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Targeting KRAS Mutant Lung Cancer Cells with siRNA-Loaded Bovine Serum Albumin Nanoparticles

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Abstract

Purpose

KRAS is the most frequently mutated gene in human cancers. Despite its direct involvement in malignancy and intensive effort, direct inhibition of KRAS via pharmacological inhibitors has been challenging. RNAi induced knockdown using siRNAs against mutant KRAS alleles offers a promising tool for selective therapeutic silencing in KRAS-mutant lung cancers. However, the major bottleneck for clinical translation is the lack of efficient biocompatible siRNA carrier systems.

Methods

Bovine serum albumin (BSA) nanoparticles were prepared by desolvation method to deliver siRNA targeting the KRAS G12S mutation. The BSA nanoparticles were characterized with respect to their size, zeta potential, encapsulation efficiency and nucleic acid release. Nanoparticle uptake, cellular distribution of nucleic acids, cytotoxicity and gene knock down to interfere with cancer hallmarks, uncontrolled proliferation and migration, were evaluated in KRAS G12S mutant A459 cells, a lung adenocarcinoma cell line.

Results

BSA nanoparticles loaded with siRNA resulted in nanoparticles smaller than 200 nm in diameter and negative zeta potentials, displaying optimal characteristics for in vivo application. Encapsulating and protecting the siRNA payload well, the nanoparticles enabled transport to A549 cells in vitro, could evade endosomal entrapment and mediated significant sequence-specific KRAS knockdown, resulting in reduced cell growth of siRNA transfected lung cancer cells.

Conclusions

BSA nanoparticles loaded with mutant specific siRNA are a promising therapeutic approach for KRAS-mutant cancers.

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Acknowledgments and Disclosures

This work was in part supported by the Deutsche Gesellschaft für Muskelkranke e.V. (Grant Number 2017-Me7/1) and ERC Starting Grant ERC-2014-StG – 637,830 “Novel Asthma Therapy” to Olivia Merkel as well as the LMU Excellent Nachwuchsförderungsfonds to Aditi Mehta.

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Authors and Affiliations

  1. Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilian University of Munich, Butenandtstr. 5-13, 81377, Munich, Germany

    Aditi Mehta, Elena Dalle Vedove, Lorenz Isert & Olivia M. Merkel

Authors
  1. Aditi Mehta
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  2. Elena Dalle Vedove
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  3. Lorenz Isert
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  4. Olivia M. Merkel
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Correspondence to Aditi Mehta or Olivia M. Merkel.

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Mehta, A., Dalle Vedove, E., Isert, L. et al. Targeting KRAS Mutant Lung Cancer Cells with siRNA-Loaded Bovine Serum Albumin Nanoparticles. Pharm Res 36, 133 (2019). https://doi.org/10.1007/s11095-019-2665-9

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