Computer simulation of polymer and biopolymer self-assembly for drug delivery

Molecular simulation is an emerging tool to bridge relevant time- and length-scales in self-assembly and interfacial processes in soft matter and biological systems. In this review, we highlight mesoscale and coarse-grained molecular dynamics simulation techniques as applied to poly(ethylene oxide)-based diblock copolymer self-assembly. Moreover, we review recent progress pertaining to diblock copolymer and biopolymer self-assembly, stability, and finally, interactions of hydrophobic drugs with polymer membranes. We expect that these computational investigations should provide a useful complement to experimental studies that address open questions in the field of polymeric drug delivery.     

Designing of 'intelligent' liposomes for efficient delivery of drugs

The liposome- vesicles made by a double phospholipidic layers which may encapsulate aqueous solutions- have been introduced as drug delivery vehicles due to their structural flexibility in size, composition and bilayer fluidity as well as their ability to incorporate a large variety of both hydrophilic and hydrophobic compounds. With time the liposome formulations have been perfected so as to serve certain purposes and this lead to the design of "intelligent" liposomes which can stand specifically induced modifications of the bilayers or can be surfaced with different ligands that guide them to the specific target sites. We present here a brief overview of the current strategies in the design of liposomes as drug delivery carriers and the medical applications of liposomes in humans.     

Receptor-targeted nanocarriers for therapeutic delivery to cancer

Abstract

Efficient and site-specific delivery of therapeutic drugs is a critical challenge in clinical treatment of cancer. Nano-sized carriers such as liposomes, micelles, and polymeric nanoparticles have been investigated for improving bioavailability and pharmacokinetic properties of therapeutics via various mechanisms, for example, the enhanced permeability and retention (EPR) effect. Further improvement can potentially be achieved by conjugation of targeting ligands onto nanocarriers to achieve selective delivery to the tumour cell or the tumour vasculature. Indeed, receptor-targeted nanocarrier delivery has been shown to improve therapeutic responses both in vitro and in vivo. A variety of ligands have been investigated including folate, transferrin, antibodies, peptides and aptamers. Multiple functionalities can be incorporated into the design of nanoparticles, e.g., to enable imaging and triggered intracellular drug release. In this review, we mainly focus on recent advances on the development of targeted nanocarriers and will introduce novel concepts such as multi-targeting and multi-functional nanoparticles.     

透明质酸微针经皮递送胰岛素智能给药系统用于糖尿病治疗

本研究通过共沉淀法制备了胰岛素(insulin,INS)/Ca₃PO₄复合物和葡萄糖氧化酶(glucose oxidase,GOx)/Cu₃(PO₄)₂复合物,得到的矿化胰岛素(mineralized insulin,m-INS)呈现不规则结晶团簇状,矿化葡萄糖氧化酶(m-Gox)呈花球状形貌,直径约1–2 μm。体外模拟释放实验表明,m-INS会随介质pH值降低而释放出INS,pH为4.5时其释放量达到96.68%;酶活力检测实验表明m-GOx的酶活力稳定性高于游离的GOx,在室温放置10 d后仍保持较高活力,而GOx活力小于60%。通过配制葡萄糖溶液模拟正常血糖(5.6 mmol/L)和高血糖(22.2 mmol/L)状态,在葡萄糖溶液中加入m-INS和m-GOx,INS的释放量呈现显著的葡萄糖浓度依赖性,即葡萄糖浓度越高,INS释放量和释放速率越大。最后,将m-INS、m-GOx与透明质酸(hyaluronic acid,HA)溶液混合,制备负载m-INS和m-GOx的HA微针阵列,构建1型糖尿病模型鼠,通过微针给药的方式评估载药HA微针对糖尿病大鼠的血糖控制效果。结果表明：负载m-INS/m-GOx的HA微针能有效递送药物,糖尿病大鼠的平均血糖浓度在1 h内下降到约7 mmol/L,并能维持10 h的正常血糖,使血糖浓度低于给药前水平长达36 h。与仅负载INS的HA微针相比,m-INS微针具有更好的葡萄糖耐受性、更持久的控糖效果和更小的低血糖风险。相对于其他的缓释系统,本研究中的核心成分制备流程简单、效率高和安全有效,具备较大的商业化潜力。     

Microencapsulation methods for delivery of protein drugs

Recent advances in recombinant DNA technology have resulted in development of many new protein drugs. Due to the unique properties of protein drugs, they have to be delivered by parenteral injection. Although delivery of protein drugs by other routes, such as pulmonary and nasal routes, has shown some promises, to date most protein drugs are administered by parenteral routs. For long-term delivery of protein drugs by parenteral administration, they have been developed, and the currently used microencapsulation methods are reviewed here. The microencapsulation methods have been divided based on the method used. They are: solvent evaporation/extraction; phase separation (coacervation); spray drying; ionotropic gelation/polyelectrolyte complexation; interfacial polymerization; and supercritical fluid precipitation. Each method is described for its applications, advantages, and limitations.     

