Vol.:(0123456789) 1 3 Drug Delivery and Translational Research https://doi.org/10.1007/s13346-020-00867-5 ORIGINAL ARTICLE Co‑delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer Vivek Patel 1  · Rohan Lalani 1  · Imran Vhora 1  · Denish Bardoliwala 1  · Akanksha Patel 1  · Saikat Ghosh 1  · Ambikanandan Misra 1,2 Accepted: 12 October 2020 © Controlled Release Society 2020 Abstract The resistance of cancer cells to chemotherapy has presented a formidable challenge. The current research aims at evaluat- ing whether silencing of the cisplatin efux promoter gene ABCC3 using siRNA co-loaded with the drug in a nanocarrier improves its efcacy in non-small cell lung cancer (NSCLC). Hybrid nanocarriers (HNCs) comprising lipids and poly(lactic acid-polyethylene glycol) di-block copolymer (PEG-PLA) were prepared for achieving the simultaneous delivery of cisplatin caprylate and ABCC3-siRNA to the cancer cells. PEGylation of the formulated HNCs was carried out using post-insertion technique for imparting long circulation characteristics to the carrier. The optimized formulation exhibited an entrapment efciency of 71.9 ± 2.2% and 95.83 ± 0.39% for cisplatin caprylate and siRNA respectively. Further, the HNC was found to have hydrodynamic diameter of 153.2 ± 1.76 nm and + 25.39 ± 0.49 mV zeta potential. Morphological evaluation using cryo transmission electron microscopy confrmed the presence of lipid bilayer surrounding the polymeric core in HNCs. The in vitro cellular uptake studies showed improved uptake, while cell viability studies of the co-loaded formulation in A549 cell-line indicated signifcantly improved cytotoxic potential when compared with drug solution and drug-loaded HNCs; cell cycle analysis indicated increased percentage of cell arrest in G2-M phase compared with drug-loaded HNCs. Further, the gene knock-down study showed that silencing of ABCC3 mRNA might be improved in vitro efcacy of the formulation. The optimized cisplatin and ABCC3 siRNA co-loaded formulation presented signifcantly increased half-life and tumour regression in A549 xenograft model in BALB/c nude mice. In conclusion, siRNA co-loaded formulation presented reduced drug resistance and increased efcacy, which might be promising for the current cisplatin-based treatments in NSCLC. Keywords Cisplatin · Lung cancer · Nanocarrier · Resistance · Simultaneous · siRNA Abbreviations HNCs Hybrid nanocarriers CCL-HNCs Cisplatin caprylate-loaded HNCs CCL-p-HNCs PEGylated CCL-HNCs rCCL-p-HNCs SiRNA complexed CCL-p-HNCs ncr FITC-labelled negative control siRNA (FITC-NC-siRNA) ncrL2K FITC-labelled negative control siRNA complexed with lipofectamine 2000 ncrCCL-p-HNCs FITC-labelled negative control siRNA complexed CCL-p-HNCs Introduction Lung cancer has been the leading cause for cancer death, making up 25% of all cancer related deaths. The treatment regimen for metastatic forms of non-small cell lung cancer (NSCLC) includes intravenous administration of chemother- apeutic agents in combination with either another chemo- therapeutic agent or radiation [1, 2]. However, delivery of these agents is nonselective and has led to toxicity to unin- tended organs. Additionally, the efcacy of these treatments has been reduced due to emergence of drug resistance. Drug resistance has been associated with decreased efectiveness * Ambikanandan Misra Ambikanandan.misra@nmims.edu 1 Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara Gujarat 390001, India 2 Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS University, Mumbai, Maharashtra 400056, India