Bioinspired Microenvironment Responsive Nanoprodrug as an Efficient Hydrophobic Drug Self-Delivery System for Cancer Therapy

Abstract

Artemisinin compounds have shown satisfactory safety records in anti-malarial clinical practice over decades and have revealed value as inexpensive anti-tumor adjuvant chemotherapeutic drugs. However, the rational design and precise preparation of nanomedicines based on the artemisinin drugs are still limited due to their non-aromatic and fragile chemical structure. Herein, a bioinspired coordination-driven self-assembly strategy was developed to manufacture the artemisinin-based nanoprodrug with a significantly increased drug loading efficacy (∼70 wt %) and decreased preparation complexity compared to conventional nanodrugs. The nanoprodrug has suitable size distribution and robust colloidal stability for cancer targeting in vivo. The nanoprodrug was able to quickly disassemble in the tumor microenvironment with weak acidity and a high glutathione concentration, which guarantees a better tumor inhibitory effect than direct administration and fewer side effects on normal tissues in vivo. This work highlights a new strategy to harness a robust, simplified, organic solvent-free, and highly repeatable route for nanoprodrug manufacturing, which may offer opportunities to develop cost-effective, safe, and clinically available nanomedicines.

Nanomedicines Based on Responsive Nanocarriers for Cancer Therapy

“…[117] Responsive nanocarrier system is a promising strategy to improve drug solubility, permeability, and stability, which can promote continuous controlled release, improve efficacy, and reduce side effects. [118] Currently, there has been some pioneering work in the development of PTX-based responsive nanocarriers. Zhai et al developed a pH-sensitive polymer-PTX micelle (MPEG-PCL-ACE-PTX) by grafting PTX onto the polyethylene glycol-polycarbonate backbone to accelerate drug release in tumor cells.…”

“…[ 117 ] Responsive nanocarrier system is a promising strategy to improve drug solubility, permeability, and stability, which can promote continuous controlled release, improve efficacy, and reduce side effects. [ 118 ] Currently, there has been some pioneering work in the development of PTX‐based responsive nanocarriers. Zhai et al.…”

Advance Progress in Assembly Mechanisms of Carrier-Free Nanodrugs for Cancer Treatment

“…For example, pH-responsive imine (Schiff-base) bonds [28], reduction-responsive disulfide bonds [29], easily hydrolyzable ester bonds [16], and enzyme-cleavable specific peptide linkers [30]. Third, carrier-free nanodrugs can be also designed directly by coordination-driven self-assembly of metal ions with drug molecules or functional biomolecules [31,32]. Coordination covalent bonds exhibit stable and dynamic behavior in complex environments, and the strength is between weak noncovalent interactions and strong covalent bonds [33].…”

One-pot synthesis and enzyme-responsiveness of amphiphilic doxorubicin prodrug nanomicelles for cancer therapeutics

“…14 To expedite regulatory approval and clinical use of nanomedicines, the one-pot synthesis method exploiting endogenous materials is gaining recognition as a simple and easily-applicable strategy to construct novel nanomedicines, especially for drug self-delivery systems. [15][16][17][18][19] These drug selfdelivery systems have been developed for various drugs such as methotrexate, [20][21][22] doxorubicin, [23][24][25][26][27][28][29][30] and melphalan. 31 However, their clinical application remained limited owing to the use of exogenous materials.…”