可共载基因与敏化剂用以增强多西他赛抗肿瘤效果的脂质纳米载药系统的制备与评价

本研究制备了一种纳米载药系统,通过对几种化学或基因药物的同时递送,实现多种药物的协同效应或降低肿瘤对药物的耐药性,从而达到提高肿瘤治疗的目的。在本研究中,通过考察粒径分布及载药量对不同的阳性脂材进行筛选,成功制备可以同时传递阴离子小干扰RNA（siRNA）和化疗药物多西他赛的阳性纳米脂质载体（cNLC）。同时,利用能与肝癌细胞表面特异性结合的新型肽SP94对cNLC的表面进行修饰,最终制得具有主动靶向功能的cNLC。琼脂糖凝胶色谱结果显示制得的cNLC可以有效的装载siRNA。超滤离心法去除游离药物后,HPLC图谱显示cNLC能够高效的包载多西他赛。与市售制剂泰索帝相比,制得的SP94-cNLC显示出更强的细胞毒性,这表明SP94修饰的cNLC能更高效的递送多西他赛进入肝癌细胞。而在姜黄素和多西他赛共载的NLC中,通过姜黄素对多西他赛的敏化作用提高多西他赛在侵袭性癌细胞中的细胞毒性,这种共载系统能够改善化疗药物单独使用时疗效较差的缺点。     

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).     

Loco-regional administration of nanomedicines for the treatment of lung cancer

Lung cancer poses one of the most significant challenges to modern medicine, killing thousands every year. Current therapy involves surgical resection supplemented with chemotherapy and radiotherapy due to high rates of relapse. Shortcomings of currently available chemotherapy protocols include unacceptably high levels of systemic toxicity and low accumulation of drug at the tumor site. Loco-regional delivery of nanocarriers loaded with anticancer agents has the potential to significantly increase efficacy, while minimizing systemic toxicity to anticancer agents. Local drug administration at the tumor site using nanoparticulate drug delivery systems can reduce systemic toxicities observed with intravenously administered anticancer drugs. In addition, this approach presents an opportunity for sustained delivery of anticancer drug over an extended period of time. Herein, the progress in the development of locally administered nanomedicines for the treatment of lung cancer is reviewed. Administration by inhalation, intratumoral injection and means of direct in situ application are discussed, the benefits and drawbacks of each modality are explored.     

一氧化氮供体和阿霉素的共递送系统用于逆转肿瘤低氧耐药研究

目的构建一种一氧化氮供体和阿霉素的共递送系统,以逆转肿瘤低氧耐药。方法利用酰胺反应合成一氧化氮供体单硝酸异山梨酯(IM)修饰的透明质酸(HA-IM),再通过硫化学作用将其嫁接于二硫化钼(MoS₂)纳米片,制备出载体二硫化钼-单硝酸异山梨酯修饰的透明质酸(MoS₂-HA-IM),考察此载体的理化特性。通过疏水作用装载抗癌药阿霉素(DOX),构建一氧化氮供体和抗癌药物的共递送系统,并在细胞水平上考察此系统的抗肿瘤效果。结果二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素(MoS₂-HA-IM-DOX)可通过透明质酸受体介导的内吞作用有效地将装载的单硝酸异山梨酯和阿霉素输送到肿瘤细胞内,且在肿瘤弱酸性内环境和近红外光照射的双重刺激下迅速将药物释放出来,提高胞内游离药物的浓度。同时,装载的单硝酸异山梨酯能够逆转肿瘤细胞的低氧耐受性,进一步增强二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素的化疗效果,再联合基于二硫化钼材料产生的光热,共使肿瘤细胞的生长抑制率高达93.6%,明显高于其他组。结论二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素能够靶向输送一氧化氮供体和抗癌药物至肿瘤细胞内,双重响应控制药物释放,逆转肿瘤低氧耐药,最大限度地提高化疗效果,结合光热治疗,显示出优异的抗肿瘤效果。     

Combination therapy: Opportunities and challenges for polymer–drug conjugates as anticancer nanomedicines

The discovery of new molecular targets and the subsequent development of novel anticancer agents are opening new possibilities for drug combination therapy as anticancer treatment. Polymer–drug conjugates are well established for the delivery of a single therapeutic agent, but only in very recent years their use has been extended to the delivery of multi-agent therapy. These early studies revealed the therapeutic potential of this application but raised new challenges (namely, drug loading and drugs ratio, characterisation, and development of suitable carriers) that need to be addressed for a successful optimisation of the system towards clinical applications.     

Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells.     

Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy

Combination therapy for the treatment of cancer is becoming more popular because it generates synergistic anticancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. In recent years, nanotechnology-based combination drug delivery to tumor tissues has emerged as an effective strategy by overcoming many biological, biophysical and biomedical barriers that the body stages against successful delivery of anticancer drugs. The sustained, controlled and targeted delivery of chemotherapeutic drugs in a combination approach enhanced therapeutic anticancer effects with reduced drug-associated side effects. In this article, we have reviewed the scope of various nanotechnology-based combination drug delivery approaches and also summarized the current perspective and challenges facing the successful treatment of cancer.     

