Regenerative inductive therapy based on DDS technology of protein and gene

Recent development of biomedical engineering including biomaterials and drug delivery system (DDS) as well as basic biology and medicine has enabled cells to induce regeneration repairing of defective tissues as well as substitute the biological functions of damaged organs. For successful tissue regeneration, it is undoubtedly indispensable to give cells a local environment which allows cells to efficiently promote their proliferation and differentiation and consequently induce cell-based tissue regeneration. Tissue engineering is one of the biomedical forms to create this regeneration environment of cells. The tissue and organ repairing based on their regeneration induction has been realized by combining cells with the tissue engineering technology or methodology in a surgical or internally medical manner. This paper overviews the present status and future direction of tissue engineering for regenerative inductive therapy, briefly explaining the key technology of tissue engineering, especially DDS of growth factor and gene.     

How controlled release technology can aid gene delivery

Introduction: Many types of gene delivery systems have been developed to enhance the level of gene expression. Controlled release technology is a feasible gene delivery system which enables genes to extend the expression duration by maintaining and releasing them at the injection site in a controlled manner. This technology can reduce the adverse effects by the bolus dose administration and avoid the repeated administration. Biodegradable biomaterials are useful as materials for the controlled release-based gene delivery technology and various biodegradable biomaterials have been developed.

Areas covered: Controlled release-based gene delivery plays a critical role in a conventional gene therapy and genetic engineering. In the gene therapy, the therapeutic gene is released from biodegradable biomaterial matrices around the tissue to be treated. On the other hand, the intracellular controlled release of gene from the sub-micro-sized matrices is required for genetic engineering. Genetic engineering is feasible for cell transplantation as well as research of stem cells biology and medicine.

Expert opinion: DNA hydrogel containing a sequence of therapeutic gene and the exosome including the individual specific nucleic acids may become candidates for controlled release carriers. Technologies to deliver genes to cell aggregates will play an important role in the promotion of regenerative research and therapy.     

Significance of release technology in tissue engineering

Regenerative medical therapy has been expected to compensate for the therapeutic disadvantages of reconstructive surgery and organ transplantation, as well as offering a new therapeutic strategy. The objective of regenerative medical therapy is to induce the repair of defective tissues based on the natural healing potential of patients. For successful tissue regeneration, it is indispensable to provide cells with a local environment of artificial extracellular matrix where they can proliferate and differentiate efficiently. Tissue engineering is the key to this regeneration environment; release technology often enhances the in vivo stability of growth factors and related genes and prolongs the maintenance of biological functions for tissue regeneration.     

多糖及其衍生物在药物传递系统中的应用研究新进展

多糖是一类生物相容性好、无毒、非免疫原性的生物材料,现已广泛应用于药物传递系统。综述海藻酸盐、几丁质、葡聚糖、透明质酸和肝素等多糖及其衍生物的理化和生物学特性以及在药物传递系统中的应用进展。     

Analysis of the Postoperative Periarticular Environment and Influence on Sustained Drug Delivery From a Gel Formulation

Regional intraarticular delivery of local anesthetics is effective in treating postoperative pain following total knee or hip replacement. Recent research efforts have been only partially successful in achieving sustained release of the analgesic agent, in part due to limited understanding of the biological environment into which these formulations are administered. This study aimed to detail the composition and properties of postoperative periarticular fluid (PO-PAF). PO-PAF was collected from 8 patients, and the composition and physicochemical properties were determined. A number of components were identified which are lacking from phosphate buffered saline (PBS) or other synthetic media. The differences in composition led to variation in the physicochemical properties of PO-PAF compared with PBS. Notably, significantly lower surface tension (p <0.05) and higher buffer capacity (p <0.05) were observed in the biological fluid. We demonstrated that the solubility of lidocaine is almost double in PO-PAF compared to PBS (p <0.05) and that lidocaine release from a poloxamer gelling system occurred faster into PO-PAF under both sink and nonsink conditions. Collectively, these data indicate PBS is inappropriate for the in vitro evaluation of intraarticular drug delivery systems. The presented data describe that PO-PAF and will support the future development of biorelevant media to ultimately improve in vivo–in vitro correlation.     

