In the present investigation, we have strategically synthesized Glutathione (GSH) stimuli-sensitive analogues using carbamate linkers (CL) of DOX (DOX-CL) and RB (RB-CL) which were then anchored to gold nanoparticles (Au-DOX-CL, Au-RB-CL) using mPEG as a spacer. It was observed that carbamate linkage (CL) with four carbon spacer is critical, to position the terminal thiol group, to access the carbamate group efficiently to achieve GSH-assisted release of DOX and RB in tumor-specific environment. When assessed for GSH reductase activity in MDA-MB 231 cell lines, Au-DOX-CL and Au-RB-CL showed nearly 4.18 and 3.13 fold higher GSH reductive activity as compared to the control group respectively. To achieve spatial tumor targeting with a high payload of DOX and RB, Au-DOX-CL and Au-RB-CL were encapsulated in the cell-penetrating peptide (CPP) modified liquid crystalline cubosomes i.e. CPP-Cu(Au@CL-DR). After internalization, the prototype nanocarriers release respective drugs at a precise GSH concentration inside the tumor tissues, amplifying drug concentration to a tune of five-fold. The drug concentrations remain within the therapeutic window for 72 h with a significant reduction of RB (7.8-fold) and DOX (6-fold) concentrations in vital organs, rendering reduced toxicity and improved survival. Overall, this constitutes a promising chemotherapeutic strategy against cancer and its potential application in the offing.
Keywords: Cell penetrating peptides; Doxorubicin; GSH reduction; Gold nanoparticle-drug conjugates; Ribociclib; Target drug delivery.
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