血脑屏障与脑药物转运

血脑屏障的存在使大分子药物难以进入脑中发挥疗效。成为中枢神经系统疾病治疗的瓶颈。本就血脑屏障的结构特点、大分子药物转运入脑的途径及药物与载体间的连接策略等问题进行了综述。     

Numerical simulation of iontophoresis in the drug delivery system

The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone.     

Cyclodextrins in drug delivery: An updated review

The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes. Published: October 14, 2005     

Biomimetic nanoparticles for siRNA delivery in the treatment of leukaemia

Leukaemia is a bone marrow cancer occurring in acute and chronic subtypes. Acute leukaemia is a rapidly fatal cancer potentially causing death within a few weeks, if untreated. Leukaemia arises as a result of disruption to haematopoietic precursors, caused either by acquired gene fusions, gene mutations or inappropriate expression of the relevant oncogenes. Current treatment options have made significant progress, but the 5 year survival for acute leukaemia remains under 10% in elderly patients, and less than 50% for some types of acute leukaemia in younger adults. For chronic leukaemias longer survival is generally expected and for chronic myeloid leukaemia patients on tyrosine kinase inhibitors the median survival is not yet reached and is expected to exceed 10 years. Chemotherapy and haematopoietic stem cell transplantation (HSCT) for acute leukaemia provide the mainstay of therapy for patients under 65 and both carry significant morbidity and mortality. Alternative and superior therapeutic strategies for acute leukaemias are urgently required. Recent molecular-based knowledge of recurring chromosome rearrangements, in particular translocations and inversions, has resulted in significant advances in understanding the molecular pathogenesis of leukaemia. Identification of a number of unique fusion genes has facilitated the development of highly specific small interfering RNAs (siRNA). Although delivery of siRNA using multifunctional nanoparticles has been investigated to treat solid cancers, the application of this approach to blood cancers is at an early stage. This review describes current treatments for leukaemia and highlights the potential of leukaemic fusion genes as therapeutic targets for RNA interference (RNAi). In addition, the design of biomimetic nanoparticles which are capable of responding to the physiological environment of leukaemia and their potential to advance RNAi therapeutics to the clinic will be critically evaluated.     

Adhesive thermosensitive gels for local delivery of viral vectors

Local delivery of viral vectors can enhance the efficacy of therapies by selectively affecting necessary tissues and reducing the required vector dose. Pluronic F127 is a thermosensitive polymer that undergoes a solution–gelation (sol–gel) transition as temperature increases and can deliver vectors without damaging them. While pluronics can be spread over large areas, such as the surface of an organ, before gelation, they lack sufficient adhesivity to remain attached to some tissues, such as the surface of the heart or mucosal surfaces. Here, we utilized blends of pluronic F127 and polycarbophil (PCB), a mucoadhesive agent, to provide the necessary adhesivity for local delivery of viral vectors to the cardiac muscle. The effects of PCB concentration on adhesive properties, sol–gel temperature transition and cytocompatibility were evaluated. Rheological studies showed that PCB decreased the sol–gel transition temperature at concentrations >1% and increased the adhesive properties of the gel. Furthermore, these gels were able to deliver viral vectors and transduce cells in vitro and in vivo in a neonatal mouse apical resection model. These gels could be a useful platform for delivering viral vectors over the surface of organs where increased adhesivity is required.     

庆大霉素生物合成基因genA的功能

【目的】在绛红色小单孢菌G1008(Micromonospora purpurea G1008)上构建genA基因缺失工程菌,通过分析其次级代谢产物的变化,推测genA基因功能。【方法】构建用于gen A基因框内敲除的质粒pAB103,经接合转移导入绛红色小单孢菌G1008,安普抗性及PCR扩增筛选获得genA缺失工程菌GA1048。【结果】与出发菌G1008相比,工程菌GA1048不再合成庆大霉素C族组分,主要积累中间代谢产物庆大霉素A2。【结论】genA基因失活导致庆大霉素生物合成代谢流中断,暗示gen A基因参与加洛糖胺C-3″位的氨甲基化。     

Targeted drug delivery in pancreatic cancer

Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.     

