A Nanostrategy for Efficient Imaging-Guided Antitumor Therapy through a Stimuli-Responsive Branched Polymeric Prodrug

A stimuli-responsive polymeric prodrug-based nanotheranostic system with imaging agents (cyanine5.5 and gadolinium-chelates) and a therapeutic agent paclitaxel (PTX) is prepared via polymerization and conjugating chemistry. The branched polymeric PTX-Gd-based nanoparticles (BP-PTX-Gd NPs) demonstrate excellent biocompatibility, and high stability under physiological conditions, but they stimuli-responsively degrade and release PTX rapidly in a tumor microenvironment. The in vitro behavior of NPs labeled with fluorescent dyes is effectively monitored, and the NPs display high cytotoxicity to 4T1 cells similar to free PTX by impairing the function of microtubules, downregulating anti-apoptotic protein Bcl-2, and upregulating the expression of Bax, cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and p53 proteins. Great improvement in magnetic resonance imaging (MRI) is demonstrated by these NPs, and MRI accurately maps the temporal change profile of the tumor volume after injection of NPs and the tumor treatment process is also closely correlated with the T-1 values measured from MRI, demonstrating the capability of providing real-time feedback to the chemotherapeutic treatment effectiveness. The imaging-guided chemotherapy to the 4T1 tumor in the mice model achieves an excellent anti-tumor effect. This stimuli-responsive polymeric nano-agent opens a new door for efficient breast cancer treatment under the guidance of fluorescence/MRI.

通过聚合和偶联化学方法制备了一种基于刺激响应性聚合物前药的纳米诊疗系统，其中包含成像剂（菁5.5和钆螯合物）以及治疗剂紫杉醇（PTX）。基于支化聚合物PTX - 钆的纳米粒子（BP - PTX - 钆纳米粒子）在生理条件下表现出优异的生物相容性和高稳定性，但在肿瘤微环境中会发生刺激响应性降解并快速释放PTX。用荧光染料标记的纳米粒子的体外行为得到了有效监测，并且这些纳米粒子通过损害微管功能、下调抗凋亡蛋白Bcl - 2以及上调Bax、裂解的半胱天冬酶 - 3、裂解的半胱天冬酶 - 9、裂解的PARP和p53蛋白的表达，对4T1细胞显示出与游离PTX相似的高细胞毒性。这些纳米粒子在磁共振成像（MRI）方面有很大改进，MRI能够准确绘制注射纳米粒子后肿瘤体积的时间变化曲线，并且肿瘤治疗过程也与MRI测量的T - 1值密切相关，这表明其能够为化疗治疗效果提供实时反馈。在小鼠模型中对4T1肿瘤进行的成像引导化疗取得了优异的抗肿瘤效果。这种刺激响应性聚合物纳米制剂为在荧光/MRI引导下高效治疗乳腺癌开辟了新的途径。