Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 163, Issue -, Pages 188-197Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2021.04.008
Keywords
Dasatinib; Prodrug; Tumor therapy; Ortho ester; Nanoparticles
Categories
Funding
- National Natural Science Foundation of China [51803001, 51503001]
- Anhui Provincial Natural Science Foundation [2008085ME136, 2008085QE210]
- Research Foundation of Education Department of Anhui Province of China [KJ2018ZD003, KJ2018A0006, KJ2019A0015]
- Academic and Technology Introduction Project of Anhui University [AU02303203]
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The study developed a self-delivered prodrug system with nanoscale characteristics to enhance tumor therapy efficacy. The pH-sensitive prodrug nanoparticles simultaneously released dasatinib and doxorubicin, demonstrating remarkable antitumor effects. This prodrug system shows great potential in cancer therapy.
The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.
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