Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

Context: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells.

Objective: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX).

Methods: Folate (FA)-conjugated PEG–PE (FA–PEG–PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical–chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100?µl of 10?mg/kg different solutions.

Results: FA–PEG–PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229?nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812?mm³ tumor volume after 13?d of injection) than non-modified NPs/DOX (1290?mm³) and free DOX solution (1832?mm³) in vivo.

Conclusion: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy.     

Peptide-guided gene delivery

Although currently less efficient than their viral counterparts, nonviral vectors are under intense investigation as a safer alternative for gene therapy. For successful delivery, the nonviral vector must be able to overcome many barriers to protect DNA and specifically deliver it for efficient gene expression in target cells. The use of peptides as gene delivery vectors is advantageous over other nonviral agents in that they are able to achieve all of these goals. This review will focus on the application of peptides to mediate nonviral gene delivery. By examining the literature over the past 20 years, it becomes clear that no other class of biomolecules are simultaneously capable of DNA condensation, blocking metabolism, endosomal escape, nuclear localization, and receptor targeting. Based on virtually limitless diversity of peptide sequence and function information from nature, it is increasingly clear that peptide-guided gene delivery is still in its infancy.     

Nanostructured lipid carriers as novel drug delivery system for lung cancer gene therapy

Context: Nanostructured lipid carriers (NLC) are potentially good colloidal drug carriers for gene delivery. They are advised to be the second lifetime of lipid nanocarriers.

Objective: The aim of this study is to develop novel modified NLC as nanomedicine for delivery of plasmid-containing enhanced green fluorescence protein (pEGFP). This system could target the lung cancer cells through receptor-mediated pathways to increase the nuclear uptake of genetic materials.

Methods: In the present study, pEGFP-loaded NLC (NLC/pEGFP) were prepared. Transferrin (Tf) containing ligands were used for the surface coating of the vectors. In vitro transfection efficiency of the modified vectors was evaluated in human alveolar adenocarcinoma cell line (A549 cells) and in vivo transfection efficiency of the modified vectors was evaluated on mice bearing A549 cells model.

Results: Tf-modified NLC/pEGFP (Tf-NLC/pEGFP) has a particle size of 157?nm, and ～82% of gene loading quantity. Tf-NLC/pEGFP displayed remarkably higher transfection efficiency than non-modified NLC/pEGFP both in vitro and in vivo.

Conclusion: The results demonstrate that the novel NLC gene delivery system offers an effective strategy for lung cancer gene therapy.     

iRGD-paclitaxel conjugate nanoparticles for targeted paclitaxel delivery

Paclitaxel (PTX) is a chemotherapeutic agent which shows antitumor activities against a broad spectrum of cancers. Yet, the current formulation of PTX used in clinic may cause a number of adverse reactions, which significantly limit its application. To obtain better clinical use of PTX, we report, for the first time, iRGD-PTX conjugate nanoparticles (NPs) for targeted PTX delivery. iRGD-PTX conjugate was synthesized from thiolated iRGD and 6-maleimidocaproic acid-PTX through Michael addition reaction. iRGD-PTX NPs with hydrodynamic diameter of ~110 nm were self-assembled from iRGD-PTX conjugate in deionized water. The as-prepared iRGD-PTX NPs exhibit good stability in phosphate buffered saline (PBS) buffer and fetal bovine serum containing PBS buffer. iRGD-PTX NPs exhibit sustained drug release behaviors. The in vitro studies show that iRGD-PTX NPs can be internalized by 4T1 cells by integrin αV-mediated endocytosis, resulting in better in vitro antitumor activity as compared to free PTX. The in vivo studies demonstrate that iRGD-PTX NPs exhibit enhanced tumor accumulation. The iRGD-PTX NPs reported here represent a novel PTX nanoplatform to achieve targeted PTX delivery.     

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.     