Doxorubicin-conjugated siRNA lipid nanoparticles for combination cancer therapy

Evasion of apoptosis is a hallmark of cancer, attributed in part to overexpression of the antiapoptotic protein B-cell lymphoma 2(Bcl-2). In a variety of cancer types, including lymphoma, Bcl-2 is overexpressed. Therapeutic targeting of Bcl-2 has demonstrated efficacy in the clinic and is the subject of extensive clinical testing in combination with chemotherapy. Therefore, the development of co-delivery systems for Bcl-2 targeting agents, such as small interfering RNA(siRNA), and chemotherapeut...     

Nanocarriers for the simultaneous co-delivery of therapeutic genes and anticancer drugs

Due to the molecular complexity of cancer, combination therapy is becoming increasingly important for better long-term prognosis with fewer side effects. To further increase the therapeutic effects, advanced drug delivery systems (DDSs), capable of simultaneously delivering multiple drugs to the site of action with specific time-programmed release profiles, are important requirements. Nanocarriers for the simultaneous co-delivery of multiple chemical drugs in combination therapy have been extensively reviewed. Here we focus on the nanotechnology enabled DDSs for the simultaneous co-delivery of therapeutic genes and chemical drugs for cancer treatment. The opportunities for this combination strategy and their challenges will be discussed.     

Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment

Context: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers.

Objective: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.

Methods: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line.

Results: PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity.

Conclusions: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.     

Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy

Introduction: Cancer is the leading cause of death worldwide. Current cancer treatments in the clinic mainly include chemotherapy, radiotherapy and surgery, with chemotherapy being the most common.

Areas covered: Cancer treatments based on the single ‘magic-bullet’ concept are often associated with limited therapeutic efficacy, unwanted adverse effects, and drug resistance. The combination of multiple drugs is a promising strategy for effective cancer treatment due to the synergistic or additive effects. Small interfering RNA (siRNA) has the ability to knock down the expression of carcinogenic genes or drug efflux transporter genes, paving the way for cancer treatment. Treatment with both a chemotherapeutic agent and siRNA based on nanoparticle (NP)-mediated co-delivery is a promising approach for combination cancer therapy.

Expert opinion: The combination of chemotherapeutic agents and siRNAs for cancer treatment offers the potential to enhance therapeutic efficacy, decrease side effects, and overcome drug resistance. Co-delivery of chemical drug and siRNA in the same NP would be much more effective in cancer therapy than application of chemical agent or siRNA alone. With the development of material science, NPs have come to be the most widely used platform for co-delivery of chemotherapeutic drugs and siRNAs.     

Multiple-delayed release formulation approach for the treatment of methicillin-resistant Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most frequent nosocomial pathogens in developed countries. Although several novel antibacterial agents possessing novel mode of action have been developed to date, the continuous effort to investigate an effective combination of front-line drugs is considered important in anti-MRSA drug development. The combination chemotherapy with front-line drugs is expected to provide effective, safe, and less expensive treatment. Oral trimethoprim/sulfamethoxazole combination therapy has been utilized for treatment of several nosocomical infections. Importantly, no antagonism has been reported for combinations of trimethoprim with many other front-line antibiotics. MiddleBrook Pharmaceuticals has developed the pulsatile delivery systems of three to four different antibacterial agents, including trimethoprim and sulfamethoxazole, for the treatment of MRSA infections. The liberation of individual drugs theoretically follows a programmable lag phase (no release) from the time of administration. Pulsatile drug delivery system provides optimal release profiles for a combination of drugs. The clinical data that would be obtained based on these claims are expected to be of significance in terms of developing combination chemotherapy for MRSA infections via a pulsatile drug release control system.     

Amplification of anticancer efficacy by co-delivery of doxorubicin and lonidamine with extracellular vesicles

Chemotherapy is commonly used for the treatment of lung cancer, but strong side effects and low treatment efficacy limit its clinical application. Here, extracellular vesicles (EVs) as natural drug delivery carriers were used to load conventional anticancer drug doxorubicin (DOX) and a chemosensitizer lonidamine (LND). Two types of EVs with different sizes (16k EVs and 120k EVs) were prepared using different centrifugation forces. We found that co-delivery of DOX and LND with both EVs enhanced the cytotoxicity and reduced the dose of the anticancer drug significantly in vitro. Effective delivery of anti-cancer drugs to cancer cells was achieved by direct fusion of EVs with the plasma membrane of cancer cells. On the other hand, DOX and LND inhibited cancer cell proliferation by increasing DNA damage, suppressing ATP production, and accelerating ROS generation synergistically. DOX and LND loaded EVs were also applied to the mouse lung cancer model and exhibited significant anticancer activity. In vivo study showed that smaller EVs exhibited higher anticancer efficiency. In conclusion, the co-delivery of the anticancer drug and the chemosensitizer with EVs may have potential clinical applications for cancer therapy.     

