Tavares Marina R, Hrabánková Klára, Konefał Rafał, Kaňa Martin, Říhová Blanka, Etrych Tomáš, Šírová Milada, Chytil Petr
Institute of Macromolecular Chemistry of the Czech Academy of Sciences, Heyrovského náměstí 2, CZ-162 06 Prague 6, Czech Republic.
Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 20 Prague 4, Czech Republic.
Pharmaceutics. 2021 Jan 28;13(2):179. doi: 10.3390/pharmaceutics13020179.
The study describes the synthesis, physicochemical properties, and biological evaluation of polymer therapeutics based on -(2-hydroxypropyl)methacrylamide (HPMA) copolymers intended for a tumor-targeted immuno-oncotherapy. Water-soluble linear and cholesterol-containing HPMA precursors were synthesized using controlled reversible addition-fragmentation chain transfer polymerization to reach molecular weight about 2 × 10 g·mol and low dispersity. These linear or self-assembled micellar conjugates, containing immunomodulatory agent cucurbitacin-D (CuD) or the anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond, showed a hydrodynamic size of 10-30 nm in aqueous solutions. The CuD-containing conjugates were stable in conditions mimicking blood. Importantly, a massive release of active CuD in buffer mimicking the acidic tumor environment was observed. In vitro, both the linear (LP-CuD) and the micellar (MP-CuD) conjugates carrying CuD showed cytostatic/cytotoxic activity against several cancer cell lines. In a murine metastatic and difficult-to-treat 4T1 mammary carcinoma, only LP-CuD showed an anticancer effect. Indeed, the co-treatment with Dox-containing micellar polymer conjugate and LP-CuD showed potentiation of the anticancer effect. The results indicate that the binding of CuD, characterized by prominent hydrophobic nature and low bioavailability, to the polymer carrier allows a safe and effective delivery. Therefore, the conjugate could serve as a potential component of immuno-oncotherapy schemes within the next preclinical evaluation.
该研究描述了基于聚（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物的聚合物疗法的合成、物理化学性质及生物学评价，这些共聚物用于肿瘤靶向免疫肿瘤治疗。采用可控可逆加成-断裂链转移聚合反应合成了水溶性线性含胆固醇HPMA前体，以达到约2×10⁴ g·mol的分子量和低分散度。这些线性或自组装胶束缀合物含有通过可水解降解的腙键共价结合的免疫调节剂葫芦素-D（CuD）或抗癌药物阿霉素（Dox），在水溶液中的流体力学尺寸为10-30 nm。含CuD的缀合物在模拟血液的条件下稳定。重要的是，在模拟酸性肿瘤环境的缓冲液中观察到活性CuD的大量释放。在体外，携带CuD的线性（LP-CuD）和胶束（MP-CuD）缀合物对几种癌细胞系均表现出细胞生长抑制/细胞毒性活性。在小鼠转移性且难以治疗的4T1乳腺癌中，只有LP-CuD显示出抗癌作用。实际上，含Dox的胶束聚合物缀合物与LP-CuD联合治疗显示出抗癌作用的增强。结果表明，具有显著疏水性和低生物利用度的CuD与聚合物载体的结合实现了安全有效的递送。因此，在接下来的临床前评估中，该缀合物可作为免疫肿瘤治疗方案的潜在组成部分。
