and foodstuffs.     

A new evolutionary and pharmacokinetic-pharmacodynamic scenario for rapid emergence of resistance to single and multiple anti-tuberculosis drugs

The current understanding of the mechanism of anti-tuberculosis drug resistance has been shaped by the history of development of anti-tuberculosis drugs in the past 60 years and was arrived at as part of inductive generalization. Recently, these standard beliefs have been tested in controlled hollow fiber systems experiments. Drug resistance in Mycobacterium tuberculosis was shown to be related to pharmacokinetic-pharmacodynamic (PK/PD) factors, and factors such as pharmacokinetic variability. Poor PK/PD exposures owing to our current non-optimized dosing regimens initiate a chain of evolution driven events, starting with induction of multi-drug efflux pumps, followed by the development of chromosomal mutations in time, which together lead to high level resistance multi-drug resistant tuberculosis and extremely drug resistant tuberculosis.     

Synthesis of thiolated alginate and evaluation of mucoadhesiveness, cytotoxicity and release retardant properties

Modification of polymers by covalent attachment of thiol bearing pendant groups is reported to impart many beneficial properties to them. Hence in the present study, sodium alginate–cysteine conjugate was synthesized by carbodiimide mediated coupling under varying reaction conditions and the derivatives characterized for thiol content. The thiolated alginate species synthesized had bound thiol content ranging from 247.8±11.03–324.54±10.107 ΅mol/g of polymer depending on the reaction conditions. Matrix tablets based on sodium alginate-cysteine conjugate and native sodium alginate containing tramadol hydrochloride as a model drug were prepared and mucoadhesive strength and in vitro drug release from the tablets were compared. Tablets containing 75 mg sodium alginate-cysteine conjugate could sustain release of 10 mg of model drug for 3 h, whereas 90% of the drug was released within 1 h from corresponding tablets prepared using native sodium alginate. An approximately 2-fold increase in the minimal detachment force of the tablets from an artificial mucin film was observed for sodium alginate–cysteine conjugate as compared to native sodium alginate. In vitro cytotoxicity studies in L-929 mouse fibroblast cells studied using an MTT assay revealed that at low concentrations of polymer, sodium alginate–cysteine conjugate was less toxic to L-929 mouse fibroblast cell line when compared to native sodium alginate. Hence, thiolation is found to be a simple route to improving polymer performance. The combination of improved controlled drug release and mucoadhesive properties coupled with the low toxicity of these new excipients builds up immense scope for the use of thiolated polymers in mucoadhesive drug delivery systems.     

Bone-targeting macromolecular therapeutics

Musculoskeletal diseases such as osteoporosis are recognized as major public health problems worldwide. Many novel therapeutic agents have been identified for the treatment of these diseases. However, the majority of them are not specific to hard tissue, resulting significant toxicity. Bone-targeting drug delivery systems based on water-soluble polymers can specifically direct candidate drugs to bone thereby reducing side effects due to non-specific tissue interactions. Incorporation of a targeting moiety, a drug release mechanism, drug selection and optimization of the polymer carrier are all essential elements in the development of bone-targeting macromolecular therapeutics. Successful clinical application of this approach can significantly contribute to the development of treatments for many musculoskeletal diseases.     

Inhibition of macrophage phagocytotic activity by a receptor-targeted polymer vesicle-based drug delivery formulation of pravastatin

Ruptures of macrophage-rich atherosclerotic plaques in the coronary arteries are the main reason for heart attack. Targeted therapeutic interventions with an inhibitory effect on the macrophages promise to be beneficial, but currently available drugs such as statins achieve event reductions of only 30%. Dose-limiting adverse effects in remote organs prohibit achieving higher drug levels known to have strong inhibitory effects on macrophages. Receptor-specific targeting using statin-loaded nanometer-sized triblock copolymer vesicles with targeting moieties might allow high-dose treatment for improved efficacy, while minimizing toxicity in other cells. Vesicle uptake by target cells but not other cell types and slow intracellular content release was observed. A major improvement in biologic efficacy was observed for polymer vesicles compared to free drug, whereas no increased cytotoxicity was observed in muscle cells. Such high-dose, targeted therapy of statins through cell-specific polymer vesicles allows novel treatment paradigms not only for atherosclerosis, but appears promising for a wide range of drugs and diseases.     

