Abstract:
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 psulfo-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 nDNA 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.
