Kaipei Luo,Shaoping Yin,Ruixia Zhang,Hua Yu,Guangji Wang,Juan Li
The efficient delivery of chemotherapeutic drugs to the tumor tissues unavoidably encounters numerous obstacles, such as poor tumor targeting capability, slow intracellular drug release and massive accumulation in the liver. In this study, by self-assembling methoxy poly (ethylene glycol)-poly (lactide) block copolymer (mPEG-PLA) and hyaluronic acid-paclitaxel conjugate (HA-PTX), the composite nanoparticles (mPPHP NPs) were fabricated for efficient therapy of cancer. mPPHP NPs formed self-assembled nanoparticles (116 nm in diameter) with a narrow size distribution; and showed a rapid release of PTX in the presence of hyaluronidase and esterase . mPPHP NPs exhibited enhanced internalization by cells via CD44 receptors and selected cytotoxicity against A549 cells in vitro . More importantly, compared with other PTX formulations, mPPHP NPs were demonstrated to present the reduced liver accumulation, excellent tumor-targeting ability and superior antitumor efficacy in vivo , with a TIR of 75.9%. The multifunctional composite nanoparticles could be developed as a promising nano-carrier for improved therapeutic efficacy.
Tirapazamine (TPZ), an antitumor prodrug, can be activated in hypoxic environment. It specifically targets the hypoxic microenvironment of tumors and produces toxic free radicals. However, due to the tumor is not completely hypoxic, TPZ often fails to effectively treat the entire tumor tissue, resulting in suboptimal therapeutic outcomes. Herein, a low pathogenic Escherichia coli TOP10 is utilized to selectively colonize tumor tissues, disrupt blood vessels, and induce thrombus formation, leading to the expansion of hypoxic region and improving the therapeutic effect of TPZ. Additionally, a thermosensitive hydrogel is constructed by Pluronic F-127 (F127), which undergoes gelation in situ at the tumor site, resulting in sustained release of TPZ. To monitor the therapeutic process, it is genetically modified TOP10 by integrating the bioluminescent system luxCDABE (TOP10-Lux). The bioluminescent signal is associated with tumor hypoxia enhancement and thrombus formation, which is beneficial for therapeutic monitoring with bioluminescence imaging. In the murine colon cancer model, the TOP10-Lux combined with TPZ-loaded F127 hydrogel effectively suppressed tumor growth, and the treatment process is efficiently monitored. Together, this work employs genetically modified TOP10-Lux to enhance the therapeutic efficacy of TPZ and monitor the treatment process, providing an effective strategy for bacteria-based tumor-targeted chemotherapy and treatment monitoring.
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