紫杉醇给药系统的研究进展

紫杉醇作为一种典型的广谱抗肿瘤药物,广泛用于卵巢癌、乳腺癌、肺癌等多种肿瘤的治疗。由于紫杉醇难溶于水,传统注射液制剂使用聚氧乙烯蓖麻油(cremophor EL)与无水乙醇(1∶1)作为增溶溶媒,临床使用中引起的不良反应较多。为提高紫杉醇制剂的治疗效果,降低不良反应,国内外学者致力于紫杉醇制剂学的研究。本文综述了近年来紫杉醇新型给药系统的研究进展,对当前研究中存在的问题进行了探讨,并对今后发展前景进行了展望,以期为未来新型紫杉醇给药系统的开发及应用提供参考。     

Recent strategies in the development of taxane anticancer drugs

Paclitaxel (Taxol^®, Bristol-Myers Squibb) and docetaxel (Taxtere^®, Rhône-Poulenc Rorer SA - now Aventis), complex polyoxygenated taxane diterpenoids bearing phenylisoserine moieties currently in extensive clinical use for the treatment of breast, ovarian and other cancers, are considered to be two of the most important drugs in cancer chemotherapy. However, low solubility, multi-drug resistance (MDR), dose-limiting toxicity as well as other adverse effects associated with these drugs present significant drawbacks. Accordingly, seeking the solutions to these problems of taxane anticancer drugs has been the main focus of both academic and industrial research activities for the period of 1997 - 1999. New taxoids (i.e., Taxol^®-like compounds) with various modifications at the baccatin skeleton and the phenylisoserine side chain have been developed, which possess improved potency, especially against cancers expressing P-glycoprotein (P-gp)-based MDR. A number of prodrugs of paclitaxel and taxoids have been designed and synthesised to tackle the solubility problem, mainly by attaching water-soluble subunit(s) to the C-2 and/or C-7 hydroxyl groups. Novel tumour-recognising taxoids and taxane-based MDR modulators have also been developed, showing considerable promise. Recently, the improvement in drug formulation and delivery of taxane anticancer agents has been receiving increasing attention.     

紫杉醇靶向制剂的研究进展

目的介绍紫杉醇靶向制剂的研究进展。方法综述近年来国内外相关研究,介绍紫杉醇靶向制剂的制备方法、性能和药效等,指出目前紫杉醇靶向制剂的研究前景。结果紫杉醇靶向制剂不仅提高紫杉醇的溶解度,而且降低其毒副作用。结论紫杉醇靶向制剂为癌症化疗提供了新的研究途径,是很有临床应用前景的抗癌药物剂型。     

壳聚糖在生物大分子药物给药中的应用

壳聚糖具有促进生物大分子药物透膜渗透和生物粘附作用。利用壳聚糖形成的自身聚集体以及用壳聚糖制备的微粒制剂、混合胶体和包衣制剂等，均可提高生物大分子药物的生物利用度。     

紫杉烷类化合物的生物转化

紫杉醇 (paclitaxel)是从红豆杉树皮或枝叶中提取出来的具有独特抗肿瘤作用的二萜类化合物 ,自1 992年美国FDA批准紫杉醇 (taxol)上市以来 ,其临床适应症不断扩展 ,成为治疗卵巢癌、乳腺癌、非小细胞肺癌等多种肿瘤的一线用药。现已上市的紫杉醇类药物从原料来源上可分为 :直接     

Liposomes as delivery systems in the prevention and treatment of infectious diseases

Research on the potential application of liposomes in the prevention and treatment of infectious diseases has focussed on improvement of the therapeutic index of antimicrobial drugs and immunomodulators and on stimulation of the immune response to otherwise weak antigens in vaccines composed of purified micro-organism subunits. In this review current approaches in this field are outlined. The improved therapeutic index of antimicrobial drugs after encapsulation in liposomes is a result of enhanced drug delivery to infected tissue or infected cells and/or a reduction of drug toxicity of potentially toxic antibiotics. Liposomal encapsulation of immunomodulators that activate macrophages aims at reducing the toxicity of these agents and targeting them to the cells of the mononuclear phagocyte system in order to increase the nonspecific resistance of the host against infections. Studies on the immunogenicity of liposomal antigens have demonstrated that liposomes can potentiate the humoral and cell mediated immunity to a variety of antigens.     

