Institute for Clean Energy and Advanced Materials, Faculty of Materials and Energy, Southwest University, Chongqing 400715, PR China; Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Chongqing 400715, PR China.
School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing 400044, PR China.
Acta Biomater. 2018 Sep 1;77:228-239. doi: 10.1016/j.actbio.2018.07.014. Epub 2018 Jul 10.
The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy.
This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy.
纳米医学的目标是寻求更有效的策略来解决传统药物面临的各种限制和挑战，包括缺乏靶向特异性、生物利用度差、过早降解和不良副作用。自组装药物两亲体由于其与原始药物相比具有有利的给药途径和治疗效率，因此代表了一种有前途的癌症治疗纳米医学。在这项工作中，我们报告了一类自递送前药两亲体，由亲水性药物甲氨蝶呤（MTX）和疏水性抗癌药物喜树碱（CPT）和阿霉素（DOX）组成，用于靶向和联合化疗。将二硫键和腙键引入到这些治疗剂中，以形成两种前药两亲体，分别命名为 MTX-CPT 和 MTX-DOX，它们可以在水介质中自组装成稳定的前药纳米聚集体（NA）。前药 NA 中的 MTX 分子促进了具有高叶酸受体（FR）表达的肿瘤细胞对 NA 的摄取。这项系统研究提供了明确的证据，证明联合使用两种前药 NA 对体外各种肿瘤细胞和体内异种移植肿瘤模型的协同治疗效果。所获得的前药两亲体为设计多功能药物递送系统和精心设计的癌症化疗治疗纳米平台提供了一种有效的策略。
