Hyaluronan-Stabilized Redox-Sensitive Nanoassembly for Chemo-Gene Therapy and Dual T1/T2 MR Imaging in Drug-Resistant Breast Cancer Cells

Tailoring combinatorial therapies along with real-time monitoring strategies has been the major focus of overcoming multidrug resistance in cancer. However, attempting to develop a multifunctional nanoplatform in a single construct leads to compromising therapeutic outcomes. Herein, we developed a s...

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Published in:Molecular pharmaceutics 2019-05, Vol.16 (5), p.2226-2234
Main Authors: Rajendrakumar, Santhosh Kalash, Venu, Akhil, Revuri, Vishnu, George Thomas, Reju, Thirunavukkarasu, Guru Karthikeyan, Zhang, Jun, Vijayan, Veena, Choi, Seok-Yong, Lee, Jae Young, Lee, Yong-Kyu, Jeong, Yong Yeon, Park, In-Kyu
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Breast Neoplasms - pathology
Breast Neoplasms - therapy
Doxorubicin - pharmacology
Doxorubicin - therapeutic use
Drug Compounding - methods
Drug Delivery Systems - methods
Drug Liberation
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm - drug effects
Female
Ferric Compounds - chemistry
Gene Silencing
Genetic Therapy - methods
Humans
Hyaluronic Acid - chemistry
Magnetic Resonance Imaging - methods
Manganese Compounds - chemistry
MCF-7 Cells
Metal Nanoparticles - chemistry
Oncogene Proteins - genetics
Oxidation-Reduction
Oxides - chemistry
Polyethyleneimine - chemistry
Transfection
Viral Proteins - genetics
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Summary:Tailoring combinatorial therapies along with real-time monitoring strategies has been the major focus of overcoming multidrug resistance in cancer. However, attempting to develop a multifunctional nanoplatform in a single construct leads to compromising therapeutic outcomes. Herein, we developed a simple, theranostic nanoassembly containing a hyaluronic acid-stabilized redox-sensitive (HART) polyethylenimine polyplex composed of a doxorubicin (DOX) intercalated Bcl-2 shRNA encoded plasmid along with a green-synthesized hausmannite (Mn3O4) and hematite (Fe3O4) nanoparticle (GMF). The highly stable HART nanoassembly has enhanced CD44-mediated intracellular uptake along with hyaluronidase (hylase) and redox-responsive drug–gene release. With Bcl-2 gene silencing induced by the successful delivery of HART in multidrug-resistant MCF7 breast cancer cells, the synergistic cytotoxic effect of Bcl-2 silencing and DOX was achieved. In addition, the HART nanoassembly containing GMF exhibited excellent dual MRI contrast (T1/T2) by reducing artifact signals. Overall, the HART nanoassembly with its enhanced theranostic properties has the potential to improve the therapeutic efficacy in future preclinical and clinical trials.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.9b00189