J Control Release. 2011 Oct 30;155(2):175-83. doi: 10.1016/j.jconrel.2011.07.040. Epub 2011 Aug 7.
The tumor margins are the barrier to hepatocellular carcinoma (HCC) eradication for tumors>3 cm. Indeed, inadequately treated tumor margins commonly result in local and regional HCC recurrence with increased size and mass. Tumor recurrence is a common problem with chemotherapy, radiotherapy, thermal ablation, and/or surgical resection, by the inability to properly treat the tumor core and the tumor margins. Here we present novel thermosensitive biopolymer-drug conjugates for thermo-targeted chemotherapy at hyperthermic isotherms produced by focal, locoregional thermal ablation. The chemotherapeutic target is heat shock protein 90 (HSP90), a key molecular chaperone of several, and potent pro-oncogenic pathways including Akt, Raf-1, and mutated p53 that is upregulated in HCC. To inhibit HSP90, we have chosen geldanamycin (GA), a potent HSP90 inhibitor. GA has gained significant attention for its low IC50 ~ 1 nM and inhibition of Akt and Raf-1, amongst other critical pro-oncogenic pathways. Despite such evidence, clinical trials of GA have not shown promise due to off-target toxicity and poor formulation design. Here, we propose using diblock elastin-based biopolymers as a Ringsdorf macromolecular GA solubilizer--a new generation containing functional poly(Asp)/(Glu) blocks for facile drug conjugation and an ELP block for thermo-targeting of hyperthermic ablative margins. GA release is controlled by pH-sensitive, covalent hydrazone bonds with the biopolymer backbone to avoid systemic toxicity and off-target effects. The resultant biopolymer-conjugates form stable nanoconstructs and display tunable, acute phase transitions at high temperatures. Drug release kinetics are favorable with or without the presence of serum. Thermo-targeted chemotherapy and synchronous thermal ablation provide a unique opportunity for simultaneous destruction of the HCC ablative margins and tumor core for focal, locoregional control of HCC.
肿瘤边缘是 3cm 以上肝癌（HCC）根治的障碍。事实上，肿瘤边缘处理不当通常会导致 HCC 局部和区域性复发，肿瘤增大和转移。化疗、放疗、热消融和/或手术切除后，由于无法正确治疗肿瘤核心和肿瘤边缘，肿瘤复发是一个常见问题。在这里，我们提出了用于在由局部热消融产生的高热恒温下进行热靶向化疗的新型温敏生物聚合物-药物偶联物。化疗靶点是热休克蛋白 90（HSP90），它是 Akt、Raf-1 和突变型 p53 等几个关键的原癌途径的主要分子伴侣，在 HCC 中上调。为了抑制 HSP90，我们选择了geldanamycin（GA），一种有效的 HSP90 抑制剂。GA 因其低 IC50~1 nM 和对 Akt 和 Raf-1 的抑制作用而受到广泛关注，此外还有其他关键的原癌途径。尽管有这样的证据，但由于非靶点毒性和不良的配方设计，GA 的临床试验并未显示出前景。在这里，我们建议使用二嵌段弹性蛋白基生物聚合物作为 Ringsdorf 大分子 GA 增溶剂-一种包含功能性聚（天冬氨酸）/（谷氨酸）块的新一代生物聚合物，用于方便的药物偶联和 ELP 块用于高热消融边缘的热靶向。GA 释放受生物聚合物主链上的 pH 敏感共价腙键控制，以避免全身毒性和非靶点效应。所得的生物聚合物偶联物形成稳定的纳米结构，并在高温下显示出可调节的急性相转变。无论是否存在血清，药物释放动力学都是有利的。热靶向化疗和同步热消融为同时破坏 HCC 消融边缘和肿瘤核心提供了一个独特的机会，以实现 HCC 的局部和区域性控制。
