Guerassimoff Léa, Ferrere Marianne, Van Herck Simon, Dehissi Samy, Nicolas Valérie, De Geest Bruno G, Nicolas Julien
Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, Orsay 91400, France.
Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, Ghent 9000, Belgium.
J Control Release. 2024 May;369:376-393. doi: 10.1016/j.jconrel.2024.03.049. Epub 2024 Apr 4.
Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the "drug-initiated" synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50-80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination.
尽管大多数用于药物递送的聚合物基纳米载体具有很强的通用性且易于功能化，但它们往往面临严重的局限性，这些局限性可能会阻碍其临床应用，例如药物释放不受控制和脱靶毒性，这主要源于突释现象。此外，制剂过程中残留的溶剂会诱导毒性、改变物理化学和生物学性质，并严重损害进一步的药物研发。为了解决这些问题，我们报道了聚合物前药纳米颗粒，它们是通过全水性制剂工艺在无有机溶剂的情况下制备的，并能实现药物的持续释放。这是通过“药物引发”合成具有较低临界溶解温度（LCST）且基于抗癌药物吉西他滨（Gem）的明确共聚物前药来实现的。在筛选了不同的结构参数后，基于两亲性二嵌段共聚物的前药通过全水性纳米沉淀法制成了稳定的纳米颗粒，粒径分布相当窄，平均直径在50 - 80纳米范围内。它们在人血清和醋酸盐缓冲液中表现出吉西他滨的持续释放、快速的细胞摄取以及对A549和Mia PaCa - 2癌细胞的显著细胞毒性。我们还通过制备负载阿霉素（Dox）用于联合治疗的基于吉西他滨的聚合物前药纳米颗粒，证明了这种方法的通用性。双药纳米颗粒在人血清中表现出吉西他滨的持续释放，在加速的病理生理条件下表现出阿霉素的酸性释放。重要的是，它们还对三阴性乳腺癌细胞系MDA - MB - 231产生了协同作用，该细胞系与这种联合治疗相关。
