Camptothecin (CPT) is a promising anticancer drug, yet its therapeutic potential has been limited by poor water solubility and facile hydrolysis of the lactone form into an inactive carboxylate form at neutral pH. In this work, a fundamental synthetic methodology was advanced to allow for the preparation of well-defined functional polyphosphoramidate (PPA)-based block copolymers that coassembled with CPT into nanoparticles, which underwent coincident acid-triggered polymer backbone degradation, nanoparticle disassembly, and CPT release. Encapsulation of CPT by the PPA polymer inhibited premature hydrolysis of CPT at pH 7.4 and enabled accelerated CPT release at pH 5.0 (ca. 4× faster than at pH 7.4). Two degradable oxazaphospholidine monomers, with one carrying an alkyne group, were synthesized to access well-defined block PPAs (dispersity, Đ<1.2) via sequential organobase-catalyzed ring-opening polymerizations (ROP). The resulting amphiphilic block copolymers (PEOMP-b-PBYOMP) were physically loaded with CPT to achieve well-dispersed nanotherapeutics, which allowed the aqueous suspension of CPT at concentrations up to 3.2 mg/mL, significantly exceeding the aqueous solubility of the drug (<2.0 μg/mL at 37 °C). Cytotoxicity studies revealed enhanced efficacy of the CPT-loaded nanoparticles over free CPT in cancer cells and similar toxicity in normal cells.

中文翻译：

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酸引发的聚合物主链降解和分解以实现从功能性聚磷酰胺纳米颗粒中释放喜树碱

喜树碱 (CPT) 是一种很有前途的抗癌药物，但其治疗潜力受到水溶性差和内酯形式在中性 pH 下容易水解成无活性羧酸盐形式的限制。在这项工作中，提出了一种基本的合成方法，以允许制备定义明确的功能性聚磷酰胺 (PPA) 基嵌段共聚物，该嵌段共聚物与 CPT 共组装成纳米颗粒，同时经历酸引发的聚合物骨架降解、纳米颗粒分解和 CPT发布。PPA 聚合物对 CPT 的封装抑制了 CPT 在 pH 7.4 下的过早水解，并在 pH 5.0 下加速了 CPT 的释放（比在 pH 7.4 下快 4 倍）。合成了两种可降解的恶氮杂磷脂单体，其中一种带有炔基，以获得明确定义的嵌段 PPA（分散性，Đ <1.2）通过顺序有机碱催化的开环聚合（ROP）。所得两亲嵌段共聚物 (PEOMP- b -PBYOMP) 与 CPT 物理负载以实现良好分散的纳米治疗，这使得 CPT 的水悬浮液浓度高达 3.2 mg/mL，显着超过药物的水溶性 (< 37 °C 时为 2.0 μg/mL）。细胞毒性研究表明，负载 CPT 的纳米颗粒比游离 CPT 在癌细胞中的功效增强，并且在正常细胞中具有相似的毒性。