Targeted cancer drug delivery with aptamer-functionalized polymeric nanoparticles

Abstract

Based on exceptional advantages of aptamers, increasing attention has been presented in the utilise of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer-targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual’s tumour to the development of personalised medicine seems to be needed.     

叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

Hydrophobically modified carboxymethyl chitosan nanoparticles targeted delivery of paclitaxel

Specific targeting of tumor cells to achieve higher drug levels in tumor tissue and to overcome the side effects is the major goal in cancer therapy. Nanoparticles encapsulating a hydrophobic core in their nanoreservoir structure were developed as a carrier for a water-insoluble drug, paclitaxel. In the present study, target-oriented nanoparticles based on biodegradable O-carboxymethyl chitosan modified with stearic acid. The surface of the nanoparticles was modified by covalent attachment of folic acid (FA) by simple carbodimide reaction to achieve tumor cell targeting property. Nanoparticles were prepared by the sonication method without involving any surfactants/emulsifiers. The nanoparticles were characterized by various state-of-the-art techniques, including laser light scattering for particles size distribution, field emission scanning electron microscopy and transmission electron microscope for surface morphology. The drug release property and the cytotoxicity of the drug loaded nanoparticles to both cancerous and noncancerous cells were evaluated in cell culture system. To our knowledge, this is the first study demonstrating a FA modified hydrophobically chitosan with paclitaxel-loaded nanoparticles targeting of folate receptor overexpressing cancer cells.     

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.     

Application of hyaluronic acid as carriers in drug delivery

Hyaluronic acid has good biocompatibility, biodegradability, and nonimmunogenicity. In addition, it has the ability to recognize specific receptors that are overexpressed on the surface of tumor cells, and cancer drugs can be targeted to the tumor cells to better kill them. Therefore, hyaluronic acid has attracted much attention as drug delivery vehicle. Herein, the application of hyaluronic acid as carrier in drug delivery was analyzed and summarized in detail. It showed that hyaluronic acid would have broad prospects for drug delivery.     

Nanoparticles as delivery carriers for anticancer prodrugs

Introduction: Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies.

Areas covered: This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review.

Expert opinion: More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.     

Magnetic iron oxide nanoparticles for drug delivery: applications and characteristics

Introduction: For many years, the controlled delivery of therapeutic compounds has been a matter of great interest in the field of nanomedicine. Among the wide amount of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) stand out from the crowd and constitute robust nanoplatforms since they can achieve high drug loading as well as targeting abilities stemming from their remarkable properties (magnetic and biological properties). These applications require precise design of the nanoparticles regarding several parameters which must be considered together in order to attain highest therapeutic efficacy.

Areas covered: This short review presents recent developments in the field of cancer targeted drug delivery using magnetic nanocarriers as drug delivery systems.

Expert opinion: The design of nanocarriers enabling efficient delivery of therapeutic compounds toward targeted locations is one of the major area of research in the targeted drug delivery field. By precisely shaping the structural properties of the iron oxide nanoparticles, drugs loaded onto the nanoparticles can be efficiently guided and selectively delivered toward targeted locations. With these goals in mind, special attention should be given to the pharmacokinetics and in vivo behavior of the developed nanocarriers.     

Current trends in chemical modifications of magnetic nanoparticles for targeted drug delivery in cancer chemotherapy

Abstract

Nowadays, magnetic nanoparticles (MNPs) have been rapidly investigated and attracted worldwide attention due to their great potential as mediators of heat for treating hyperthermia and their possibility to deliver drugs at specific locations, which can thereby limit systematic effects. Cancer therapy via MNPs proposes novel properties rather than normal methods such as almost zero side effects and a high-efficiency rate of effectiveness. The key aim of targeted drug delivery is to reduce side effects of the main cancer treatment that other usual chemotherapies will attend to the body, and thus controlling the effectiveness of the drug on a specific location that tumoral tissue exist. Herein, the high potential of MNPs has been studied, and different examples of their effectiveness on drug delivery and hypothermia therapy have been provided.     

自组装药物传递系统

自组装药物传递系统（SADDS）是基于药质体提出的新概念和新给药系统,融合了前药、分子自组装和纳米技术,是两亲前药形成的自组装纳米体系。其突出的特点是自组装体几乎没有辅料的参与,载药量大,稳定性好,在体内可获得靶向、控释效果,特别适合于抗病毒和抗肿瘤治疗。SADDS是学科交叉的产物,是药剂学研究的新方向。本文阐述了SADDS概念的来源、特点和研究进展,并展望了SADDS的研究前景。     

Development and characterization of hyaluronic acid decorated PLGA nanoparticles for delivery of 5-fluorouracil

The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of ^99mTc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.     

