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

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 (SC 4 )-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 SC 4 -capped HGNPs (HGNPSC 4 ) 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 SC 4 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.

Targeted Delivery Polymeric Nanosystem Reinforced by Synergism of Embilin and RPI-1 for Therapeutics of Pancreatic Cancer

“…After the establishment of a synergic combination ratio of Emb and RPI-1, the next motive is to load the dual cargo into a suitable n-DS to transform a personalized nanoconstruct for precise delivery at the target site. 15 FDA-approved biodegradable polymer PLGA was chosen as the material of choice to fabricate PLGA-n-DS with a modified o/w emulsion evaporation method. 19 Preoptimized ratio of Emb and RPI-1 was loaded into PLGA-n-DS (Figure 2a) which was later surface-functionalized to achieve PC targeting.…”

Nanomedicines for combating multidrug resistance of cancer

“…In this scenario, the engineered MWCNTs were demonstrated to generate high phototoxicity toward drug‐resistant cancer cell‐formed tumor spheroids, and thus may serve as a promising therapeutic platform to overcome MDR. Benefiting from the excellent antitumor efficiency of PTT, researchers have endeavored to integrate PTAs with chemodrugs via nanotechnology in the hope of addressing the MDR in a synergistic way (Deng et al, 2018; Du et al, 2019; F. Gao et al, 2020a; D. Guo, Ji, et al, 2018a; Jing et al, 2018; Lin et al, 2016; Nair et al, 2020; T. Wang, Wang, et al, 2016b; L. Xu, Liu, et al, 2018b; G. G. Yang, Pan et al, 2020b; Yao et al, 2018; Yu et al, 2015; Zhong et al, 2013). On the one hand, the photo‐induced hyperthermia can be exploited as a trigger to stimulate the on‐demand release of chemodrugs in multidrug‐resistant cancer cells, which is beneficial for increasing the intracellular concentrations of the delivered drugs (W. Huang, Zhao, et al, 2019b; H. Wu, Zhang, et al, 2020b; Zhong et al, 2013).…”

“…For example, gene silencing technology (Q. Meng, Yin, & Li, 2013b; Naghizadeh et al, 2019) and many molecular inhibitors (Mohammad et al, 2018) are commonly employed to knock down the expression and cause the dysfunction of drug efflux pumps, respectively, resulting in the accumulation of chemodrugs inside cancer cells. In addition, synergistic therapy, which involves the use of two (or more) chemodrugs (with different anticancer mechanisms) or therapeutic modalities (e.g., PDT and PTT; F. Gao et al, 2020a; Khdair et al, 2010; Nair et al, 2020), also emerges as a promising solution to minimize the risk of MDR development. However, how to orchestrate various strategies for optimal therapeutic efficiency remains a huge challenge.…”

Raman Imaging: An Impending Approach Towards Cancer Diagnosis

“… A) (i) Bright field, Raman and Cluster mapped image of HeLa cell, (ii) Spectra obtained from different clusters; Adapted with permission [98] . Copyright 2015, Elsevier B) Stack scan images and corresponding cluster mapped images of the spheroids treated with the nanotag, Adapted with permission [103] . Copyright 2020, American chemical society.…”

“…Gold mesoporous silica hybrid and hollow gold NPs (Figure 6B) decorated with various cancer biomarkers were also investigated for the SERS imaging capability. The results gave the opportunity to furnish multifunctional nanoplatforms for imaging cancer cells [102,103] …”