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Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy

Authors Amreddy N, Muralidharan R, Babu A, Mehta M, Johnson EV, Zhao YD, Munshi A, Ramesh R

Received 28 July 2015

Accepted for publication 19 September 2015

Published 29 October 2015 Volume 2015:10(1) Pages 6773—6788

DOI https://doi.org/10.2147/IJN.S93237

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Govarthanan Muthusamy

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster

Narsireddy Amreddy,1,2 Ranganayaki Muralidharan,1,2 Anish Babu,1,2 Meghna Mehta,2,3 Elyse V Johnson,4 Yan D Zhao,2,5 Anupama Munshi,2,3 Rajagopal Ramesh1,2,6

1Department of Pathology, 2Stephenson Cancer Center, 3Department of Radiation Oncology University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 4CytoViva Inc., Auburn, AL, USA; 5Department of Biostatistics and Epidemiology, 6Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Background: In lung cancer, the efficacy of conventional chemotherapy is limited due to poor drug accumulation in tumors and nonspecific cytotoxicity. Resolving these issues will increase therapeutic efficacy.
Methods: GNR-Dox-Tf-NPs (gold nanorod-doxorubicin-transferrin-nanoparticles) were prepared by different chemical approaches. The efficacy of these nanoparticles was carried out by cell viability in lung cancer and primary coronary artery smooth muscle cells. The receptor-mediated endocytosis studies were done with human transferrin and desferrioxamine preincubation. The GNR-Dox-Tf nanoparticles induced apoptosis, and DNA damage studies were done by Western blot, H2AX foci, and comet assay.
Results: We developed and tested a gold nanorod-based multifunctional nanoparticle system (GNR-Dox-Tf-NP) that carries Dox conjugated to a pH-sensitive linker and is targeted to the transferrin receptor overexpressed in human lung cancer (A549, HCC827) cells. GNR-Dox-Tf-NP underwent physicochemical characterization, specificity assays, tumor uptake studies, and hyperspectral imaging. Biological studies demonstrated that transferrin receptor-mediated uptake of the GNR-Dox-Tf-NP by A549 and HCC827 cells produced increased DNA damage, apoptosis, and cell killing compared with nontargeted GNR-Dox-NP. GNR-Dox-Tf-NP-mediated cytotoxicity was greater (48% A549, 46% HCC827) than GNR-Dox-NP-mediated cytotoxicity (36% A549, 39% HCC827). Further, GNR-Dox-Tf-NP markedly reduced cytotoxicity in normal human coronary artery smooth muscle cells compared with free Dox.
Conclusion: Thus, GNR-Dox-Tf nanoparticles can selectively target and deliver Dox to lung tumor cells and alleviate free Dox-mediated toxicity to normal cells.

Keywords: doxorubicin, gold, lung cancer, nanoparticles, transferrin, tumor targeting

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