An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy
An oral drug delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy
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用于原位结肠癌治疗的具有程序化药物释放和成像特性的口服药物递送系统
DOI：
10.1039/c9nr03802g
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发表时间：
2019-09-14
期刊：
影响因子：
6.7
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
--
作者：
Song, Qingling;Jia, Jiajia;Zhang, Yun
口服给药系统（ODDS）由于某些受欢迎的优点，在原位结肠癌治疗方面引起了相当大的关注。不幸的是，它们的临床应用通常受到全身药物暴露引起的副作用和实时监测能力差的限制。受胃肠道pH值变化和结肠菌群分泌特异性酶的特点的启发，我们将聚丙烯酸（PAA）和壳聚糖（CS）锚定在Gd 3+掺杂的介孔羟基磷灰石纳米颗粒（Gd-MHAp NPs）上，实现肿瘤部位的程序化药物释放和磁共振成像（MRI）。特别是，接枝PAA，作为pH响应开关，可以实现药物在结肠中的控制释放。此外，CS被官能化为酶敏感部分，其可以被结肠中的β-糖苷酶降解。钆是一种用于螯合物的顺磁性镧系元素，用作MRI系统的造影剂。有趣的是，口服给药后，CS和PAA可以保护载药纳米颗粒（NP）免受GIT中可变生理条件的影响，使药物到达结肠肿瘤部位，防止药物过早释放。通过这种程序化的药物释放实现了结肠肿瘤部位的药物浓度提高，随后改善了治疗效果。此外，将化疗药物（5-氟尿嘧啶，5-FU）和靶向治疗药物（吉非替尼，Gef）包封在Gd-MHAp NP内产生协同治疗效果。总之，本研究表明，这种新型药物系统（Gd-MHAp/5-FU/Gef/CS/PAA NPs）可以在结肠环境中局部保护、转运和程序化药物释放;此外，该系统表现出有价值的治疗效果，为原位结肠癌提供了一种有前途的新型治疗策略。
Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by beta-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.