Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
J Control Release. 2017 Oct 28;264:169-179. doi: 10.1016/j.jconrel.2017.08.028. Epub 2017 Aug 25.
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 3days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24-48h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20mg/kg PTX formulated in nano-formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24h 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，过去四十年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减灭术后辅以几轮化疗。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。新的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有深远影响。在这里，我们报道了一种用于卵巢癌治疗的独特的超长肿瘤滞留、多响应硼酸交联胶束（BCM）。我们系统地研究了 BCM 在血清和血浆中的稳定性，以及它们对酸性 pH 和顺式二醇（如甘露醇，一种用于利尿的安全 FDA 批准药物）的响应性，通过粒径测量和Förster 共振能量转移（FRET）方法。紫杉醇（PTX）负载的 BCM（BCM-PTX）在存在血浆或血清的情况下比非交联胶束（NCM）更稳定。与 NCM 相比，BCM 在体内的血液循环时间更长。此外，BCM 可以在酸性 pH 环境下或通过给予甘露醇而分解，促进在酸性肿瘤环境中的药物释放，并在外源刺激下在肿瘤部位药物富集后触发。SKOV-3 卵巢癌小鼠模型的近红外荧光（NIRF）成像表明，封装在 BCM 中的近红外染料 DiD 可以优先积聚在肿瘤部位，其肿瘤保留时间非常长，在注射后 12 天仍有 66%保留。DiD-NCM 在第 1 天至第 3 天内在肿瘤中的摄取水平相似，但在第 4 天明显减少，12 天后仅留下 15%的染料。在这两种制剂中，正常器官中的染料摄取在 24-48 小时内大部分被冲洗掉。在体内肿瘤治疗研究中，负载 PTX 的 BCM 显示出比 NCM 和 Taxol 更好的治疗效果。可以耐受纳米制剂中 20mg/kg 的 PTX，是 Taxol 的最大耐受剂量（MTD）的两倍。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，并延长了小鼠的生存时间。新型硼酸-儿茶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，不仅对卵巢癌治疗有用，而且对许多其他实体瘤的治疗也有益。
