A Self-Assembling Amphiphilic Peptide Dendrimer-Based Drug Delivery System for Cancer Therapy

Abstract

Despite being a mainstay of clinical cancer treatment, chemotherapy is limited by its severe side effects and inherent or acquired drug resistance. Nanotechnology-based drug-delivery systems are widely expected to bring new hope for cancer therapy. These systems exploit the ability of nanomaterials to accumulate and deliver anticancer drugs at the tumor site via the enhanced permeability and retention effect. Here, we established a novel drug-delivery nanosystem based on amphiphilic peptide dendrimers (AmPDs) composed of a hydrophobic alkyl chain and a hydrophilic polylysine dendron with different generations (AmPD KK2 and AmPD KK2K4). These AmPDs assembled into nanoassemblies for efficient encapsulation of the anti-cancer drug doxorubicin (DOX). The AmPDs/DOX nanoformulations improved the intracellular uptake and accumulation of DOX in drug-resistant breast cancer cells and increased permeation in 3D multicellular tumor spheroids in comparison with free DOX. Thus, they exerted effective anticancer activity while circumventing drug resistance in 2D and 3D breast cancer models. Interestingly, AmPD KK2 bearing a smaller peptide dendron encapsulated DOX to form more stable nanoparticles than AmPD KK2K4 bearing a larger peptide dendron, resulting in better cellular uptake, penetration, and anti-proliferative activity. This may be because AmPD KK2 maintains a better balance between hydrophobicity and hydrophilicity to achieve optimal self-assembly, thereby facilitating more stable drug encapsulation and efficient drug release. Together, our study provides a promising perspective on the design of the safe and efficient cancer drug-delivery nanosystems based on the self-assembling amphiphilic peptide dendrimer.

An NIR-II Responsive Nanoplatform for Cancer Photothermal and Oxidative Stress Therapy

“…As an adaptive response, tumor cells will improve their antioxidant capacity, for example, the increased glutathione (GSH) levels in tumor cells further endow the tumor cells with anti-apoptosis and drug-resistant performance (Bansal and Simon, 2018;Liu Z. et al, 2020). Even worse, the exorbitant GSH in tumor cells as a reactive oxygen species (ROS) scavenger not only dramatically reduces the therapeutic efficacy of ROS-medicated therapy but also facilitates tumor metastasis, which makes cancer with high mortality and more difficult to be treated (McCarty et al, 2010;Lin X. et al, 2019;Liu M. D. et al, 2020;Zhu et al, 2021).…”

Structural parameters of nanoparticles affecting their toxicity for biomedical applications: a review

“…In 2021, based on amphiphilic peptide dendrimers, safe and effective cancer drug-delivery nanosystems were established to encapsulate doxorubicin (the anti-cancer drug) efficiently. Compared to free doxorubicin, the dendrimer-based drug delivery system increased intracellular uptake of the drug in drug-resistant breast cancer cells [ 97 ].…”

A DFX-based iron nanochelator for cancer therapy

“…The higher the PL-DFX concentration, the lesser number of cells, and the cells became small and round. Polylysine, as a biodegradable drug delivery platform, not only enhances the cytotoxicity of free drugs in tumor cells, while showing no higher toxicity in non-tumor cells (Du et al, 2020;Zhu et al, 2021). Due to nephrotoxicity of DFX, the cytotoxicity of DFX and PL-DFX was also investigated in human renal tubular epithelial cells (HK2).…”