口服结肠释药系统的研究进展

目的:综述近年来口服结肠释药系统临床和药学研究动态,为今后在此领域的研究和临床应用提供参考。方法:通过对国内外相关文献资料的整理,对比和分析,总结口服结肠释药系统制剂进展和临床应用的发展方向。结果结论:口服结肠释药系统是通过口服给药,在结肠处定位释放药物的靶向制剂。此类制剂以其靶向释药方式和独特的临床使用价值,越来越广泛地引起了临床医生的关注,同时也成为药学研究领域的一大热点。     

Porous silicon based intravitreal platform for dual-drug loading and controlled release towards synergistic therapy

The number of blind and low vision persons in the US is projected to increase to 5.68 million by 2020. The eye diseases causing loss of vision are life-long, chronic, and often need protracted presence of therapeutics at the disease site to keep the disease in remission. In addition, multiple pathologies participate in the disease process and a single therapy seems insufficient to bring the disease under control and prevent vision loss. This study demonstrates the use of porous silicon (pSi) particles sequentially loaded with daunorubicin (DNR) and dexamethasone (DEX) to create a synergistic intravitreally injectable dual-drug delivery system. DEX targets chronic inflammation while DNR inhibits excessive cell proliferation as well as suppresses hypoxia-inducible factor 1 to reduce scarring. This pSi-based delivery system releases therapeutic concentrations of DNR for 100?days and DEX for over 165?days after a single dose. This intravitreal dual-drug delivery system is also well tolerated after injection into the rabbit eye model, attested by ocular biomicroscopy, ocular tonometry, electroretinography, and histology. This novel dual-drug delivery system opens an attractive modality for combination therapy to manage refractory chorioretinal diseases and further preclinical studies are warranted to evaluate its efficacy.     

Recent developments in cationic lipid-mediated gene delivery and gene therapy

Gene therapy will revolutionize medicine, helping us to cure and prevent diseases at their core level. Until becoming a widespread reality, the problem of efficient gene transfer and expression (transfection) must be solved. Cationic lipids represent a safer alternative than viral vectors, which, although more efficient, have the drawback of immunogenicity and propagation risks. Additionally, cationic lipids and cationic liposomes allow the delivery of larger plasmids and may be GMP manufactured and stored in bulk quantities. However, their specific transfection efficiency must be improved in order to reach the performance of biological vectors. In recent years, new structures have been released and tested, with designs adapted to recent findings in lipid-mediated transfection mechanisms. Another trend is the increased use of natural, biodegradable, building blocks in the backbone of these compounds. Here we review the very recent developments in the field of cationic lipids, both from industry and academia. Physicochemical characteristics, insights of transfection mechanisms, as well as therapeutic applications are also presented. Finally, some future prospects and trends are proposed.     

我国药剂学基础研究的热点领域和基本思路简析

通过对国家自然科学基金委员会近10余年来在药剂学基础研究方面的资助项目的总结，分析和探讨了我国药剂学基础研究中的热点领域和基本思路，并进行回顾和反思。     

Therapeutic applications of hydrogels in oral drug delivery

Introduction: Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications.

Areas covered: This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed.

Expert opinion: Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.     

Biodegradable polymers: an update on drug delivery in bone and cartilage diseases

ABSTRACT

Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair.

Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering.

Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.     

基于外泌体的抗肿瘤药物靶向递送的研究进展

外泌体是生命体内细胞进行信息传递的重要方式之一,主要的生理病理过程均离不开外泌体的参与,包括细胞耐药、感染传播、肿瘤发展和心血管疾病等。外泌体的生物学职能使其天然具有免疫原性低、递送效率高、可跨过多种生物屏障和具有靶向性等特点,这些优点也促使人们尝试将其用作药物递送载体,以克服一些药物稳定性差、溶解度低、生物利用度不足和毒性较高的缺点。本文介绍了外泌体在抗肿瘤药物递送方面的最新研究进展,包括小分子化疗药物、生物大分子和核酸类药物的递送,还讨论了外泌体的提取、载药及改造方法,并对其应用前景进行了展望。     