Polydopamine and peptide decorated doxorubicin-loaded mesoporous silica nanoparticles as a targeted drug delivery system for bladder cancer therapy

We reported a simple polydopamine (PDA)-based surface modification method to prepare novel targeted doxorubicin-loaded mesoporous silica nanoparticles and peptide CSNRDARRC conjugation (DOX-loaded MSNs@PDA-PEP) for enhancing the therapeutic effects on bladder cancer. Drug-loaded NPs were characterized in terms of size, size distribution, zeta potential, transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) surface area and drug loading content. In vitro drug release indicated that DOX-loaded MSNs@PDA and MSNs@PDA-PEP had similar release kinetic profiles of DOX. The PDA coating well controlled DOX release and was highly sensitive to pH value. Confocal laser scanning microscopy (CLSM) showed that drug-loaded MSNs could be internalized by human bladder cancer cell line HT-1376, and DOX-loaded MSNs@PDA-PEP had the highest cellular uptake efficiency due to ligand–receptor recognition. The antitumor effects of DOX-loaded nanoparticles were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted nanocarriers DOX-loaded MSNs@PDA-PEP were significantly superior to free DOX and DOX-loaded MSNs@PDA. The novel DOX-loaded MSNs@PDA-PEP, which specifically recognized HT-1376 cells, can be used as a potential targeted drug delivery system for bladder cancer therapy.     

载抗肿瘤药物纳米靶向给药系统的研究进展

利用纳米微粒作为小分子抗肿瘤药物靶向传递系统的研究正在快速的发展和进行中,将抗肿瘤药物用各种不同材料的纳米微粒包裹,可以有助于提高其水溶性,增加肿瘤组织中的药物分布,以及加强抗肿瘤活性,同时减小对其他组织器官的非特异性毒性。此类研究主要集中在如何使得抗肿瘤药物在靶向肿瘤组织部位释放传递以及限制其对健康组织器官的影响,本文从当今常见纳米载药系统的类型以及肿瘤细胞靶向、肿瘤微环境靶向以及肿瘤转移灶靶向等多方面综述载抗肿瘤药物纳米微粒传递系统的研究进展。     

Viral-based gene delivery and regulated gene expression for targeted cancer therapy

Importance of the field: Cancer is both a major health concern and a care-cost issue in the US and the rest of the world. It is estimated that there will be a total of 1,479,350 new cancer cases and 562,340 cancer deaths in 2009 within the US alone. One of the major obstacles in cancer therapy is the ability to target specifically cancer cells. Most existing chemotherapies and other routine therapies (such as radiation therapy and hormonal manipulation) use indiscriminate approaches in which both cancer cells and non-cancerous surrounding cells are treated equally by the toxic treatment. As a result, either the cancer cell escapes the toxic dosage necessary for cell death and consequently resumes replication, or an adequate lethal dose that kills the cancer cell also causes the cancer patient to perish. Owing to this dilemma, cancer- or organ/tissue-specific targeting is greatly desired for effective cancer treatment and the reduction of side effect cytotoxicity within the patient.

Areas covered in this review: In this review, the strategies of targeted cancer therapy are discussed, with an emphasis on viral-based gene delivery and regulated gene expression.

What the reader will gain: Numerous approaches and updates in this field are presented for several common cancer types.

Take home message: A summary of existing challenges and future directions is also included.     

Non-condensing polymeric nanoparticles for targeted gene and siRNA delivery

Gene therapy has shown a tremendous potential to benefit patients in a variety of disease conditions. However, finding a safe and effective systemic delivery system is the major obstacle in this area. Although viral vectors showed promise for high transfection rate, the immunogenicity associated with these systems has hindered further development. As an alternative to viral gene delivery, this review focuses on application of novel safe and effective non-condensing polymeric systems that have shown high transgene expression when administered systemically or by the oral route. Type B gelatin-based engineered nanocarriers were evaluated for passive and active tumor-targeted delivery and transfection using both reporter and therapeutic plasmid DNA. Additionally, we have shown that nanoparticles-in-microsphere oral system (NiMOS) can efficiently deliver reporter and therapeutic gene constructs in the gastrointestinal tract. Additionally, there has been a significant recent interest in the use small interfering RNA (siRNA) as a therapeutic system for gene silencing. Both gelatin nanoparticles and NiMOS have shown activity in systemic and oral delivery of siRNA, respectively.     

