Targeting of EGFR, VEGFR2, and Akt by Engineered Dual Drug Encapsulated Mesoporous Silica–Gold Nanoclusters Sensitizes Tamoxifen-Resistant Breast Cancer

• Published in: Molecular pharmaceutics Vol. 15; no. 7; pp. 2698 - 2713
• Main Authors: Kumar, B. N. Prashanth, Puvvada, Nagaprasad, Rajput, Shashi, Sarkar, Siddik, Mahto, Madhusudan Kr, Yallapu, Murali M, Pathak, Amita, Emdad, Luni, Das, Swadesh K, Reis, Rui L, Kundu, S. C, Fisher, Paul B, Mandal, Mahitosh
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.07.2018
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Catechin - analogs & derivatives; Catechin - pharmacology; Catechin - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Engineering; Drug Carriers - chemistry; Drug Resistance, Neoplasm - drug effects; ErbB Receptors - metabolism; Female; Gold - chemistry; Humans; Metal Nanoparticles - chemistry; Mice, Nude; Piperidines - pharmacology; Piperidines - therapeutic use; Porosity; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; Silicon Dioxide - chemistry; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Xenograft Model Antitumor Assays; VEGFR2; Akt; epigallocatechin gallate; ZD6474; EGFR; silica-gold nanoclusters
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00218

Tamoxifen administration enhanced overall disease-free survival and diminished mortality rates in cancer patients. However, patients with breast cancer often fail to respond for tamoxifen therapy due to the development of a drug-resistant phenotype. Functional analysis and molecular studies suggest that protein mutation and dysregulation of survival signaling molecules such as epidermal growth factor receptor, vascular endothelial growth factor receptor 2, and Akt contribute to tamoxifen resistance. Various strategies, including combinatorial therapies, show chemosensitize tamoxifen-resistant cancers. Based on chemotoxicity issues, researchers are actively investigating alternative therapeutic strategies. In the current study, we fabricate a mesoporous silica gold cluster nanodrug delivery system that displays exceptional tumor-targeting capability, thus promoting accretion of drug indices at the tumor site. We employ dual drugs, ZD6474, and epigallocatechin gallate (EGCG) that inhibit EGFR2, VEGFR2, and Akt signaling pathways since changes in these signaling pathways confer tamoxifen resistance in MCF 7 and T-47D cells. Mesoporous silica gold cluster nanodrug delivery of ZD6474 and EGCG sensitize tamoxifen-resistant cells to apoptosis. Western and immune-histochemical analyses confirmed the apoptotic inducing properties of the nanoformulation. Overall, results with these silica gold nanoclusters suggest that they may be a potent nanoformulation against chemoresistant cancers.