New microtubular agents in pediatric oncology

Summary The taxanes are a new group of anticancer agents with a novel mechanism of action. They promote microtubule assembly and stabilize the microtubules. Paclitaxel (Taxol), the first agent in this group in clinical trials was isolated from the Pacific yew, Taxus brevifolia in 1971. Both in preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review will provide an overview of the clinical experience with the group of anti-microtubular agents, the taxanes in pediatric oncology. Address for offprints: Nita L. Seibel, Department of Hematology/Oncology. Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC 20010, USA     

生物大分子结晶技术研究进展

获得具有高分辨率的晶体是目前生物大分子结构测定的主要瓶颈,生物大分子的结晶是一个复杂的物理化学过程,涉及多方面的影响因素。本文综述了近年来生物大分子结晶的热点方法和技术。     

Albumin-bound paclitaxel: a next-generation taxane

Taxanes are standard treatment for metastatic breast cancer; however, the solvents used as vehicles in these formulations cause severe toxicities. The FDA recently approved a solvent-free formulation of paclitaxel for the treatment of metastatic breast cancer that utilises 130-nanometer albumin-bound (nab?) technology (Abraxane^®; nab-paclitaxel) to circumvent the requirement for solvents. nab-Paclitaxel utilises the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell and concentrate it in areas of tumour. The proposed mechanism of drug delivery involves, in part, glycoprotein 60-mediated endothelial cell transcytosis of paclitaxel-bound albumin and accumulation in the area of tumour by albumin binding to SPARC (secreted protein, acidic and rich in cysteine). Clinical studies have shown that nab-paclitaxel is significantly more effective than paclitaxel formulated as Cremophor^® EL (CrEL, Taxol^®, CrEL-paclitaxel), with almost double the response rate, increased time to disease progression and increased survival in second-line patients. The absence of CrEL from the formulation is associated with decreased neutropenia and rapid improvement of peripheral neuropathy with nab-paclitaxel, compared with CrEL-paclitaxel. For these reasons, nab-paclitaxel can be administered using higher doses of paclitaxel than that achievable with CrEL-paclitaxel, with shorter infusion duration and without the requirement for corticosteroid and antihistamine premedication to reduce the risk of solvent-mediated hypersensitivity reactions. Taken together, these studies have demonstrated that nab technology has increased the therapeutic index of paclitaxel compared with the conventional, solvent-based formulation.     

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol?, Bristol-Myers Squibb and docetaxel, Taxotere?, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.     

Formulation and Antitumor Activity Evaluation of Nanocrystalline Suspensions of Poorly Soluble Anticancer Drugs

Purpose. Determine if wet milling technology could be used to formulate water insoluble antitumor agents as stabilized nanocrystalline drug suspensions that retain biological effectiveness following intravenous injection. Methods. The versatility of the approach is demonstrated by evaluation of four poorly water soluble chemotherapeutic agents that exhibit diverse chemistries and mechanisms of action. The compounds selected were: piposulfan (alkylating agent), etoposide (topoisomerase II inhibitor), camptothecin (topoisomerase I inhibitor) and paclitaxel (antimitotic agent). The agents were wet milled as a 2% w/v solids suspension containing 1 % w/v surfactant stabilizer using a low energy ball mill. The size , physical stability and efficacy of the nanocrystalline suspensions were evaluated. Results. The data show the feasibility of formulating poorly water soluble anticancer agents as physically stable aqueous nanocrystalline suspensions. The suspensions are physically stable and efficacious following intravenous injection. Conclusions. Wet milling technology is a feasible approach for formulating poorly water soluble chemotherapeutic agents that may offer a number of advantages over a more classical approach.     

Polymers for colon targeted drug delivery

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems.     

Transferrin coupled vesicular system for intracellular drug delivery for the treatment of cancer: Development and characterization

Objectives: In the present study attempt has been made to enhance the selective tumor cell killing in mouse xenograft model using DQAsomes as a mitochondriotropic carrier and transferrin (Tf) as a ligand to target tumor cells.

