Overcoming multidrug resistance through inhalable siRNA nanoparticles-decorated porous microparticles based on supercritical fluid technology

Pei-Yao Xu,1,2 Ranjith Kumar Kankala,1–3 Yu-Jing Pan,1,2 Hui Yuan,1,2 Shi-Bin Wang,1–3 Ai-Zheng Chen1–3 1College of Chemical Engineering, Huaqiao University, Xiamen 361021, P. R. China; 2Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, P. R. China; 3Fujian Provincial Key Laboratory of Biochemical Technology (Huaqiao University), Xiamen 361021, P. R. China Background: In recent times, the co-delivery therapeutics have garnered enormous interest from researchers in the treatment of cancers with multidrug resistance (MDR) due to their efficient delivery of multiple agents, which result in synergistic effects and capable of overcoming all the obstacles of MDR in cancer. However, an efficient delivery platform is required for the conveyance of diverse agents that can successfully devastate MDR in cancer. Methods: Initially, short-interfering RNA-loaded chitosan (siRNA-CS) nanoparticles were synthesized using the ionic gelation method. Further, the siRNA-CS nanoparticles and doxorubicin hydrochloride (DOX) were co-loaded in poly-L-lactide porous microparticles (PLLA PMs) (nano-embedded porous microparticles, [NEPMs]) by the supercritical anti-solvent (SAS) process. Results and discussion: The NEPM formulation exhibited an excellent aerodynamic performance and sustained release of DOX, which displayed higher anticancer efficacy in drug-resistant cells (human small cell lung cancer, H69AR cell line) than those treated with either free DOX and DOX-PLLA PMs due to the siRNA from CS nanoparticles silenced the MDR gene to DOX therapy. Conclusion: This eco-friendly process provides a convenient way to fabricate such innovative NEPMs co-loaded with a chemotherapeutic agent and a gene, which can devastate MDR in cancer through the co-delivery system. Keywords: pulmonary delivery, short-interfering RNA, multidrug resistance, doxorubicin, supercritical carbon dioxid