载药聚合物胶束的制备和肿瘤靶向性研究进展

聚合物胶束具有增溶难溶性药物、选择性靶向、P-gp抑制以及改变药物摄取途径等特点,作为药物传递系统具有广泛的应用前景。本文着重综述载药聚合物胶束的制备方法与肿瘤靶向策略的研究现状及进展。     

聚合物胶束作为肿瘤靶向给药载体的研究

聚合物胶束是近年来出现的一种新型胶态药物载体,具有很多优良的性能,如体内外稳定性高、良好的生物相容性、难溶性药物的增溶作用等.它可以作为靶向肿瘤的给药载体,通过多种机制,如环境响应的聚合物胶束、特异性配基耦合的聚合物胶束、免疫聚合物胶束、通透性增强与滞留(EPR)效应、肿瘤的血管系统等途径来实现药物靶向给药.现主要讨论肿瘤给药的靶向策略和聚合物胶束作为靶向肿瘤给药载体的研究进展.     

Actively targeted nanocarriers for drug delivery to cancer cells

Introduction: Progressive breakthroughs in nanomedicine have been instrumental for the clinical translation of actively targeted drug-delivery approaches. Besides storing large payloads of drugs within the nanoparticle core, the conjugation of targeting moieties confers specific targeting ability to the nanoplatforms. In this respect, clinical results suggest that actively targeted nanocarriers can exhibit an overall improved antitumor efficacy, minimizing off-target toxicity.

Areas covered: This review article summarizes the advances in active targeting of nanocarriers to cancer cells. Specifically, we discuss the various types of nanocarriers, describe the receptors that are frequently overexpressed in solid tumors, and discuss how this approach can be used to improve clinical outcomes. We particularly focus on ongoing clinical trials of actively targeted nanoparticles that are yet to be clinically approved.

Expert opinion: Further investment in active targeting will likely pose clinical benefits. We envisage a future requiring the use of longitudinal measures in the clinical setting to profile the patients that are likely to benefit from actively targeted nanocarriers. At the preclinical stage, a complete picture of intratumoral barriers combined with a quantitative approach of the intratumoral fate of nanomaterials will be instrumental in defining more effective strategies to improve their clinical translation.     

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。     

Polymeric micelles as a new drug carrier system and their required considerations for clinical trials

Importance of the field: A polymeric micelle is a macromolecular assembly composed of an inner core and an outer shell, and most typically is formed from block copolymers. In the last two decades, polymeric micelles have been actively studied as a new type of drug carrier system, in particular for drug targeting of anticancer drugs to solid tumors.

Areas covered in this review: In this review, polymeric micelle drug carrier systems are discussed with a focus on toxicities of the polymeric micelle carrier systems and on pharmacological activities of the block copolymers. In the first section, the importance of the above-mentioned evaluation of these properties is explained, as this importance does not seem to be well recognized compared with the importance of targeting and enhanced pharmacological activity of drugs, particularly in the basic studies. Then, designs, types and classifications of the polymeric micelle system are briefly summarized and explained, followed by a detailed discussion regarding several examples of polymeric micelle carrier systems.

What the reader will gain: Readers will gain a strategy of drug delivery with polymeric carriers as well as recent progress of the polymeric micelle carrier systems in their basic studies and clinical trials.

Take home message: The purpose of this review is to achieve tight connections between the basic studies and clinical trials.     

Block copolymer micelles as a solution for drug delivery problems

Micelles, nanosized colloidal particles with a hydrophobic core and hydrophilic shell, can be successfully used for the solubilisation of various poorly soluble pharmaceuticals, and demonstrate a series of attractive properties as drug carriers. Polymeric micelles, such as micelles formed by amphiphilic block copolymers, are of a special interest as they possess high stability both invitro and invivo, and good biocompatibility. Drug-loaded micelles can spontaneously accumulate in body areas with compromised vasculature (tumours, infarcts) via the enhanced permeability and retention (EPR) effect. Micelles made of stimuli-responsive (pH- or temperature-sensitive) amphiphilic block copolymers can release their contents in pathological areas demonstrating hyperthermia or acidosis. Various specific targeting ligand molecules, such as antibodies, can be attached to the micelle surface and bring drug-loaded micelles to, and into, target cells (cancer cells being a primary target). Micelles carrying various reporter (contrast) groups may become the imaging agents of choice in different imaging modalities. This review will consider some recent trends in using micelles as pharmaceutical carriers.     