非病毒型基因传递系统

介绍基因治疗的基本原理与非病毒型基因传递系统的设计方法、作用机制的研究进展 ,对基因传递系统的研究前景进行了展望。     

Studies on bioadhesive PLGA nanoparticles: A promising gene delivery system for efficient gene therapy to lung cancer

The study aimed to design novel bioadhesive PLGA nanoparticles for efficient gene delivery to lung cancer cells. The bioadhesive agent and stabilizer, Carbopol 940 was chosen to establish bioadhesive PLGA nanoparticles and Pluronic F68, Pluronic F127 stabilized PLGA nanoparticles were formulated as control. The effects of different surfactants on the physicochemical and biological characterizations of PLGA nanoparticles were compared. All the obtained nanoparticles showed negative surface charge, similar spherical morphology, a relatively narrow particle size distribution, and lower cytotoxicity to A549 cells comparing with Lipofectamine 2000. Carbopol stabilized nanoparticles hold advantages in DNA-binding efficiency (>80%) at an optimal Carbopol concentration, DNA protection from enzymatic degradation in vitro release and better buffering capacity. Most importantly, higher transfection efficiency in A549 cells was observed comparing to Pluronics stabilized nanoparticles or naked DNA, similar to that of Lipofectamine 2000. These results revealed that the bioadhesive PLGA nanoparticles formulated with Carbopol might be a very attractive candidate as a non-viral vector for lung cancer gene therapy and might alleviate the drawbacks of the conventional cationic vectors/DNA complexes for gene delivery in vivo.     

Ultrasound targeted microbubble destruction for drug and gene delivery

Background: Gas-filled microbubbles have been used as ultrasound contrast agents for some decades. More recently, such microbubbles have evolved as experimental tools for organ- and tissue-specific drug and gene delivery. When sonified with ultrasound near their resonance frequency, microbubbles oscillate. With higher ultrasound energies, oscillation amplitudes increase, leading to microbubble destruction. This phenomenon can be used to deliver a substance into a target organ, if microbubbles are co-administered loaded with drugs or gene therapy vectors before i.v. injection. Objective: This review focuses on different experimental applications of microbubbles as tools for drug and gene delivery. Different organ systems and different classes of bioactive substances that have been used in previous studies will be discussed. Methods: All the available literature was reviewed to highlight the potential of this non-invasive, organ-specific delivery system. Conclusion: Ultrasound targeted microbubble destruction has been used in various organ systems and in tumours to successfully deliver drugs, proteins, gene therapy vectors and gene silencing constructs. Many proof of principle studies have demonstrated its potential as a non-invasive delivery tool. However, too few large animal studies and studies with therapeutic aims have been performed to see a clinical application of this technique in the near future. Nevertheless, there is great hope that preclinical large animal studies will confirm the successful results already obtained in small animals.     

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.     

壳聚糖在靶向制剂中的应用进展

壳聚糖是一种天然高分子化合物，壳聚糖及其衍生物具有优良的生物相容性和生物可降解性，在制药业有广阔的应用前景。综述了近几年来壳聚糖及其衍生物在靶向制剂中的应用。     

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。     

超声靶向微泡破坏技术在心肌梗死基因治疗中的应用

急性心肌梗死（AMI）是严重威胁人类健康的疾病之一。心肌梗死时由于受累心肌细胞功能丧失，导致心功能受损甚至进展为心力衰竭。AMI的一线治疗是尽早通过经皮冠状动脉介入治疗（PCI）对闭塞的冠状动脉进行再灌注。然而，目前临床上的手术和药物等治疗手段均不能挽救死亡的心肌细胞，大面积心肌梗死后仍可能发生心室功能障碍。近年来，靶向基因治疗逐渐应用于临床，已成为AMI可能的有效干预措施。但是，由于缺乏安全有效的靶向递送系统，转染基因难以持续表达，基因治疗的临床应用受到限制。超声靶向微泡破坏技术（UTMD）是一种介导基因转染的新技术，通过将基因递送到特定的解剖和病理部位，在心血管疾病中具有潜在的治疗价值。本文对UTMD在心肌梗死基因治疗中的应用研究进展进行综述。     