Calcein Release from Polymeric Vesicles in Blood Plasma and PVA Hydrogel

Purpose  The main goal of this study was to show the long-term stability of vesicles from poly(2-methyl oxazoline-block-polydimethylsiloxane-block poly(2-methyl oxazoline) (PMOXA-PDMS-PMOXA) in PBS, blood plasma and the feasibility to use these vesicles for drug release from PVA hydrogels. Methods  The vesicle formation properties and loading efficiency was evaluated using fluorescent dyes. The stability of the vesicles was evaluated in buffer at pH 7 at room temperature and in 50% blood plasma at 37°C. The calcein loaded vesicles were dispersed in a UV crosslinked PVA hydrogel. The stability of the vesicles in the hydrogel was observed over one week, before the vesicles were ruptured with Triton X-100. Results  The vesicles are very stable in buffer, blood plasma, and the PVA hydrogel. In plasma 50% of the calcein is released in 48 h in the presence of sodium azide. The vesicles can be evenly dispersed in PVA and are stable. The release can be triggered and the calcein diffuses afterwards quickly throughout the gel. Conclusion  Polymeric vesicles can be used as diffusion barrier in hydrogels for the controlled release of water soluble drugs. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Application of pectin in oral drug delivery

Introduction: Biopolymers have been used extensively in the pharmaceutical field. Pectin, a biopolymer, has several unique properties that enable it to be used as an excipient or carrier for oral drug delivery systems. Accordingly, several investigators have identified the benefits of pectin-based delivery systems for oral drug administration.

Areas covered: This review first describes the chemical structure, source and production, degree of esterification and gel formation properties of pectin. The application of pectin in various oral drug delivery platforms is also discussed, that is, controlled release systems, gastro-retentive systems, colon-specific delivery systems and mucoadhesive delivery systems.

Expert opinion: Pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in delivery characteristics. Scintigraphic studies and in vivo studies, in both animals and human volunteers, demonstrate the successful development of a pectin-based colon-specific drug delivery system. Pectin-based controlled release systems, gastro-retentive systems and mucoadhesive systems present promising approaches for increasing the bioavailability of drugs, but are in their infancy. A lack of direct correlation between in vitro release and in vivo absorption studies is a major concern with these systems.     

Localized,non-viral delivery of nucleic acids: Opportunities,challenges and current strategies

Localized delivery of drugs is an emerging field both with regards to drug delivery during disease as well as in tissue engineering. Despite significant achievements made in the last decades, the efficient delivery of proteins and peptides remains challenging, especially in cases requiring long-term release of proteins after application. The localized delivery of nucleic acids (NA) represents an interesting alternative due to higher physicochemical stability of NA, increased efficiency by harnessing cells as bioreactors for the production of required proteins and improved versatility with regards to expression of specific proteins through plasmid DNA or repression of gene products through siRNA. However, unlike most proteins and peptides, NA must be delivered to the cytoplasm or nucleus to be efficacious, resulting in significant delivery challenges. We herein describe frequently used non-viral vectors for the delivery of NA including polyplexes, lipoplexes and lipopolyplexes and summarize recent developments in the field of nucleic acid delivery systems for local application based on hydrogels, solid scaffolds and physical delivery methods. The challenges associated with the different approaches are identified and options to address these challenges are discussed.     

In vitro and in vivo assessment of polymer microneedles for controlled transdermal drug delivery

Microneedles (MNs) system for transdermal drug delivery has the potential to improve therapeutic efficacy, proving an approach that is more convenient and acceptable than traditional medication systems. This study systematically researched dissolving polymer MNs fabricated from various common FDA-approved biocompatible materials, including gelatine, chitosan, hyaluronic acid (HA) and polyvinyl alcohol (PVA). Upon application of MN patches to the porcine cadaver skin, the MNs effectively perforated the skin and delivered drugs to subcutaneous tissue on contact with the interstitial fluid. Both the in vitro and in vivo drug release tests showed the similar trends but different release rates among the prepared MNs. Interestingly, the drug-release kinetics of PVA MNs were able to be altered by changing the molecular weight. To evaluate the feasibility using the proposed MNs for treating diabetes, an in vivo insulin absorption study in diabetic mice was performed. The results showed different insulin release properties of MNs fabricated from various kinds of polymer, leading to different decrease in blood glucose levels. We made a systematic and comprehensive study of some drug-loaded polymer MNs, and anticipated that dissolving polymer MNs have potential to improve therapeutic efficacy through controlled drug release.     

pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.     

抗生素新剂型新技术研究进展

随着现代科学与技术的长足进步,新辅料、新设备、新技术和新理论的不断涌现,抗生素的新剂型研究呈现出更广阔的前景,使得抗生素类药物的使用更有效、更安全、更方便、更好地满足临床用药需求.本文综述了速释、缓控释、靶向、经皮给药途径及复方制剂在抗生素新剂型新技术研究中的应用进展,为今后抗生素新剂型的开发提供新的思路.