Koshrovski-Michael Shani, Ajamil Daniel Rodriguez, Dey Pradip, Kleiner Ron, Tevet Shahar, Epshtein Yana, Green Buzhor Marina, Khoury Rami, Pozzi Sabina, Shenbach-Koltin Gal, Yeini Eilam, Woythe Laura, Blau Rachel, Scomparin Anna, Barshack Iris, Florindo Helena F, Lazar Shlomi, Albertazzi Lorenzo, Amir Roey J, Satchi-Fainaro Ronit
Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Chemistry, Siksha Bhavana, Visva-Bharati University, Santiniketan, West Bengal 731235, India.
Sci Adv. 2024 Dec 13;10(50):eadr4762. doi: 10.1126/sciadv.adr4762.
Combined therapies in cancer treatment aim to enhance antitumor activity. However, delivering multiple small molecules imposes challenges, as different drugs have distinct pharmacokinetic profiles and tumor penetration abilities, affecting their therapeutic efficacy. To circumvent this, poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-based nanoparticles were developed as a platform for the codelivery of synergistic drug ratios, improving therapeutic efficacy by increasing the percentage of injected dose reaching the tumor. Nonetheless, extravasation-dependent tumor accumulation is susceptible to variations in tumor vasculature; therefore, PLGA-PEG was modified with sulfates to actively target P-selectin-expressing cancers. Here, we show the potential of our platform in unique three-dimensional (3D) in vitro and in vivo models. The P-selectin-targeted nanoparticles showed enhanced accumulation in 3D spheroids and tissues of P-selectin-expressing BRAF-mutated melanomas and BRCA-mutated breast cancers, resulting in superior in vivo efficacy and safety. This nanoplatform could advance the codelivery of a plethora of anticancer drug combinations to various P-selectin-expressing tumors.
癌症治疗中的联合疗法旨在增强抗肿瘤活性。然而，递送多种小分子存在挑战，因为不同药物具有不同的药代动力学特征和肿瘤穿透能力，这会影响它们的治疗效果。为了规避这一问题，聚乳酸-羟基乙酸共聚物（PLGA）-聚乙二醇（PEG）基纳米颗粒被开发为一种协同药物比例共递送的平台，通过提高到达肿瘤的注射剂量百分比来提高治疗效果。尽管如此，依赖于血管外渗的肿瘤蓄积易受肿瘤血管系统变化的影响；因此，用硫酸盐对PLGA-PEG进行修饰，以主动靶向表达P-选择素的癌症。在此，我们展示了我们的平台在独特的三维（3D）体外和体内模型中的潜力。P-选择素靶向纳米颗粒在表达P-选择素的BRAF突变黑色素瘤和BRCA突变乳腺癌的3D球体和组织中显示出增强的蓄积，从而产生卓越的体内疗效和安全性。这种纳米平台可以推动大量抗癌药物组合共递送至各种表达P-选择素的肿瘤。
