Nanoparticle–Peptide–Drug Bioconjugates for Unassisted Defeat of Multidrug Resistance in a Model Cancer Cell Line

Abstract

Multidrug resistance (MDR) is a significant challenge in the treatment of many types of cancers as membrane-associated transporters actively pump drugs out of the cell, limiting therapeutic efficacy. While nanoparticle (NP)-based therapeutics have emerged as a mechanism for overcoming MDR, they often rely on the delivery of multiple anticancer drugs, nucleic acid hybrids, or MDR pump inhibitors. The effectiveness of these strategies, however, can be limited by their off-target toxicity or the need for genetic transfection. In this paper, we describe a NP–peptide–drug bioconjugate that achieves significant cell killing in MDR-positive cancer cells without the need for additional drugs. We use a quantum dot (QD) as a central scaffold to append two species of peptide, a cell-uptake peptide to facilitate endocytic internalization and a peptide–drug conjugate that is susceptible to cleavage by esterases found within the endocytic pathway. This approach relies on spatiotemporal control over drug release, where endosomes traffic drug away from membrane-resident pumps and release it closer to the nucleus. Cellular internalization studies showed high uptake of the NP–drug complex and nuclear localization of the drug after 48 h in MDR-positive cells. Additionally, cellular proliferation assays demonstrated a 40% decrease in cell viability for the NP–drug bioconjugate compared to free drug, confirming the utility of this system in overcoming MDR in cancer cells.

Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine

“…18 Also the presence of efflux pumps, overexpression of specific transporters on the cell membrane, as well as mitosis can reduce NP accumulation in the target cells. 19,20 Consequently, a very low number of NPs reach the target cells and might not be sufficient to treat the disease. 21 For this reason, it becomes important to enhance NP-based targeted delivery and, at the same time, avoid internalization by MPS if this system is not the targeted one.…”

Ditelluride-Bridged PEG-PCL Copolymer as Folic Acid-Targeted and Redox-Responsive Nanoparticles for Enhanced Cancer Therapy

“…To amplify the therapeutic benefits, the ideal nanocarriers should boost the drug release rapidly after entering the cells (Deepagan et al, 2018;Wang et al, 2018;Sangtani et al, 2019). Unfortunately, it is difficult for conventional nanocarriers to achieve timely on-demand drug release, leading to marginal drug exposure to cancer cells.…”

In Situ Self‐Assembly of Quantum Dots at the Plasma Membrane Mediates Energy Transfer‐Based Activation of Channelrhodopsin

“…[23] QDs capped with this ligand system have been used previously for the QD-mediated intracellular assembly of proteins [23] and QD-enhanced drug delivery . [26,27] As determined by transmission electron microscopy (TEM), the diameter of the QDs was ≈4.6 nm (Figure S1, Supporting Information). Spectrally, the QDs exhibit strong absorbance which increases into the UV portion of the spectrum and a narrow emission profile centered at 530 nm (Figure 1b).…”