Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.
Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
J Control Release. 2018 Oct 28;288:45-61. doi: 10.1016/j.jconrel.2018.08.039. Epub 2018 Aug 30.
In the current study, thermoresponsive poly(N-isopropylacrylamide)-doxorubicin (PNIPAM-DOX) hydrogel was synthesized and loaded into pH-responsive poly ethylene glycol)-2,4,6- trimethoxy benzylidene pentaerythritol carbonate (PEG-PTMBPEC) polymersomes in order to fabricate a smart thermo-pH stimuli responsive drug delivery system. Thermo-pH responsive polymersomal formulation of DOX revealed average size of 170 ± 11.2 nm. The prepared system was loaded with PNIPAM-DOX conjugate with encapsulation efficiency of 30.80%. The in vivo release evaluation demonstrated that the DOX release from polymersomal formulation was pH-dependent, i.e. significantly faster drug release at pH 5.5and 6.5 compared to physiological pH. On the other hand, the drug release rate was significantly decreased at 37 °C due to the gelation of PNIPAM-DOX conjugate in the interior compartment of the pH-responsive polymersomes. The in vivo anti-tumor efficiency of the prepared polymersomal formulation of DOX was evaluated implementing C26 tumor-bearing mice after either intravenous (i.v.) or intratumoral (i.t.) single dose injection. The obtained results demonstrated that the prepared system significantly inhibited tumor growth rate in mice receiving single dose via either intravenous or intratumoral injection in comparison with free DOX-treatment group. Furthermore, treatment with polymersomal formulation did not cause any systematic toxicity in terms of pathological alteration of vital organs, survival rate and body weight loss. The prepared smart hydrosomal formulation significantly increased the blood half life time of drug and modified the biodistribution and pharmacokinetic parameters of formulated DOX. In this regard, thermo-pH-dual-stimuli responsive hydrosomal formulation represent a novel approach in nanomedicine development for effective cancer therapy.
在本研究中，合成了温敏性聚（N-异丙基丙烯酰胺）-阿霉素（PNIPAM-DOX）水凝胶，并将其装载到 pH 响应性聚乙二醇）-2,4,6-三甲氧基苄叉基五赤藓糖醇碳酸酯（PEG-PTMBPEC）聚合物囊泡中，以构建智能温- pH 刺激响应药物递送系统。DOX 的温-pH 响应聚合物囊泡制剂的平均粒径为 170 ± 11.2nm。该系统用 PNIPAM-DOX 缀合物进行了负载，包封效率为 30.80%。体内释放评价表明，DOX 从聚合物囊泡制剂中的释放是 pH 依赖性的，即在 pH 5.5 和 6.5 时比生理 pH 时药物释放更快。另一方面，由于 pH 响应性聚合物囊泡内部隔室中 PNIPAM-DOX 缀合物的胶凝作用，药物释放速率在 37°C 时显著降低。通过静脉（i.v.）或肿瘤内（i.t.）单次剂量注射后，在 C26 荷瘤小鼠中评价了所制备的 DOX 聚合物囊泡制剂的体内抗肿瘤效率。结果表明，与游离 DOX 治疗组相比，通过静脉或肿瘤内注射单次剂量，所制备的系统显著抑制了小鼠的肿瘤生长速度。此外，聚合物囊泡制剂治疗不会引起任何系统性毒性，包括重要器官的病理改变、存活率和体重减轻。所制备的智能水囊泡制剂显著增加了药物的血液半衰期，并改变了制剂 DOX 的生物分布和药代动力学参数。在这方面，温-pH-双重刺激响应水囊泡制剂代表了纳米医学发展中的一种新方法，可用于有效的癌症治疗。