细胞膜仿生纳米技术在肿瘤靶向递药系统中的研究进展

纳米技术的发展为构建安全高效、精准可控的药物递送系统(drug delivery system, DDS)提供了可能。其中,有机或无机合成纳米载体已被广泛报道并用于肿瘤治疗药物的递送,但部分载体存在易被机体内免疫系统清除、制备过程繁琐和体内安全性较差等问题。近年来,随着生物医学的发展,基于仿生技术的生物膜介导的纳米药物递送系统,因其有机整合了天然生物膜的低免疫原性、肿瘤靶向性和智能纳米载体设计的可调控性、多功能性,有望实现纳米技术在肿瘤靶向治疗上的新突破。本文基于细胞膜仿生技术和纳米医学在肿瘤治疗领域的最新进展,从细胞膜仿生纳米技术的实验基础、膜仿生纳米递药平台的分类和在肿瘤靶向治疗上的应用三方面进行阐述,旨在为仿生智能DDS的设计及其在肿瘤靶向治疗中的发展提供参考。     

Fluorocarbon nanoparticles as multifunctional drug delivery vehicles

The history and current status of fluorocarbon nanoparticles in biomedicine is briefly reviewed. The deficiencies of current fluorocarbon nanoparticle formulations are highlighted. Strategies to remedy such deficiencies and to functionalize fluorocarbon nanoparticles are presented. Potential applications of fluorocarbon nanoparticles as multifunctional drug delivery vehicles are discussed. The strength of fluorocarbon nanoparticles as drug delivery vehicles is that they integrate drug delivery with non-invasive MR imaging so that the biodistribution of the pharmaceutical entity (drug+delivery vehicle) can be monitored in real time. This, in turn, permits the physician to adjust treatment plan for each patient based on his/her actual response to the ongoing treatment.     

Cell-mediated drug delivery

Introduction: Drug targeting to sites of tissue injury, tumor or infection with limited toxicity is the goal for successful pharmaceutics. Immunocytes (including mononuclear phagocytes (dendritic cells, monocytes and macrophages), neutrophils and lymphocytes) are highly mobile; they can migrate across impermeable barriers and release their drug cargo at sites of infection or tissue injury. Thus, immune cells can be exploited as Trojan horses for drug delivery.

Areas covered: This paper reviews how immunocytes laden with drugs can cross the blood–brain or blood–tumor barriers to facilitate treatments for infectious diseases, injury, cancer, or inflammatory diseases. The promises and perils of cell-mediated drug delivery are reviewed, with examples of how immunocytes can be harnessed to improve therapeutic end points.

Expert opinion: Using cells as delivery vehicles enables targeted drug transport and prolonged circulation times, along with reductions in cell and tissue toxicities. Such systems for drug carriage and targeted release represent a new disease-combating strategy being applied to a spectrum of human disorders. The design of nanocarriers for cell-mediated drug delivery may differ from those used for conventional drug delivery systems; nevertheless, engaging different defense mechanisms in drug delivery may open new perspectives for the active delivery of drugs.     

Targeted nanoparticle-based drug delivery and diagnosis

Nanotechnology, or systems/device manufacture at sizes generally ranging between 1 and 100 nm, is a multidisciplinary scientific field undergoing explosive development. The genesis of nanotechnology can be traced to advances in medicine, communications, genomics and robotics. One of the greatest values of nanotechnology will be in the development of new and effective medical treatments (i.e. nanomedicine). This review focuses on the potential of nanomedicine as it relates to the development of nanoparticles for enabling and improving the targeted delivery of therapeutic and diagnostic agents. We highlight the use of nanoparticles for specific intra-compartmental analysis using the examples of delivery to malignant cancers, to the central nervous system, and across the gastrointestinal barriers.     

Chitosan-based nanoparticles as drug delivery systems: a review on two decades of research

Abstract

Chitosan (CS) is one of the most functional natural biopolymer widely used in the pharmaceutical field due to its biocompatibility and biodegradability. These privileges lead to its application in the synthesis of nanoparticles for the drug during the last two decades. This article gives rise to a general review of the different chitosan nanoparticles (CSNPs) preparation techniques: Ionic gelation, emulsion cross-linking, spray-drying, emulsion-droplet coalescence method, nanoprecipitation, reverse micellar method, desolvation method, modified ionic gelation with radial polymerisation and emulsion solvent diffusion, from the point of view of the methodological and mechanistic aspects involved. The physicochemical behaviour of CSNPs including drug loading, drug release, particles size, zeta potential and stability are briefly discussed. This review also directs to bring an outline of the major applications of CSNPs in drug delivery according to drug and route of administration. Finally, derivatives of CSNPs and CS nano-complexes are also discussed.     

Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers

In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chemical functionalization for biotechnological and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.     

核苷酸适体在靶向给药系统中的应用进展

适体,即体外合成筛选得到的能特异性地与靶分子结合的一段寡核苷酸序列。由于其独特的性质,在靶向给药系统中有着广阔的应用前景,目前已成为靶向给药研究领域的热点。综述了适体在靶向给药系统中的优势及其应用进展,并对其应用前景和面临的问题进行分析。     

Calcium carbonate nanoparticles as cancer drug delivery system

Introduction: Calcium carbonate (CaCO₃) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO₃ nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO₃ matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration.

Areas covered: Development of drug delivery carriers using CaCO₃ nanoparticles has been reviewed. The current state of CaCO₃ nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated.

Expert opinion: According to our review, CaCO₃ nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.     

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.