Gelucire-stabilized nanoparticles as a potential DNA delivery system

Clinical viability of gene delivery systems has been greatly impacted by potential toxicity of the delivery systems. Recently, we reported the nanoparticle (NP) preparation process that employs biocompatible materials such as Gelucire® 44/14 and cetyl alcohol as matrix materials. In the current study, the NP preparation was modified for pDNA loading through: (i) inclusion of cationic lipids (DOTAP or DDAB) with NP matrix materials; or (ii) application of cationic surfactants (CTAB) to generate NPs with desired surface charges for pDNA complexation. Colloidal stability and efficiency of loading pGL3-DR4X2-luciferase plasmid DNA in NPs were verified by gel permeation chromatography. Compared to pDNA alone, all the NPs were effective in preserving pDNA from digestion by DNase. While pDNA loading using CTAB-NPs involved fewer steps compared to DOTAP-NPs and DDAB-NPs, CTAB-NPs were greatly impacted by elevated cytotoxicity level which could be ascribed to the concentrations of CTAB in NP formulations. In vitro transfection studies (in HepG2 cells) based on luciferase expression showed the ranking of cell transfection efficiency as DOTAP-NPs?>?DDAB-NPs?>?CTAB-NPs. The overall work provided an initial assessment of gelucire-stabilized NPs as a potential platform for gene delivery.     

Metal nanoparticles as a promising technology in targeted cancer treatment

Traditional anticancer treatments have several limitations, but cancer is still one of the deadliest diseases. As a result, new anticancer drugs are required for the treatment of cancer. The use of metal nanoparticles (NPs) as alternative chemotherapeutic drugs is on the rise in cancer research. Metal NPs have the potential for use in a wide range of applications. Natural or surface-induced anticancer effects can be found in metals. The focus of this review is on the therapeutic potential of metal-based NPs. The potential of various types of metal NPs for tumor targeting will be discussed for cancer treatment. The in vivo application of metal NPs for solid tumors will be reviewed. Risk factors involved in the clinical application of metal NPs will also be summarized.     

Lactoferrin bioconjugated solid lipid nanoparticles: a new drug delivery system for potential brain targeting

Background: Delivery of drugs to brain is a subtle task in the therapy of many severe neurological disorders. Solid lipid nanoparticles (SLN) easily diffuse the blood–brain barrier (BBB) due to their lipophilic nature. Furthermore, ligand conjugation on SLN surface enhances the targeting efficiency. Lactoferin (Lf) conjugated SLN system is first time attempted for effective brain targeting in this study.

Purpose: Preparation of Lf-modified docetaxel (DTX)-loaded SLN for proficient delivery of DTX to brain.

Methods: DTX-loaded SLN were prepared using emulsification and solvent evaporation method and conjugation of Lf on SLN surface (C-SLN) was attained through carbodiimide chemistry. These lipidic nanoparticles were evaluated by DLS, AFM, FTIR, XRD techniques and in vitro release studies. Colloidal stability study was performed in biologically simulated environment (normal saline and serum). These lipidic nanoparticles were further evaluated for its targeting mechanism for uptake in brain tumour cells and brain via receptor saturation studies and distribution studies in brain, respectively.

Results: Particle size of lipidic nanoparticles was found to be optimum. Surface morphology (zeta potential, AFM) and surface chemistry (FTIR) confirmed conjugation of Lf on SLN surface. Cytotoxicity studies revealed augmented apoptotic activity of C-SLN than SLN and DTX. Enhanced cytotoxicity was demonstrated by receptor saturation and uptake studies. Brain concentration of DTX was elevated significantly with C-SLN than marketed formulation.

Conclusions: It is evident from the cytotoxicity, uptake that SLN has potential to deliver drug to brain than marketed formulation but conjugating Lf on SLN surface (C-SLN) further increased the targeting potential for brain tumour. Moreover, brain distribution studies corroborated the use of C-SLN as a viable vehicle to target drug to brain. Hence, C-SLN was demonstrated to be a promising DTX delivery system to brain as it possessed remarkable biocompatibility, stability and efficacy than other reported delivery systems.