Resonance energy transfer for assessing the molecular integrity of proteins for local delivery

It remains unclear whether the limitations to the therapeutic potential of angiogenic growth factors stem from pharmacokinetic concerns related to inadequate delivery or from a reduced sensitivity of target tissues. Here, we report a novel method using resonance energy transfer to assess the molecular integrity of proteins after local delivery. As an example, we labeled fibroblast growth factor-2 with a fluorescent donor and nonfluorescent acceptor pair, tetramethylrhodamine and QSY-7, and demonstrate in an ex vivo bovine carotid artery model that this growth factor is not limited by proteolytic constraints imposed by the tissue. Our data indicate that FGF-2 is unlikely to be degraded within the arterial wall and suggest that pharmacokinetic limitations alone cannot fully explain the muted response seen thus far in therapeutic angiogenesis. In general, resonance energy transfer may serve as a novel approach to assess the molecular integrity of protein-based therapies in local delivery.     

Peptide-based hydrogels as delivery systems for doxorubicin

Hydrogels (HGs) and nanogels (NGs) have been recently identified as innovative supramolecular materials for many applications in biomedical field such as in tissue engineering, optoelectronic, and local delivery of active pharmaceutical ingredients (APIs). Due to their in vivo biocompatibility, synthetic accessibility, low cost, and tunability, peptides have been used as suitable building blocks for preparation of HGs and NGs formulations. Peptide HGs have shown an outstanding potential to deliver small drugs, protein therapeutics, or diagnostic probes, maintaining the efficacy of their loaded molecules, preventing degradation phenomena, and responding to external physicochemical stimuli. In this review, we discuss the possible use of peptide-based HGs and NGs as vehicles for the delivery of the anticancer drug doxorubicin (Dox). This anthracycline is clinically used for leukemia, stomach, lung, ovarian, breast, and bladder cancer therapy. The loading of Dox into supramolecular systems (liposomes, micelles, hydrogels, and nanogels) allows reducing its cardiotoxicity. According to a primary sequence classification of the constituent peptide, doxorubicin-loaded systems are here classified in short and ultra-short peptide-based HGs, RGD, or RADA-peptide-based HGs and peptide-based NGs.     

非侵入性脑内给药

血脑屏障使许多具有中枢神经活性的药物无法到达脑部发挥作用,非侵入性脑内给药因对机体无创伤而受到研究者广泛关注。本文介绍了血脑屏障的物质转运系统以及经鼻粘膜、渗透性血脑屏障开放、纳米粒载体和转运载体法等非侵入性脑内给药方法的机制和特点。     

Polymethyl-methacrylate-sorbitol-based capsules as local drug delivery vehicles: a preliminary study

Local delivery of antibiotics via PMMA (polymethyl-methacrylate) has been widely used in the treatment of chronic osteomyelitis for over 40 years. Unfortunately, PMMA is water insoluble, which seriously limits antibiotic delivery. In addition, the polymerization temperature of PMMA is high, and consequently, only heat-stable antibiotics can be used. Therefore our aim has been to develop an effective antibiotic delivery system, which can be loaded with a wide variety of drugs and deliver the molecules in a predictable manner. Capsules with wall thicknesses of 0.3-0.6 mm from PMMA mixtures containing 40-70 w/w% (weight percent) of sorbitol were prepared and their permeability tested with BPB (Bromophenol Blue). Sorbitol content and wall thickness correlated with the BPB release. SEM (scanning electron microscopy) showed that the canalization of capsules also was well correlated with both sorbitol content and wall thickness. The PMMA-sorbitol-based capsule can potentially be a versatile tool in assuring effective delivery of antibiotics and other substances.     

In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin

Acute renal failure is one of the most frequent effects observed after taking medicine. Such situations have been tardily discovered, given that existing methods for assessing toxicity are not predictive. In this light, the present work evaluated the effects of gentamicin, a form of nephrotoxic drug, on HK‐2 and HEK‐293 cells. By using MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) and flow cytometry, both cells demonstrated that cytotoxicity occurs in a dose‐dependent manner through the processes of apoptosis and cell necrosis. Gene expression analysis showed a relative increase of expression for genes related to cell processes and classic biomarkers, such as TP53, CASP3, CASP8, CASP9, ICAM‐1, EXOC3, KIM‐1, and CST3. A decrease in expression for genes BCL2L1 and EGF was observed. This study, therefore, indicates that, when the methods are used together, gene expression analysis is able to evaluate the nephrotoxic potential of a substance.     

肿瘤治疗中细胞因子递送策略的研究进展

细胞因子多数是由机体免疫细胞和某些非免疫细胞产生的,对细胞的生长、增殖、分化均有调节作用的一类具有生物活性的蛋白质。在肿瘤治疗中,细胞因子作为一种蛋白质药物,具有体内半衰期短、全身毒副作用大等特点,因而选择细胞因子递送策略时需考虑以上因素。文章简要介绍了几种常见的细胞因子,并综述了近年来在肿瘤治疗中细胞因子递送策略的研究进展。