Journal
PHARMACEUTICS
Volume 12, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics12121169
Keywords
prodrug conjugates; self-assembled; microfluidics; lung cancer; combination therapy
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Funding
- Distinguished Clinical Investigator Grant of Jiangsu Province, China [JSTP201701]
- Jiangsu Provincial Key Research and Development Programme [BE2018690]
- Natural Science Basic Research Program of Shanxi [2020JM-141]
- Project for Graduate Innovation Team of Northwestern Polytechnical University
- Department of Science & Technology of Shaanxi Province [2020GXLH-Z-017]
- Northwestern Polytechnical University [2020GXLH-Z-017]
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Self-assembled prodrugs (SAPDs), which combine prodrug strategy and the merits of self-assembly, not only represent an appealing type of therapeutics, enabling the spontaneous organization of supramolecular nanocomposites with defined structures in aqueous environments, but also provide a new method to formulate existing drugs for more favorable outcomes. To increase drug loading and combination therapy, we covalently conjugated paclitaxel (PTX) and camptothecin (CPT) through a disulfide linker into a prodrug, designated PTX-S-S-CPT. The successful production of PTX-S-S-CPT prodrug was confirmed by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). This prodrug spontaneously undergoes precipitation in aqueous surroundings. Taking advantage of a flow-focusing microfluidics platform, the prodrug nanoparticles (NPs) have good monodispersity, with good reproducibility and high yield. The as-prepared prodrug NPs were characterized with dynamic light scattering (DLS) and transmission electron microscopy (TEM), demonstrating spherical morphology of around 200 nm in size. In the end, the self-assembled NPs were added to mouse embryonic fibroblast (MEF), mouse lung adenocarcinoma and Lewis lung carcinoma (LLC) cell lines, and human non-small cell lung cancer cell line A549 to evaluate cell viability and toxicity. Due to the redox response with a disulfide bond, the PTX-S-S-CPT prodrug NPs significantly inhibited cancer cell growth, but had no obvious toxicity to healthy cells. This prodrug strategy is promising for co-delivery of PTX and CPT for lung cancer treatment, with reduced side effects on healthy cells.
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