Dragulska Sylwia A, Acosta Santiago Maxier, Swierczek Sabina, Chuang Linus, Camacho-Vanegas Olga, Camacho Sandra Catalina, Padron-Rhenals Maria M, Martignetti John A, Mieszawska Aneta J
Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA.
Rudy L. Ruggles Biomedical Research Institute, Nuvance Health, Danbury, CT 06810, USA.
Pharmaceutics. 2025 May 23;17(6):689. doi: 10.3390/pharmaceutics17060689.
We developed a novel biodegradable poly(lactic-co-glycolic acid) (PLGA) polymer chemically modified with paclitaxel (PTX) to form a PLGA-PTX hybrid. Pre-modification of PTX enhanced its loading in PLGA-PTX nanoparticles (NPs). : PTX is one of the most effective chemotherapy agents used in cancer therapy. The primary mode of PTX's action is the hyperstabilization of microtubules leading to cell growth arrest. Although highly potent, the drug is water insoluble and requires the Cremophor EL excipient. The toxic effects of the free drug (e.g., neurotoxicity) as well as its solubilizing agent are well established. Thus, there is strong clinical rationale and need for exploring alternative PTX delivery approaches, retaining biological activity and minimizing systemic effects. : The PTX modification method features reacting the C-2' and C-7 residues with a linker (succinic anhydride) to produce easily accessible carboxyl groups on the PTX for enhanced coupling to the hydroxyl group of PLGA. The PLGA-PTX hybrid, formed via esterification reaction, was used to formulate lipid-coated PLGA-PTX NPs. As proof of concept, the PLGA-PTX NPs were tested in ovarian cancer (OvCA) models, including several patient-derived cell lines (PDCLs), one of which was generated from a platinum-resistant patient. : The PLGA-PTX NPs critically remained stable in water and serum while enabling slow drug release. Importantly, PLGA-PTX NPs demonstrated biological activity. : We suggest that this approach offers both a new and effective PTX formulation and a possible path towards the development of a new generation of OvCA treatment.
我们开发了一种新型的可生物降解的聚乳酸-乙醇酸共聚物（PLGA）聚合物，该聚合物用紫杉醇（PTX）进行了化学修饰，以形成PLGA-PTX杂化物。PTX的预修饰提高了其在PLGA-PTX纳米颗粒（NPs）中的负载量。PTX是癌症治疗中使用的最有效的化疗药物之一。PTX的主要作用方式是使微管超稳定，导致细胞生长停滞。尽管该药物效力很强，但它不溶于水，需要使用聚氧乙烯蓖麻油（Cremophor EL）辅料。游离药物的毒性作用（如神经毒性）及其增溶剂的毒性作用已得到充分证实。因此，有很强的临床理由和需求来探索替代的PTX递送方法，以保持生物活性并最小化全身影响。PTX修饰方法的特点是使C-2'和C-7残基与连接体（琥珀酸酐）反应，在PTX上产生易于连接的羧基，以增强与PLGA羟基的偶联。通过酯化反应形成的PLGA-PTX杂化物用于制备脂质包被的PLGA-PTX NPs。作为概念验证，PLGA-PTX NPs在卵巢癌（OvCA）模型中进行了测试，包括几种患者来源的细胞系（PDCLs），其中一种是由铂耐药患者产生的。PLGA-PTX NPs在水和血清中保持稳定，同时能够缓慢释放药物。重要的是，PLGA-PTX NPs表现出生物活性。我们认为，这种方法既提供了一种新的有效的PTX制剂，也为开发新一代OvCA治疗方法提供了一条可能的途径。