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting

Abstract

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.     

Polymeric micelles as drug carriers: their lights and shadows

Abstract

In this review, polymeric micelles as drug-targeting carriers are concisely explained. In the first introduction part, I describe a brief history of polymer micelle’s research for drug targeting, and then I explain this review’s focus. Since most other review articles concerning polymeric micelle carriers explain only what was achieved in the polymeric micelle’s research, I describe this review by focusing on what was not done. In the second part, I take up three characteristics of polymeric micelle carriers by comparing their advantages and disadvantages, what was done and what was not done in the past studies, and what is easily achieved and what is difficult to be achieved with polymeric micelles. In the last part, I discuss three common problems of nano-sized drug carrier systems including polymeric micelles, and then I add a few comments on these problems.     

Polybutylcyanoacrylate nanocarriers as promising targeted drug delivery systems

Among the materials for preparing the polymeric nanocarriers, poly(n-butylcyanoacrylate) (PBCA), a polymer with medium length alkyl side chain, is of lower toxicity and proper degradation time. Therefore, PBCA has recently been regarded as a kind of widely used, biocompatible, biodegradable, low-toxic drug carrier. This review highlights the use of PBCA-based nanocarriers (PBCA-NCs) as targeting drug delivery systems and presents the methods of preparation, the surface modification and the advantages and limitations of PBCA-NCs. The drugs loaded in PBCA-NCs are summarized according to the treatment of diseases, and the different therapeutic applications and the most recent developments of PBCA-NCs are also discussed, which provides useful guidance on the targeting research of PBCA-NCs.     

脂质类纳米载体在难溶性药物递送中的应用

随着新技术在药物研发中的广泛应用,大量有活性的难溶性候选药物涌现出来,但水溶性差的问题又严重制约了此类药物的开发。目前纳米载体作为难溶性药物递送系统的研究日益增多。本文综述了微乳、脂肪乳、脂质体、固体脂质纳米粒、纳米脂质载体、脂质纳米混悬剂和仿生载体等脂质类纳米载体在难溶性药物递送中的应用,旨在为产品的开发提供新策略。     

Stabilized polymeric micelles by electrostatic interactions for drug delivery system

Methoxy poly(ethylene glycol)-block-oligo(l-aspartic acid)-block-poly(-caprolactone) with four aspartic acid groups was synthesized with a molecular weight and M_w/M_n of 8930 and 1.22. Polymeric micelles were formed by dialysis and stabilized by electrostatic interactions between the carboxylic acid groups and calcium cations. The critical micelle concentration of mPEG–Asp–PCL was determined to be 0.078 mg/mL. At 0.02 mg/mL, the dissociation of micelles without ionic stabilization formed an opaque, phase-separated solution, while the stabilized micelles under the same conditions showed structural stability through ionic stabilization. The paclitaxel-loading and efficiency were 8.7% and 47.6%, respectively, and the drug loading increased the mean diameter from 73.0 nm to 87 nm, which was increased further to 96 nm after ionic fixation. Rapid releases of approximately 65% of the encapsulated paclitaxel from a non-stabilized micelle and 45% from a stabilized micelle were observed in the first 24 h at pH 7.4 in a PBS solution containing 0.1 wt% Tween 80. The stabilized micelles then showed a sustained, slow release pattern over a couple of weeks, while the profile from the non-stabilized micelles reached a plateau at approximately 75% after 50 h. The enhanced micelle stability independent of concentration through ionic stabilization opens a way for preparing long circulating delivery systems encapsulating water-insoluble drugs.     

The potential of magneto-electric nanocarriers for drug delivery

Introduction: The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery.

Areas covered: This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood?brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted.

Expert opinion: Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical–magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.     

