Hypoxia-Responsive, Polymeric Nanocarriers for Targeted Drug Delivery to Estrogen Receptor-Positive Breast Cancer Cell Spheroids

• Published in: Molecular pharmaceutics Vol. 17; no. 11; pp. 4312 - 4322
• Main Authors: Mamnoon, Babak, Feng, Li, Froberg, Jamie, Choi, Yongki, Sathish, Venkatachalem, Mallik, Sanku
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02-11-2020
• Subjects: Antineoplastic Agents - administration & dosage; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Hypoxia - drug effects; Cell Survival - drug effects; Doxorubicin - administration & dosage; Drug Carriers - chemistry; Estradiol - administration & dosage; Female; Humans; Ligands; MCF-7 Cells; Nanoparticles - chemistry; Polymers - chemistry; Receptors, Estrogen - metabolism; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Tumor Microenvironment; hypoxia; breast cancer; targeted drug delivery; estrogen receptor; polymersomes
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.0c00754

Uncontrolled cell growth, division, and lack of enough blood supply causes low oxygen content or hypoxia in cancerous tumor microenvironments. 17β-Estradiol (E2), an estrogen receptor (ER) ligand, can be incorporated on the surface of nanocarriers for targeted drug delivery to breast cancer cells overexpressing ER. In the present study, we synthesized estradiol-conjugated hypoxia-responsive polymeric nanoparticles (polymersomes) encapsulating the anticancer drug doxorubicin (E2-Dox-HRPs) for targeted delivery into the hypoxic niches of estrogen-receptor-positive breast cancer microtumors. Estradiol-conjugated polymersomes released over 90% of their encapsulated Dox in a sustained manner within hypoxia (2% oxygen) after 12 h. However, they released about 30% of Dox in normal oxygen partial pressure (21% oxygen, normoxia) during this time. Fluorescence microscopic studies demonstrated higher cytosolic and nuclear internalization of E2-Dox-HRPs (targeted polymersomes) compared to those of Dox-HRPs (nontargeted polymersomes). Monolayer cell viability studies on ER-positive MCF7 cells showed higher cytotoxicity of targeted polymersomes in hypoxia compared to in normoxia. Cytotoxicity studies with hypoxic three-dimensional spheroid cultures of MCF7 cells treated with targeted polymersomes indicated significant differences compared to those of normoxic spheroids. The novel estradiol-conjugated hypoxia-responsive polymersomes described here have the potential for targeted drug delivery in estrogen-receptor-positive breast cancer therapy.