Tumor-Targeting, pH-Responsive, and Stable Unimolecular Micelles as Drug Nanocarriers for Targeted Cancer Therapy

Abstract

A new type of multifunctional unimolecular micelle drug nanocarrier based on amphiphilic hyperbranched block copolymer for targeted cancer therapy was developed. The core of the unimolecular micelle was a hyperbranched aliphatic polyester, Boltorn H40. The inner hydrophobic layer was composed of random copolymer of poly(ε-caprolactone) and poly(malic acid) (PMA-co-PCL) segments, while the outer hydrophilic shell was composed of poly(ethylene glycol) (PEG) segments. Active tumor-targeting ligands, i.e., folate (FA), were selectively conjugated to the distal ends of the PEG segments. An anticancer drug, i.e., doxorubicin (DOX) molecules, was conjugated onto the PMA segments with pH-sensitive drug binding linkers for pH-triggered drug release. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis showed that the unimolecular micelles were uniform with a mean hydrodynamic diameter around 25 nm. The drug loading content was determined to be 14.2%. The drug release profile, cell uptake and distribution, and cytotoxicity of the unimolecular micelles were evaluated in vitro. The folate-conjugated micelles can be internalized by the cancer cells via folate-receptor-mediated endocytosis; thus, they exhibited enhanced cell uptake and cytotoxicity. At pH 7.4, the physiological condition of bloodstream, DOX conjugated onto the unimolecular micelles exhibited excellent stability; however, once the micelles were internalized by the cancer cells, the pH-sensitive hydrazone linkages were cleavable by the intracellular acidic environment, which initially caused a rapid release of DOX. These findings indicate that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy.

The polyion complex nano-prodrug of doxorubicin (DOX) with poly(lactic acid-co-malic acid)-block-polyethylene glycol: preparation and drug controlled release

“…The availability of negatively charged free carboxyl groups is capable of reacting with a positively charged molecule such as DOX through complexation. However, its application is limited since PMA or its copolymers are usually synthesized by ringopening polymerization of b-lactones and lactide, which takes long time and high costs for preparations of b-lactones and lactide (Coulembier et al, 2005;Yang et al, 2010;Poon et al, 2009;Zhao et al, 2009).…”

Bioreducible unimolecular micelles based on amphiphilic multiarm hyperbranched copolymers for triggered drug release

“…Some amphiphilic multiarm hyperbranched copolymers using H40 as the core have been produced for the improved micelle stability and drug loading ability [42,43]. In this work, to construct a unimolecular micelle system for controlled drug release triggered by reduction, we have designed and synthesized a novel bioreducible amphiphilic multiarm hyperbranched copolymer (H40-star-PLA-SS-PEG) based on H40 core, poly(L-lactide) (PLA) inner-shell, and poly(ethylene glycol) (PEG) outer-shell with disulfidelinkages between the hydrophobic and hydrophilic moieties.…”

New promising biodegradable polyesters derived from poly((R,S)-3,3-dimethylmalic acid) for cardiovascular applications

“…PMLA has many interesting properties, in addition to its functionalisable properties, such as non-toxicity in vitro and in vivo, non-immunogenicity, biodegradability, stability in the bloodstream, and cell affinity [39][40][41][42][43]. However, its application is limited because of the synthesis conditions (time and cost) and transfer reactions during its chemical synthesis and/or modification [18,[44][45][46][47][48][49][50][51][52][53].…”