Intracellular delivery of peptide cargos using iron oxide based nanoparticles: studies on antitumor efficacy of a BCL-2 converting peptide, NuBCP-9.

Abstract

Delivering peptides into cells targeting the undruggable oncoproteins is an emerging area in cancer therapeutics. Here we report a novel nanoparticle-based delivery system that can transport therapeutic cargos to the intracellular sites without the need for a cell transduction or penetration domain (CPP). In the present study, we have used iron oxide nanoparticles to deliver an oncopeptide, NuBCP-9, targeting the BCL-2 BH3 domain. Citric acid/2-bromo 2-methylpropanoic acid (CA/BMPA)-capped SPIONs were used to immobilize and deliver the NuBCP-9 peptide to the cancer cells without any noticeable off-target effects. Our results have demonstrated that NuBCP-9-SPIONs efficiently penetrate into cancer cells and bind to its intracellular target protein BCL-2. Moreover, significant inhibition of proliferation and substantial induction of cell death were observed when cancer cells were treated with NuBCP-9-SPIONs at different time intervals. Importantly, the IC50 values for killing of breast cancer cells with NuBCP-9-SPIONs were much lower compared to cells treated with the NuBCP-9 peptide linked with a CPP (Arg-8; NuBCP-9-R8). Molecular and biochemical analyses further supported that NuBCP-9-SPIONs killed breast cancer cells by apoptosis-mediated mechanisms. Furthermore, our data demonstrated that administration of NuBCP-9-SPIONs to mice bearing Ehrlich ascites tumors (EAT) was associated with loss of tumorigenicity and extensive apoptosis in tumor tissues. Taken together, these findings show that a non-CPP-tagged peptide can be successfully delivered to undruggable intracellular oncotargets using SPIONs.

• Authors: Manoj Kumar, Gurpal Singh, Sapna Sharma, Dikshi Gupta, Vivek Bansal, Vikas Arora, Madhusudan Bhat, Sandeep K Srivastava, Sameer Sapra, Surender Kharbanda, Amit K Dinda, Harpal Singh
• Journal: Nanoscale (Nanoscale) Vol. 6 Issue 23 Pg. 14473-83 (Nov 06 2014) ISSN: 2040-3372 [Electronic] England
• PMID: 25340469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2 protein, human
• Drug Carriers
• Ferric Compounds
• Oligopeptides
• Proto-Oncogene Proteins c-bcl-2
• phenylalanyl-seryl-arginyl-seryl-leucyl-histidyl-seryl-leucyl-leucine
• Bcl2 protein, mouse
• ferric oxide

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Ehrlich Tumor (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Drug Carriers
• Female
• Ferric Compounds (chemistry, pharmacology)
• Hep G2 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Nanoparticles (chemistry)
• Oligopeptides (chemistry, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)