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 h. 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 h 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.

自宣布“抗癌战争”以来的过去40年中，卵巢癌的死亡率仅略有下降。目前卵巢癌的标准治疗仍是细胞还原手术，随后是数个化疗周期。化疗药物引起的严重不良反应是患者术后长期治疗失败的主要原因。新的纳米载体能够最大程度地减少血液循环中的过早药物释放，同时在肿瘤部位按需释放药物，这对化疗药物的功效和毒性特征的改善产生了深远的影响。在这里，我们报道了一种独特类型的极长的肿瘤保留期，用于卵巢癌治疗的多反应性硼酸酯交联胶束（BCM）。我们系统地研究了BCM在血清和血浆中的稳定性，顺式二醇（例如甘露醇，一种安全的FDA批准的利尿药），通过粒度测量和förster共振能量转移（FRET）方法进行。在血浆或血清存在下，载有紫杉醇（PTX）的BCM（BCM-PTX）的稳定性高于未交联的胶束（NCM）。BCM在体内具有更长的时间与NCM相比，血液循环时间更短。此外，BCM可以在酸性pH环境中分解或通过施用甘露醇来促进，在酸性肿瘤环境中促进药物释放，并在肿瘤团块中富集药物后由外源性刺激触发。在SKOV-3卵巢癌小鼠模型上的近红外荧光（NIRF）成像表明，包裹有NIR染料DiD的BCM可以优先积聚在肿瘤部位，并且它们的肿瘤保留时间非常长，注射后第12天仍保留了66％。DiD-NCM在头3天内具有与DiD-BCM相似的高水平肿瘤摄取，但是其积累在第4天明显下降，并且在12天后仅留下15％的染料。在这两种配方中，正常器官中的染料吸收大部分在最初的24-48小时内被冲走。在在体内肿瘤治疗研究中，载有PTX的BCM显示出比NCM和紫杉醇更好的治疗效果。小鼠可以耐受以纳米制剂配制的20 mg / kg PTX，这使紫杉醇的最大耐受剂量（MTD）翻了一番。BCM-PTX注射后24小时给予甘露醇可进一步改善肿瘤治疗效果并延长小鼠的存活时间。新型的硼酸酯-邻苯二酚交联纳米载体平台展示了其在靶向药物递送方面的卓越能力，不仅可用于卵巢癌治疗，而且对许多其他实体瘤的治疗也将是有益的。