Methods: Tf modified DQAsomes (Tf-DQAsomes) were prepared by incubating preformed paclitaxel loaded DQAsomes with Tf in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Developed systems were characterized for size and size distribution, entrapment efficiency, and in vitro drug release. Fluorescence microscopy and flow cytometry were performed to evaluate cellular uptake of the carriers. Antitumor activity was determined using HeLa cells. In vivo therapeutic efficacy was determined in xenograft mouse model.

Key findings: Uptake studies demonstrated that Tf-DQAsomes result in higher flurescence intensity to the cancer cells as compared to plain DQAsomes. Tf-DQAsomes exhibited better antitumor activity in vitro as compared to plain DQAsomes and paclitaxel solution. In vivo biodistribution study revealed that paclitaxel concentration in the tumor was much higher in the case of Tf-DQAsomes as compared to plain DQAsomes and paclitaxel solution; however in other organs it was much lower than the latter two formulations. Tf-DQAsomes exhibited significant antitumor activity in the mouse xenograft model.

Conclusions: The finding demonstrated that Tf conjugated DQAsomes can effectively be delivered to the tumor in vivo and exhibit significant antitumor activity.     

Imprinted hydrophilic nanospheres as drug delivery systems for 5-fluorouracil sustained release

Molecularly imprinted hydrogel nanospheres as devices for the controlled/sustained release of 5-fluororacil in biological fluids were synthesized employing one-pot precipitation technique as the polymerization method. Methacrylic acid as a functional monomer and ethylene glycole dimethacrylate as a cross-linker were used in polymeric feed. Morphological and hydrophilic properties were determined by scanning electron microscopy and water content measurement, and recognition and selectivity properties of spherical molecularly imprinted polymers were compared with the spherical non-imprinted polymers, both in organic (acetonitrile) and water media. Finally, in vitro release studies were performed in plasma simulating fluids.     

Paclitaxel in cancer therapy

The last decade witnessed the introduction of exciting new chemotherapeutic agents. Among these, paclitaxel emerged as one of the most powerful compounds. Paclitaxel promotes the polymerisation of tubulin, thereby causing cell death by disrupting the normal microtubule dynamics required for cell division and vital interphase processes. Mechanisms of acquired resistance to paclitaxel include alterations of tubulin structure and the amplification of membrane phosphoglycoproteins that function as drug-efflux pumps. Toxicities associated with paclitaxel include hypersensitivity reaction, neurotoxicity and haematological toxicities. Toxicities may be both dose- and schedule-dependent. Paclitaxel has activity against a broad band of tumour types, including breast, ovarian, lung, head and neck cancers. Paclitaxel also has activity in other malignancies that are refractory to conventional chemotherapy, including previously-treated lymphoma and small cell lung cancers and oesophageal, gastric endometrial, bladder and germ cell tumours. Paclitaxel is also active against AIDS-associated Kaposi’s sarcoma.     

Molecularly imprinted polymers as drug delivery systems for the sustained release of glycyrrhizic acid

Objectives The aim was to synthesize molecularly imprinted polymers (MIPs) with high recognition properties towards glycyrrhizic acid and to evaluate the performance of these materials to act as base excipients in glycyrrhizic acid sustained release in gastrointestinal simulating fluids. Methods MIPs were synthesized using methacrylic acid (MAA) as acidic, 2‐(dimethylamino)ethyl methacrylate (DMAEMA) as basic, and 2‐hydroxyethylmethacrylate (HEMA) as neutral functional monomers, while ethylene glycol dimethacrylate (EGDMA) was chosen as a crosslinking agent. The imprinting effect was evaluated by binding experiments using glycyrrhizic acid and glycyrrhetic acid (analogue molecule) solutions and in‐vitro release studies were performed in gastrointestinal simulating fluids. Key findings Good recognition and selectivity properties were found in all the synthesized materials in both ethanol and ethanol–water mixture. The release from non‐imprinted polymers was indeed higher at acidic pH, while a slower release was observed in MIPs' case, because of the presence of imprinted cavities in the polymeric structure. The stronger capacity of MAA to interact by hydrogen bonds with the template makes MAA‐containing MIPs the most effective materials in both rebinding and release experiments. Conclusions The release tests confirm the applicability of imprinted polymer for glycyrrhizic acid sustained release in gastrointestinal simulating fluids.     

