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Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer

Abstract

The resistance of cancer cells to chemotherapy has presented a formidable challenge. The current research aims at evaluating whether silencing of the cisplatin efflux promoter gene ABCC3 using siRNA co-loaded with the drug in a nanocarrier improves its efficacy 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 efficiency 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 confirmed 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 significantly 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 efficacy of the formulation. The optimized cisplatin and ABCC3 siRNA co-loaded formulation presented significantly 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 efficacy, which might be promising for the current cisplatin-based treatments in NSCLC.

Graphical abstract

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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

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Acknowledgements

The authors are thankful to Prof. Paola Luciani (Former Professor of Phospholipids in drug delivery at Friedrich schiller university of Jena) for providing laboratory and technical support in completion of current work and Dr Bhavin Vyas (Head, Department of Pharmacology, Maliba Pharmacy College, Uka Tarsadia University, Bardoli) for providing facilities for animal studies. The authors acknowledge support from Indian institute of technology (IIT), Gandhinagar for AFM studies, Prof Ashish Ganguly of Institute of microbial technology (IMTech), Chandigarh for SAXS studies, Sun Pharmaceutical advanced research centre (SPARC), Vadodara for Cryo-TEM studies.

Funding

This work was supported by Department of Science and Technology (DST), Government of India and German academic exchange service (DAAD), a collaborative project between Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda and Friedrich schiller university of Jena, Germany. The contingency grant was provided by University grant commission (UGC), Government of India.

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Correspondence to Ambikanandan Misra.

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Patel, V., Lalani, R., Vhora, I. et al. Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer. Drug Deliv. and Transl. Res. 11, 2052–2071 (2021). https://doi.org/10.1007/s13346-020-00867-5

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Keywords

  • Cisplatin
  • Lung cancer
  • Nanocarrier
  • Resistance
  • Simultaneous
  • siRNA