Perspectives on percutaneous penetration: Silica nanoparticles

Abstract

Nanotechnology is a rapidly expanding area of research involved in developing science-based solutions for innovative therapeutics. Silica nanoparticles (SNPs) have received wide attention in several industries and medicine and are being developed for biomedical and biotechnological applications such as drug delivery, DNA transfection, and targeted molecular imaging of cancer. Recently, they are emerging in the fields of cosmetics and dermal preparations. SNP may offer a revolutionized treatment of several skin diseases by controlled and sustained release of drugs to skin, as well as enhanced skin penetration of encapsulated drug ingredients. SNPs are candidates for transcutaneous vaccination and transdermal gene therapy, too. Yet there exist concerns that whilst the properties of SNPs have enabled numerous industrial and medical applications, their toxicological and environmental safety mandates evaluation. The knowledge of passage of SNPs through skin following skin exposure (intentionally or unintentionally) and subsequent effects is limited. This review surveys the key experiments on SNP-based formulations in the fields of dermatology and cosmetics with the goal of rationalizing data and informing public health concerns related to SNPs’ toxicity among scientists and manufacturers handling them, while highlights the research gaps in dermal absorption of these compounds.     

Formulation and Characterization of Pyrazinamide Polymeric Nanoparticles for Pulmonary Tuberculosis: Efficiency for Alveolar Macrophage Targeting

Pyrazinamide, a highly specific agent against Mycobacterium tuberculosis is used as first-line drug to treat tuberculosis. The current work aims to formulate polymeric nanoparticles based drug delivery system to sustain the release profile and reduce the dosing frequency of pyrazinamide. Further aim was to target the macrophages within body fluid. These polymeric nanoparticles were prepared by simultaneous double-emulsion (W/O/W) solvent evaporation/diffusion technique. The prepared dispersions were characterized for various biopharmaceutical parameters such as particle size, zeta potential, polydispersity index, drug loading capacity, entrapment efficiency and targeting to alveolar macrophages. The formulated polymeric nanoparticles were in the particle size range of 45.51 to 300.4 nm with a maximum drug entrapment efficiency of 80.9%. The stability study of optimized batch conducted at 40±2°/75±5% relative humidity showed no significant changes up to 90 days. X-Ray Diffraction spectrum exhibits the transformation of crystalline form of drug to amorphous in the formulation. Scanning Electron Microscope image showed nanoparticles spherical in shape with smooth surface. In vitro release profiles were biphasic in nature with burst release followed by controlled release over a period of 24 h obeying diffusion mechanism. In vivo and ex vivo studies results of the study show significant uptake of the nanoparticles by alveolar macrophages through fluorescent micrograph. Polymeric nanoparticles formulation of pyrazinamide could encompass significant uptake by alveolar macrophages, the high first-pass metabolism, sustain the release of drug leading to reduction in dose, toxicity and improvement of patient compliance.     

Controlled release tacrine delivery system for the treatment of Alzheimer's disease

Alzheimer's disease is a neurodegenerative condition that affects approximately 5 million people and is the fourth leading cause of death in America. Tacrine is one of the three drugs approved by the FDA for the treatment of Alzheimer's disease. However, the drug has a short biologic half-life of 2-3 hr and gastrointestinal, cholinergic, and hepatic adverse reactions that are associated with high doses of the drug. The aim of our study was to formulate a controlled release delivery system of tacrine that could be used to minimize the side effects associated with the drug. Microparticles of tacrine were formulated using poly(D,L-lactide-co-glycolide) (PLG). PLG and tacrine were dissolved in mixed organic solvents and added to a polyvinyl alcohol solution that was stirred at a constant rate. The organic solvent was evaporated overnight and the formed microparticles were collected by filtration, dried, and sieve-sized. The effects of such formulation variables, as molecular weight of polymer, stir speed during preparation, and drug loading on encapsulation efficiency (EEF), and in vitro release profiles of tacrine were investigated. An increase in the molecular weight of polymer from 8,000 to 59,000 and 155,000 resulted in approximately 10-fold increase in EEF, but the rate of release decreased with increasing molecular weight. Stir speed during preparation had an effect on the EEF but not on the rate of release. Drug loading did not have a significant effect on the EEF but had an effect on the rate of tacrine release. The results suggest that tacrine could be delivered at controlled levels for weeks for the treatment of Alzheimer's disease.