Mapping the L-tryptophan Capped Copper Nanocluster Mediated Binding and Targeted pH-Responsive Release of Doxorubicin via Fluorescence Resonance Energy Transfer (FRET)

Targeted delivery of anticancer drugs to the tumour tissues poses a major challenge in cancer treatment. Herein, we designed a Tryptophan-capped copper nanocluster (Trp-Cu NC) based nano-drug carrier for the selective delivery of an anticancer drug Doxorubicin (Dox) to the cancer cells. Trp-Cu NC showed excellent spectral overlap with Dox making them a suitable FRET pair enabling the investigation of their binding interactions precisely through steady-state and time-resolved FRET. At an elevated Dox concentration (~160 μM), the photoluminescence (PL) intensity as well as the lifetime of the Trp-Cu NC (donor) exhibited a significant drop leading to a higher FRET efficiency (EFRET) and reduced donor-acceptor distance (rDA). The interaction between Trp-Cu NC and Dox under neutral pH resulted in the formation of Trp-Cu NC-Dox nanoconjugate of diameter ~ 24.7 ± 1.1 nm meeting the size criterion suitable for good drug delivery performance. Under acidic conditions (pH 5.5), the Trp-Cu NC-Dox nanoconjugate dissociated back to the nanocluster (diameter ~ 2.96 ± 0.1) releasing the drug, translated into a remarkable increase in the Trp-Cu NC (donor) lifetime followed by a decreased EFRET. Such a phenomenon was absent under physiological pH 7.4, making the Trp-Cu NC a suitable nano-carrier for targeted drug delivery in cancer cells. The cytotoxicity studies further corroborate that Trp-Cu NC can selectively deliver Dox to the cancer cells enhancing the therapeutic efficacy of the drug by ~3.6-fold, concurrently decreasing its toxicity appreciably towards the normal cells. Overall, these findings substantiate an easy and economical strategy to develop a novel nano-drug carrier that offers selectivity and improved drug-delivery performance, thereby curing the limitation of systemic toxicity imposed by conventional chemotherapy.