基于聚多巴胺特性构建的肿瘤靶向药物递送系统的研究进展

聚多巴胺(polydopamine, PDA)是受到贻贝中黏附蛋白启发而合成的一种新型聚合物,其具有良好的生物相容性、优异的光热转换性能、黏附性与高化学反应性和多重药物释放响应机制等天然优势,在肿瘤靶向药物递送系统中得到了广泛的应用。本综述就近年来基于PDA构建的药物递送系统在肿瘤靶向中的应用进行了总结,以期为构建更合理、更有效的基于PDA的多功能协同肿瘤治疗平台提供参考。     

聚合物胶束作为药物载体及其在肿瘤靶向方面的研究进展

聚合物胶束具有粒径小、稳定性高、滞留时间长、良好的生物相容性等特点,这些优良性质使得聚合物胶束作为药物载体具有许多独特的优势。近年来,涌现了许多围绕聚合物胶束设计肿瘤靶向给药系统的报道,包括利用肿瘤的病理学性质,设计被动靶向给药系统和对聚合物胶束进行表面修饰,设计主动靶向给药系统。本文主要综述了聚合物胶束作为肿瘤靶向药物载体的研究进展。     

Advances in polymeric micelles for drug delivery and tumor targeting

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α₂-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.From the Clinical EditorThis review summarizes recent developments related to targeted anticancer drug delivery to tumor sites using polymeric micelles via active and passive mechanisms. Polymeric micelles can be conjugated with diverse ligands such as antibodies fragments, epidermal growth factors, α2-glycoprotein, transferrin, folate to target micelles to cancer cells.     

Preparation and characterization of a biodegradable drug targeting system for anticancer drug delivery: microsphere-antibody conjugate

Targeted delivery of anticancer drugs is one of the most actively pursued goals in anticancer chemotherapy. A major disadvantage of anticancer drugs is their lack of selectivity for tumour tissue, which causes severe side effects and results in low cure rates. Any strategy by which a cytotoxic drug is targeted to the tumour, thus increasing the therapeutic index of the drug, is a way of improving cancer chemotherapy and minimizing systematic toxicity. This study covers the preparation of the gelatin microsphere (GM)-anti-bovine serum albumin (anti-BSA) conjugate for the development of a drug targeting approach for anticancer drug delivery. Microspheres of 5% (w/v) gelatin content were prepared by crosslinking with glutaraldehyde (GTA) at 0.05 and 0.50% (v/v) concentration. Microspheres were in the size range of 71-141?microm. The suitability of these microspheres as drug carriers for anticancer drug delivery was investigated in vitro by studying the release profiles of loaded methotrexate (MTX) and 5-fluorouracil (5-FU) and the cytotoxicities on cancer cell lines. The in vitro MTX release profiles (approximately 22-46% released in 24 h depending on the amount of GTA used) were much slower compared to 5-FU (approximately 42-91% released in 24 h). Both drugs demonstrated an initial fast release, which was followed by gradual, sustained drug release. The MTT cytotoxicity test results of GMs loaded with 5-FU and MTX showed approximately 54-70% and approximately 52-67% cytotoxicities in 4 days. In general, incorporation of MTX and 5-FU in microspheres enhanced the cytotoxic effect in a more prolonged manner compared to the free drugs. Gelatin micospheres were chemically conjugated to anti-BSA and the antigen-antibody activities were studied by immunofluorescence. Results indicated approximately 80% binding with conjugated anti-BSA and BSA-FITC. Based on their low cytotoxicity and the high antigen binding efficiencies, anti-BSA conjugated gelatin microspheres could be suitable targeted drug carrier systems for selective and long-term delivery of anticancer drugs to a specific body compartment (i.e. bladder cancer).     

Preparation and characterization of a biodegradable drug targeting system for anticancer drug delivery: Microsphere-antibody conjugate

