Elucidating a Thermoresponsive Multimodal Photo-Chemotherapeutic Nanodelivery Vehicle to Overcome the Barriers of Doxorubicin Therapy

• Published in: ACS applied materials & interfaces Vol. 12; no. 39; pp. 43365 - 43379
• Main Authors: Nair, Jyothi B, Joseph, Manu M, Arya, Jayadev S, Sreedevi, Padincharapad, Sujai, Palasseri T, Maiti, Kaustabh Kumar
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 30-09-2020
• Subjects: Animals; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Biological and Medical Applications of Materials and Interfaces; Calixarenes - chemistry; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; DNA, Mitochondrial - drug effects; DNA, Neoplasm - drug effects; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Screening Assays, Antitumor; Folic Acid - chemistry; Gold - chemistry; Humans; Male; Metal Nanoparticles - chemistry; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Particle Size; Phenols - chemistry; Photochemotherapy; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Surface Properties; Temperature; cardiotoxicity; cancer; hollow gold nanoparticles; drug resistance; SERS
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.0c08762

In an attempt to circumvent the major pitfalls associated with conventional chemotherapy including drug resistance and off-target toxicity, we have adopted a strategy to simultaneously target both mitochondrial DNA (Mt-DNA) and nuclear DNA (n-DNA) with the aid of a targeted theranostic nanodelivery vehicle (TTNDV). Herein, folic acid-anchored p-sulfo-calix­[4]­arene (SC4)-capped hollow gold nanoparticles (HGNPs) were meticulously loaded with antineoplastic doxorubicin (Dox) and its mitochondrion-targeted analogue, Mt-Dox, in a pretuned ratio (1:100) for sustained thermoresponsive release of cargo. This therapeutic strategy was enabled to eradicate both n-DNA and Mt-DNA leaving no space to develop drug resistance. The SC4-capped HGNPs (HGNPSC4) were experimented for the first time as a photothermal (PTT) agent with 61.6% photothermal conversion efficiency, and they generated tunable localized heat more efficiently than bare HGNPs. Moreover, the cavity of SC4 facilitated the formation of an inclusion complex with folic acid to target the folate receptor expressing cancer cells and imparted enhanced biocompatibility. The as-synthesized TTNDV was demonstrated to be an ideal substrate for surface-enhanced Raman scattering (SERS) to monitor the molecular-level therapeutic progression in cells and a spheroidal model. A significant reduction in the tumor mass with a marked survival benefit was achieved in syngraft murine models through this synergistic photo-chemotherapy. Collectively, this multifunctional nanoplatform offers a robust approach to treat cancer without any scope of generating Dox resistance and off-target toxicity.