siRNA-Encapsulated Hybrid Nanoparticles Target Mutant K-ras and Inhibit Metastatic Tumor Burden in a Mouse Model of Lung Cancer.
There is an unmet need in the development of an effective therapy for mutant K-ras-expressing non-small-cell lung cancer (NSCLC). Although various small molecules have been evaluated, an effective therapy remains a dream. siRNAs have the potential to downregulate mutant K-ras both at the protein and mRNA levels. However, a safe and effective delivery of siRNAs to tumors remains a limitation to their translational application in the treatment of this highly debilitating disease. Here we developed a novel hybrid nanoparticle carrier for effective delivery of anti-mutant K-ras to NSCLC (AKSLHN). The ability of this treatment modality to regress lung tumors in mouse models was evaluated as a monotherapy or as a combination treatment with erlotinib. Further, the toxicity of this treatment modality to healthy tissues was evaluated, along with its ability to elicit immune/inflammatory reactions. The results suggest that this treatment modality is a promising prospect for the treatment of mutant K-ras-expressing NSCLC without any accompanying toxicity. However, further understanding of the cellular-level interaction between AHSLHN and erlotinib needs to be attained before this promising treatment modality can be brought to the bedside.
Department of Pharmaceutical Science, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Maryna
M
Perepelyuk
Department of Pathology and Laboratory Medicine, Western Connecticut Health Network, Danbury Hospital, Danbury, CT 06810, USA.
Olubunmi
O
Shoyele
Department of Pathology and Laboratory Medicine, Cooper University Hospital-MD Anderson Cancer Center, Camden, NJ 08103, USA.
Ruth
R
Birbe
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Chellappagounder
C
Thangavel
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Yi
Y
Liu
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Robert B
RB
Den
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia 19107, PA, USA.
Adam E
AE
Snook
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Bo
B
Lu
Department of Pharmaceutical Science, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: sunday.shoyele@jefferson.edu.
Sunday A
SA
Shoyele
gene silencing; human immunoglobulin G; hybrid nanoparticles; lung cancer; mutant K-ras; orthotopic model; siRNA