Targeted delivery of anticancer drugs is one of the most actively pursued goals in anticancer chemotherapy. A major disadvantage of anticancer drugs is their lack of selectivity for tumour tissue, which causes severe side effects and results in low cure rates. Any strategy by which a cytotoxic drug is targeted to the tumour, thus increasing the therapeutic index of the drug, is a way of improving cancer chemotherapy and minimizing systematic toxicity. This study covers the preparation of the gelatin microsphere (GM)-anti-bovine serum albumin (anti-BSA) conjugate for the development of a drug targeting approach for anticancer drug delivery. Microspheres of 5% (w/v) gelatin content were prepared by crosslinking with glutaraldehyde (GTA) at 0.05 and 0.50% (v/v) concentration. Microspheres were in the size range of 71–141 μm. The suitability of these microspheres as drug carriers for anticancer drug delivery was investigated in vitro by studying the release profiles of loaded methotrexate (MTX) and 5-fluorouracil (5-FU) and the cytotoxicities on cancer cell lines. The in vitro MTX release profiles (～22–46% released in 24 h depending on the amount of GTA used) were much slower compared to 5-FU (～42–91% released in 24 h). Both drugs demonstrated an initial fast release, which was followed by gradual, sustained drug release. The MTT cytotoxicity test results of GMs loaded with 5-FU and MTX showed ～54–70% and ～52–67% cytotoxicities in 4 days. In general, incorporation of MTX and 5-FU in microspheres enhanced the cytotoxic effect in a more prolonged manner compared to the free drugs. Gelatin micospheres were chemically conjugated to anti-BSA and the antigen–antibody activities were studied by immunofluorescence. Results indicated ～80% binding with conjugated anti-BSA and BSA-FITC. Based on their low cytotoxicity and the high antigen binding efficiencies, anti-BSA conjugated gelatin microspheres could be suitable targeted drug carrier systems for selective and long-term delivery of anticancer drugs to a specific body compartment (i.e. bladder cancer).     

Recent advances in tumor vasculature targeting using liposomal drug delivery systems

Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).     

Intranasal drug delivery for brain targeting

Many drugs are not being effectively and efficiently delivered using conventional drug delivery approach to brain or central nervous system (CNS) due to its complexity. The brain and the central nervous system both have limited accessibility to blood compartment due to a number of barriers. Many advanced and effective approaches to brain delivery of drugs have emerged in recent years. Intranasal drug delivery is one of the focused delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Realization of nose to brain transport and the therapeutic viability of this route can be traced from the ancient times and has been investigated for rapid and effective transport in the last two decades. Various models have been designed and studied by scientists to establish the qualitative and quantitative transport through nasal mucosa to brain. The development of nasal drug products for brain targeting is still faced with enormous challenges. A better understanding in terms of properties of the drug candidate, nose to brain transport mechanism, and transport to and within the brain is of utmost importance. This review will discuss some pertinent issues to be considered and challenges to brain targeted intranasal drug delivery. A few marketed and investigational drug formulations will also be discussed.     

The application of nitric oxide delivery in nanoparticle-based tumor targeting drug delivery and treatment

Nitric oxide (NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogenous and exogenous stimuli. Then the application of NO donors, which was the main aim of the review, was discussed in detailed according to their functions, including inducing tumor cell apoptosis, reversing tumor multidrug resistance, inhibiting tumor metastasis and improving drug delivery.     

Exploiting M cells for drug and vaccine delivery

The specialised antigen sampling M cells represent an efficient portal for mucosal drug and vaccine delivery. Delivery may be achieved using synthetic particulate delivery vehicles including poly(DL-lactide-co-glycolide) microparticles and liposomes. M cell interaction of these delivery vehicles is highly variable, and is determined by the physical properties of both particles and M cells. Delivery may be enhanced by coating with reagents including appropriate lectins, microbial adhesins and immunoglobulins which selectively bind to M cell surfaces. Live attenuated microorganisms are also suitable as vaccines and mucosal vectors and many, including Salmonella typhimurium, innately target to M cells. After cell surface adhesion, delivery vehicles are rapidly transported across the M cell cytoplasm to underlying lymphoid cells and may subsequently disseminate via the lymphatics. Further definition of M cell development and function should permit exploitation of their high transcytotic capacity for safe and reliable mucosal delivery.     

Non-degradable polymer nanocomposites for drug delivery

INTRODUCTION: The need to optimize therapeutic outcomes while minimizing side effects is a major driving force for research and development in the controlled drug delivery field. Polymer nanocomposites (NCs) are an emerging class of materials with remarkable potential for controlled drug delivery. There are a range of release mechanisms that characterize polymer NC systems, and these may be perturbed not only by the addition of nanofillers, but also by the type of drug and the interactions of the drug with the components of the system. AREAS COVERED: The focus of this review is on non-degradable polymer NC systems. In particular, the types of drug delivery approach from these polymer NCs and the theoretical models developed to describe those approaches are discussed. The importance of component interactions and factors affecting drug delivery from polymer NCs is also addressed. EXPERT OPINION: Despite the remarkable potential and extensive research being conducted on polymer NCs for use in drug delivery, commercialization and large-scale production are limited by the cost and difficulty in consistently producing fully exfoliated NCs. A continuing challenge for the field is to understand better the key interactions and structure-property relationships arising from different polymer, filler and drug combinations.     