Cancer targeted drug delivery using active low-density lipoprotein nanoparticles encapsulated pyrimidines heterocyclic anticancer agents as microtubule inhibitors

Recently, nanomedicine had the potential to increase the delivery of active compounds to specific cell sites. Nano-LDL particles are recognized as an excellent active nano-platform for cancer-targeted delivery. Loading of therapeutic agents into nano-LDL particles achieved by surface loading, core loading, and apolipoprotein-B100 interaction. Therefore, loading nano-LDL particles’ core with pyrimidine heterocyclic anticancer agents will increase cancer cytotoxic activity targeting tubulin protein. First, by mimicking the native LDL particle''s metabolic pathway, and second the agent’s chemical functional groups like the native amino acids cytosine and thymine structures will not be recognized as a foreign entity from the cell’s immune system. Nano-LDL particles will internalize through LDL-receptors endocytosis and transport the anticancer agent into the middle of the cancer cell, reducing its side effects on other healthy cells. Generally, the data revealed that pyrimidine heterocyclic anticancer agents’ size is at the nano level. Agents’ morphological examination showed nanofibers, thin sheets, clusters, and rod-like structures. LDL particles’ size became bigger after loading with pyrimidine heterocyclic anticancer agents and ranged between 121.6 and 1045 nm. Then, particles were tested for their cytotoxicity against breast (MDA468) and prostate (DU145) cancer cell lines as surrogate models with dose-response study 10, 5, 1 µM. The IC₅₀ values of the agents against DU145 and MDA468 possessed cell growth inhibition even at the 1 µM concentration ranges of 3.88 ± 1.05 µM and 3.39 ± 0.97 µM, respectively. In sum, nano-LDL particles proved their efficiency as active drug delivery vehicles to target tubulin in cancer cells.     

Design of a novel curcumin-soybean phosphatidylcholine complex-based targeted drug delivery systems

Recently, the global trend in the field of nanomedicine has been toward the design of combination of nature active constituents and phospholipid (PC) to form a therapeutic drug-phospholipid complex. As a particular amphiphilic molecular complex, it can be a unique bridge of traditional dosage-form and novel drug delivery system. In thisarticle, on the basis of drug-phospholipid complex technique and self-assembly technique, we chose a pharmacologically safe and low toxic drug curcumin (CUR) to increase drug-loading ability, achieve controlled/sustained drug release and improve anticancer activity. A novel CUR-soybean phosphatidylcholine (SPC) complex and CUR-SPC complex self-assembled nanoparticles (CUR-SPC NPs) were prepared by a co-solvent method and a nanoprecipitation method. DSPE-PEG-FA was further functionalized on the surface of PEG-CUR-SPC NPs (designed as FA-PEG-CUR-SPC NPs) to specifically increase cellular uptake and targetability. The FA-PEG-CUR-SPC NPs showed a spherical shape, a mean diameter of about 180?nm, an excellent physiological stability and pH-triggered drug release. The drug entrapment efficiency and drug-loading content was up to 92.5 and 16.3%, respectively. In vitro cellular uptake and cytotoxicity studies demonstrated that FA-PEG-CUR-SPC NPs and CUR-SPC NPs presented significantly stronger cellular uptake efficacy and anticancer activity against HeLa cells and Caco-2 cells compared to free CUR, CUR-SPC NPs and PEG-CUR-SPC NPs. More importantly, FA-PEG-CUR-SPC NPs showed the prolonged systemic circulation lifetime and enhanced tumor accumulation compared with free CUR and PEG-CUR-SPC NPs. These results suggest that the FA targeted PEGylated CUR-SPC complex self-assembled NPs might be a promising candidate in cancer therapy.     

聚合物用作基因治疗载体的研究进展

综述了近年来聚合物用作非病毒基因治疗载体的研究进展,包括聚氨基葡糖基系统、聚氮丙啶、树枝状聚合物、明胶基系统等,简述了它们各自的特点和体内转染效果。