Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer.
Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer.
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DOI：
10.1016/j.jconrel.2017.08.028
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发表时间：
2017-10-28
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Xiao W;Suby N;Xiao K;Lin TY;Al Awwad N;Lam KS;Li Y
卵巢癌的死亡率在过去的四十年里，自“对癌症的战争”宣布以来，仅略有下降。目前卵巢癌的标准治疗仍然是细胞减灭术，然后是几个周期的化疗。化疗药物的严重不良反应是导致患者术后长期治疗失败的主要原因。新型纳米载体能够最大限度地减少药物在血液循环中的过早释放，同时在肿瘤部位按需释放药物，这对改善化疗药物的疗效和毒性特征具有深远的影响。在这里，我们报告了一种独特类型的极长的肿瘤保留，多响应硼酸酯交联胶束（胶束）的卵巢癌治疗。我们通过粒度测量和福斯特共振能量转移（FRET）方法系统研究了血清和血浆中的稳定性，以及它们对酸性pH和顺式二醇（如甘露醇，一种安全的FDA批准的利尿药物）的反应性。在血浆或血清存在下，紫杉醇（PTX）负载的胶束（BCM-PTX）表现出比非交联胶束（NCM）更高的稳定性。与NCM相比，BCM具有更长的体内血液循环时间。此外，在酸性pH环境中或通过施用甘露醇，可以分解肿瘤细胞，促进药物在酸性肿瘤环境中的释放，并在肿瘤块中药物富集后由外源性刺激触发。SKOV-3卵巢癌小鼠模型的近红外荧光（NIRF）成像表明，近红外染料DiD包封的NH3可以优先在肿瘤部位积聚，并且它们的肿瘤保留非常长，在注射后12天仍保留66%。DiD-NCM在肿瘤中的摄取量在前3天内与DiD-NCM相似，但在第4天明显减少，12天后仅剩下15%的染料。在两种制剂中，正常器官中的染料摄取在前24-48小时内大部分被洗掉。在体内肿瘤治疗研究中，紫杉醇负载的紫杉醇显示出优于NCM和Taxol的上级治疗效果。小鼠可以耐受以纳米制剂配制的20 mg/kg PTX，这是紫杉醇最大耐受剂量（MTD）的两倍。在BCM-PTX注射后24小时给予甘露醇进一步提高了肿瘤治疗效果并延长了小鼠的存活时间。新型硼酸酯-邻苯二酚交联纳米载体平台显示了其上级的靶向药物递送能力，这不仅可用于卵巢癌的治疗，而且还将有益于许多其他实体肿瘤的治疗。
Mortality rates for ovarian cancer have declined only slightly in the past forty years since the “War on Cancer” was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and förster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non-crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66% remained on 12th day post injection. DiD-NCM had similar high- level uptake in tumor with DiD-BCM within the first 3 days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12 days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24–48 hrs. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20 mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24 hrs after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors.
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