Metalloprotease-specific poly(ethylene glycol) methyl ether-peptide-doxorubicin conjugate for targeting anticancer drug delivery based on angiogenesis

This article proposes a novel cancer-targeting drug-delivery system based on angiogenesis, in which the enzymatic activity of type IV collagenases is used to cleave the inactive drug conjugate, thereby activating drug fragments. In this study, the amount and distribution of metalloprotease (MMP)-2 and MMP-9 secreted from Lewis lung carcinoma (LCC) cells and the formation of blood vessels were evaluated by gelatin zymography, in situ film zymography and immunostaining. LLC cells secreted MMP-2 and MMP-9, thereby distributing large amounts of MMPs around a solid tumor. The newly developed blood vessels were also found in a solid LLC tumor. The anticancer drug conjugate (mPEG-GPLGV-DOX) was synthesized by conjugating doxorubicin with Gly-Pro-Leu-Gly-Val (GPLGV) peptide and poly(ethylene glycol) methyl ether (mPEG). GPLGV pentapeptide was used as a substrate for MMP-2 and MMP-9, where the cleavage of Gly-Val bond by MMP was expected. In addition, mPEG was grafted to peptide-doxorubicin conjugate to increase the circulation time in the body and to reduce the cytotoxicity of the anticancer drug. The mPEG-GPLGV-DOX conjugate formed a micelle structure in aqueous solution, with a critical micelle concentration (CMC) of about 0.25 mg/ml and a diameter of 73.1 +/- 12.7 nm at 1 mg/ml. In an in vivo experiment, mPEG-GPLGV-DOX showed 20% chemotherapeutic activity compared with free doxorubicin. Although a 50 mg/kg dose of mPEG-GPLGV-DOX showed similar therapeutic effects to a 10 mg/kg dose of doxorubicin, the life span of mice in the conjugate group was significantly increased. Therefore, an efficient anticancer drug-delivery system could be created by increasing therapeutic efficiency and decreasing drug-toxicity by optimizing the degradation rate of the peptide link by MMP and circulation time in the body.     

Exploiting the enhanced permeability and retention effect for tumor targeting

Of the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of macromolecules is a key mechanism for solid tumor targeting, and considered a gold standard for novel drug design. In this review, we discuss various endogenous factors that can positively impact the EPR effect in tumor tissues. Further, we discuss ways to augment the EPR effect by use of exogenous agents, as well as practical methods available in the clinical setting. Some innovative examples developed by researchers to combat cancer by the EPR mechanism are also discussed.     

A targeting approach for delivery of polymer microparticle-antibody conjugate against Vibrio parahaemolyticus-induced cytotoxicity to human intestinal epithelial cells

A major traditional of antibacterial drugs is antibiotic which promotes more rapid release of the toxins from bacteria cells in human body, which causes severe infection. The thermostable direct hemolysin (TDH) has been proposed as a major virulence factor of Vibrio parahaemolyticus (Vp). This study covers the preparation of polymer microparticle-antibody conjugate for the development of a drug targeting approach for antibacterial drug delivery. The chemical binding of antibodies (ab) to latex bead of 0.2 mum diameter was performed by using a water-soluble carbodiimide technique. Confocal microscopy revealed that the bacteria were strongly absorbed by the latex beads with bound anti-Vp polyclonal antibody (pAb). Treatment with a latex bead bound both anti-Vp pAb and anti-TDH monoclonal antibody (mAb) significantly inhibited bacterial adherence to the Caco-2 cells (p < 0.01), and reduced TDH-induced cytotoxicity in histology. These preliminary results suggest that it may be possible to effectively protect against Vp infection by using this microparticle-antibody conjugate delivery system.     

A targeting approach for delivery of polymer microparticle-antibody conjugate against Vibrio parahaemolyticus-induced cytotoxicity to human intestinal epithelial cells

A major traditional of antibacterial drugs is antibiotic which promotes more rapid release of the toxins from bacteria cells in human body, which causes severe infection. The thermostable direct hemolysin (TDH) has been proposed as a major virulence factor of Vibrio parahaemolyticus (Vp). This study covers the preparation of polymer microparticle-antibody conjugate for the development of a drug targeting approach for antibacterial drug delivery. The chemical binding of antibodies (ab) to latex bead of 0.2 μm diameter was performed by using a water-soluble carbodiimide technique. Confocal microscopy revealed that the bacteria were strongly absorbed by the latex beads with bound anti-Vp polyclonal antibody (pAb). Treatment with a latex bead bound both anti-Vp pAb and anti-TDH monoclonal antibody (mAb) significantly inhibited bacterial adherence to the Caco-2 cells (p < 0.01), and reduced TDH-induced cytotoxicity in histology. These preliminary results suggest that it may be possible to effectively protect against Vp infection by using this microparticle-antibody conjugate delivery system.     