Nanodiamonds as vehicles for systemic and localized drug delivery

Owing to their exceptional biocompatibility and unique surface properties, nanodiamonds (NDs) are shown to be a progressively promising nanomaterial for drug delivery. In this article, NDs as a platform for a host of biomedical applications are described, with an emphasis on cancer therapy, ranging from systemic modalities to primary constituents within polymer hybrid microfilms. Experimental results and theoretical explanations of ND–drug dynamics are compared. Water-dispersion of previously insoluble therapeutics when complexed with NDs demonstrates great promise in expanding current drug delivery options. Various forms of incorporating NDs within microfilms as a localized drug release coating and implant are also discussed.     

Stents as a platform for drug delivery

Introduction: Drug delivery stents have proved their efficacy at preventing coronary restenosis and their potential in treating the occlusion or stricture of other body passageways, such as peripheral vessels and alimentary canals. The drug delivery systems on such stent platforms contribute to this improved therapeutic efficacy by providing improved drug delivery performance, along with reduced concerns encountered by current stents (e.g., in-stent restenosis, late thrombosis and delayed healing).

Areas covered: A wide variety of drug delivery stents (metallic drug-eluting stents, absorbable drug-eluting stents, and polymer-free drug-eluting stents for coronary and other applications) that are commercially available or under investigation are collected and summarized in this review, with emphasis on their drug delivery aspects. This review also gives insights into the progression of stent-based drug delivery strategies for the prevention of stent-related problems, or the treatment of local diseases. In addition, a critical analysis of the advantages and challenges of such strategies is provided.

Expert opinion: With an in-depth understanding of drug properties, tissue/organ biology and disease conditions, stent drug delivery systems can be improved further, to endow the stents with better efficacy and safety, along with lower toxicity. There is also a great need for stents that can simultaneously deliver multiple drugs, to treat complex diseases from multiple aspects, or to treat several diseases at the same time. Drug release kinetics greatly determines the stent performance, thus effective strategies should also be developed to achieve customized kinetics.     

Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery

Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it’s potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.     

Nanoparticles as drug delivery systems

Controlled drug delivery systems (DDS) have several advantages compared to the traditional forms of drugs. A drug is transported to the place of action, hence, its influence on vital tissues and undesirable side effects can be minimized. Accumulation of therapeutic compounds in the target site increases and, consequently, the required doses of drugs are lower. This modern form of therapy is especially important when there is a discrepancy between the dose or the concentration of a drug and its therapeutic results or toxic effects. Cell-specific targeting can be accomplished by attaching drugs to specially designed carriers. Various nanostructures, including liposomes, polymers, dendrimers, silicon or carbon materials, and magnetic nanoparticles, have been tested as carriers in drug delivery systems. In this review, the aforementioned nanocarriers and their connections with drugs are analyzed. Special attention is paid to the functionalization of magnetic nanoparticles as carriers in DDS. Then, the advantages and disadvantages of using magnetic nanoparticles as DDS are discussed.     

Extracellularly activatable nanocarriers for drug delivery to tumors

Introduction: Nanoparticles (NPs) for drug delivery to tumors need to satisfy two seemingly conflicting requirements: they should maintain physical and chemical stability during circulation and be able to interact with target cells and release the drug at desired locations with no substantial delay. The unique microenvironment of tumors and externally applied stimuli provide a useful means to maintain a balance between the two requirements.

Areas covered: We discuss nanoparticulate drug carriers that maintain stable structures in normal conditions but respond to stimuli for the spatiotemporal control of drug delivery. We first define the desired effects of extracellular activation of NPs and frequently used stimuli and then review the examples of extracellularly activated NPs.

Expert opinion: Several challenges remain in developing extracellularly activatable NPs. First, some of the stimuli-responsive NPs undergo incremental changes in response to stimuli, losing circulation stability. Second, the applicability of stimuli in clinical settings is limited due to the occasional occurrence of the activating conditions in normal tissues. Third, the construction of stimuli-responsive NPs involves increasing complexity in NP structure and production methods. Future efforts are needed to identify new targeting conditions and increase the contrast between activated and nonactivated NPs while keeping the production methods simple and scalable.