J. Control Release：载紫杉醇的纳米脂质体-微泡复合物作为超声促发的药物载体

最新发布的2013年1月国际学术期刊《控释杂志》（Journal of Controlled Release）发表了中国科学院深圳先进技术研究院生物医学与健康工程研究所生物医学超声研究组的最新成果：载紫杉醇的纳米脂质体-微泡复合物作为超声促发的药物载体及其抗肿瘤作用的研究。（在线发表于2013年1月7日）

超声不仅仅是一种重要的医学成像诊断工具，其机械波及辐射力特性也赋予其在声操控、给药及治疗领域的重要应用潜力。近年来，载药超声微泡的出现，使得微泡在作为超声造影剂用于疾病诊断的同时，也可作为药物载体用于疾病的治疗。一方面，载药超声微泡在受到低频超声辐照时，微泡会发生爆破从而释放其中携载的药物；另一方面，超声微泡在较低声压作用下产生的空化或声孔效应，可使临近细胞产生瞬间可修复的细胞膜空隙，从而大大增加药物的细胞摄取和生物利用度。迄今，超声靶向微泡爆破介导药物或基因的靶向传递已经成为一种新型的给药方法，是目前药物传递系统研究的热点课题。然而，现行应用的单层微泡脂质壳层的载药能力有限，往往难于达到疾病治疗的有效剂量。

针对这一问题，严飞等将紫杉醇药物包裹于具有高载药量的脂质体中，进而偶联到超声微泡的表面，获得了具有高载药量和具有超声爆破释放性能的载药脂质体-微泡复合物，从而巧妙地解决了这一问题。经过1年多的实验研究，研究人员对这一新型的声敏载药脂质体-微泡复合物进行了详细的表征，发现这种新型的脂质体-微泡复合物能够大大增加药物的载药量和包封率，并对其体外药物释放特性进行了测定、在优化的超声参数条件下可以显著增加肿瘤细胞对药物的摄取，在体外细胞以及体内动物实验证实了该载药脂质体-微泡复合物联合超声可以显著提高紫杉醇药物的抗肿瘤效果并增加药物在肿瘤部位的浓度，免疫组织化学进一步分析发现其抗肿瘤作用的机制主要是通过增加肿瘤组织的细胞凋亡和抑制肿瘤新生血管生成来实现的。

本研究进一步证实了载药脂质体-微泡复合物在体内的抗肿瘤疗效并揭示了其抗肿瘤效应的作用机制，为超声敏锐成像诊断/给药/治疗一体化应用研究奠定了基础。

DOI:10.1016/j.jconrel.2012.12.009
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Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel

Rui Zhanga, 1, Kui Luoa, 1, Jiyuan Yanga, Monika Simaa, Yongen Sunb, Margit M. Janát-Amsburyb, Jindřich Kopečeka, c

The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.