Synthetic polymer systems in drug delivery

The development of synthetic polymers for applications in drug delivery is reviewed, with particular reference to polymers that can be activated to release a medicinal agent in vivo or that can respond to changes in environment to enhance the effectiveness of therapy. The mechanisms by which these polymers are designed to deliver drugs are highlighted, along with the challenges facing synthetic chemists and pharmaceutical scientists in designing new and more active therapeutic vehicles. Currently, synthetic materials with biomimetic properties are attracting growing attention as possible new dosage formulations and the potential applications of these increasingly sophisticated polymers in cell-specific drug targeting and in the emerging field of gene therapy are also considered. Finally, the potential development issues for delivery of therapeutics using active or 'smart' polymers are discussed with an analysis of the future trends in this rapidly expanding area of research.     

经鼻脑靶向递药系统的研究进展

鼻腔与脑在解剖生理上的独特联系使得鼻腔给药作为脑内递药途径成为可能.鼻腔给药作为脑靶向的途径之一,可有效地使通过其他给药途径不易透过血脑屏障的药物绕过血脑屏障到达脑部,为中枢神经系统疾病的治疗提供了一种极有发展前景的脑内递药途径.就鼻腔给药脑靶向的依据、影响因素、评价方法、剂型等方面对经鼻脑靶向递药系统的研究现状进行总结.     

经鼻脑靶向给药系统研究进展

由于血脑屏障的存在,血液中的药物难以进入中枢神经系统.近些年研究表明,经鼻腔给药后,药物可以绕过血脑屏障直接进入脑部,而且其对机体的损伤和副作用都较小,因此经鼻脑靶向给药系统不断受到更多人的关注.首先探讨了药物经鼻入脑的通路及机制,并针对鼻腔给药的不同影响因素提出了相应的优化方案,还介绍了脑靶向性的评价方法,为进一步研究鼻脑靶向制剂提供了参考.     

Anti-P-glycoprotein conjugated nanoparticles for targeting drug delivery in cancer treatment

Targeting therapeutics to specific sites can enhance the efficacy of drugs, reduce required doses as well as unwanted side effects. In this work, using the advantages of the specific affinity of an immobilized antibody to membrane P-gp in two different nanoparticle formulations were thus developed for targeted drug delivery to multi-drug resistant cervical carcinoma (KB-V1) cells. Further, this was compared to the human drug sensitive cervical carcinoma cell line (KB-3-1) cells. The two nanoparticle preparations were: NP1, anti-P-gp conjugated with poly (DL-lactic-coglycolic acid) (PLGA) nanoparticle and polyethylene glycol (PEG); NP2, anti-P-gp conjugated to a modified poloxamer on PLGA nanoparticles. The cellular uptake capacity of nanoparticles was confirmed by fluorescent microscopy. Comparing with each counterpart core particles, there was a higher fluorescence intensity of the targeted nanoparticles in KBV1 cells compared to KB-3-1 cells suggesting that the targeted nanoparticles were internalized into KB-V1 cells to a greater extent than KB-3-1 cell. The results had confirmed the specificity and the potential of the developed targeted delivery system for overcoming multi-drug resistance induced by overexpression of P-gp on the cell membrane.     

Advances in lipid nanodispersions for parenteral drug delivery and targeting

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release. Thus, there is growing need to expand the array of targetable lipid-based systems to deliver a wide variety of drugs and produce stable formulations which can be easily manufactured in a sterile form, are cost-effective and at least as safe and efficacious as the earlier developed systems. These advanced parenteral lipid-based systems are at various stages of preclinical and clinical development which include nanoemulsions, nanosuspensions and polymeric phospholipid micelles. This review article will showcase these parenteral lipid nanosystems and discuss advances in relation to formulation development, processing and manufacturing, and stability assessment. Factors controlling drug encapsulation and release and in vivo biodistribution will be emphasized along with in vitro/in vivo toxicity and efficacy case studies. Emerging lipid excipients and increasing applications of injectable lipid nanocarriers in cancer chemotherapy and other disease indications will be highlighted and in vitro/in vivo case studies will be presented. As these new parenteral lipid systems advance through the clinic and product launch, their therapeutic utility and value will certainly expand.