Targeted thermosensitive liposomes: an attractive novel approach for increased drug delivery to solid tumors

Introduction: Currently available chemotherapy is hampered by a lack in tumor specificity and resulting toxicity. Small and long-circulating liposomes can preferentially deliver chemotherapeutic drugs to tumors upon extravasation from tumor vasculature. Although clinically used liposomal formulations demonstrated significant reduction in toxicity, enhancement of therapeutic activity has not fully met expectations.

Areas covered: Low drug bioavailability from liposomal formulations and limited tumor accumulation remain major challenges to further improve therapeutic activity of liposomal chemotherapy. The aim of this review is to highlight strategies addressing these challenges. A first strategy uses hyperthermia and thermosensitive liposomes to improve tumor accumulation and trigger liposomal drug bioavailability. Image-guidance can aid online monitoring of heat and drug delivery and further personalize the treatment. A second strategy involves tumor-specific targeting to enhance drug delivery specificity and drug internalization. In addition, we review the potential of combinations of the two in one targeted thermosensitive-triggered drug delivery system.

Expert opinion: Heat-triggered drug delivery using thermosensitive liposomes as well as the use of tumor vasculature or tumor cell-targeted liposomes are both promising strategies to improve liposomal chemotherapy. Preclinical evidence has been encouraging and both strategies are currently undergoing clinical evaluation. A combination of both strategies rendering targeted thermosensitive liposomes (TTSL) may appear as a new and attractive approach promoting tumor drug delivery.     

Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era

Membrane-disruptive peptides/peptidomimetics (MDPs) are antimicrobials or anticarcinogens that present a general killing mechanism through the physical disruption of cell membranes, in contrast to conventional chemotherapeutic drugs, which act on precise targets such as DNA or specific enzymes. Owing to their rapid action, broad-spectrum activity, and mechanisms of action that potentially hinder the development of resistance, MDPs have been increasingly considered as future therapeutics in the drug-resistant era. Recently, growing experimental evidence has demonstrated that MDPs can also be utilized as adjuvants to enhance the therapeutic effects of other agents. In this review, we evaluate the literature around the broad-spectrum antimicrobial properties and anticancer activity of MDPs, and summarize the current development and mechanisms of MDPs alone or in combination with other agents. Notably, this review highlights recent advances in the design of various MDP-based drug delivery systems that can improve the therapeutic effect of MDPs, minimize side effects, and promote the co-delivery of multiple chemotherapeutics, for more efficient antimicrobial and anticancer therapy.     

Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect

For over half a century extensive research has been undertaken for the control of cancer. However, success has been limited to certain malignancies, and surgical intervention is potentially curative for early stage patients. For the majority of patients with advanced stage of cancer, the treatment is limited to chemotherapy or radiation. Chemotherapy in particular has limitations due to the lack of selectivity with severe toxicity. Under these circumstances tumor-targeted delivery of anticancer drugs is perhaps one of the most important steps for cancer chemotherapy. We reported such a drug for the first time, styrene-maleic acid copolymer-conjugated neocarzinostatin (SMANCS) in 1979, and it eventually led to formulate the concept of the enhanced permeability and retention (EPR) effect of solid tumors in 1986. Monoclonal antibody conjugates are another direction, of which interest is increasing recently though with limited success. The EPR-effect appears as a universal phenomenon in solid tumors which warrants the development of other polymeric drugs or nanomedicine.EPR-effect is applicable for any biocompatible macromolecular compounds above 40 kDa, even larger than 800 kDa, or of the size of bacteria; thus complexed molecules like micelles and liposomes containing anticancer drugs are hallmark examples. The drug concentration in tumor compared to that of the blood (T/B ratio) can be usually as high as 10-30 times. In case of SMANCS/Lipiodol given via tumor feeding artery, the T/B ratio can be as high as 2000, a real pin-point targeting. EPR-effect is not just passive targeting for momentary tumor delivery, but it means prolonged drug retention for more than several weeks or longer.This review describes the pathophysiological mechanisms of the EPR-effect, architectural difference of tumor blood vessel, various factors involved and artificial augmentation of EPR-effect with respect to tumor-selective delivery, and then advantages and problems of macromolecular drugs.     

纳米载药系统逆转肿瘤及骨肉瘤多药耐药的研究进展

多药耐药是肿瘤化疗中的重要难题,多药耐药的机制复杂,目前尚无有效的治疗策略。纳米载药系统具有靶向性、载药种类多样等优点,近年来成为对抗肿瘤多药耐药的递药载体的重要研究方向。对肿瘤抑制的不同机制进行讨论,并对纳米载药系统逆转骨肉瘤多药耐药的研究进展进行综述。     

Novel Central Nervous System Drug Delivery Systems

For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood–brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood–brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection‐enhanced infusion, and ultrasound‐mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.     

Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This “all-in-one” delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.     

Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.