Abstract
To achieve effective intracellular anticancer drug delivery, the polymeric vesicles supplemented with the pH-responsive outlayered gels as a delivery system of doxorubicin (DOX) were developed from self-assembly of the lipid/polypeptide adduct, distearin grafted poly(γ-glutamic acid) (poly(γ-GA)), followed by sequential deposition of chitosan and poly(γ-GA-co-γ-glutamyl oxysuccinimide)-g-monomethoxy poly(ethylene glycol) in combination with in situ covalent cross-linking on assembly surfaces. The resultant gel-caged polymeric vesicles (GCPVs) showed superior performance in regulating drug release in response to the external pH change. Under typical physiological conditions (pH 7.4 and 37°C) at which the γ-GA/DOX ionic pairings remained mostly undisturbed, the dense outlayered gels of GCPVs significantly reduced the premature leakage of the uncomplexed payload. With the environmental pH being reduced from pH 7.4 to 4.7, the drug liberation was appreciably promoted by the massive disruption of the ionic γ-GA/DOX complexes along with the significant swelling of nanogel layers upon the increased protonation of chitosan chain segments. After being internalized by HeLa cells via endocytosis, GCPVs exhibited cytotoxic effect comparable to free DOX achieved by rapidly releasing the payload in intracellular acidic endosomes and lysosomes. This strongly implies the great promise of such unique GCPVs as an intracellular drug delivery carrier for potential anticancer treatment.
Highlights
Over the past decades, various nanoassemblies such as liposomes, polymeric micelles and polymeric vesicles have been exploited extensively as anticancer drug transport vehicles due to their great capability of delivering payloads to tumor regions achieved primarily by the enhanced permeability and retention effects [1,2,3,4,5,6]
Substantial efforts have been devoted to the development of stimuli-responsive devices as novel drug delivery systems capable of controlling payload release in response to biological stimuli such as temperature [10,11], pH [12,13,14,15], and redox potential [16,17,18]
Pristine vesicles at pH 7.4 DOX-loaded vesicles at pH 7.4 DOX-loaded chitosan-caged vesicles at pH 6.0 DOX-loaded gel-caged polymeric vesicles (GCPVs) at pH 7.4
Summary
Various nanoassemblies such as liposomes, polymeric micelles and polymeric vesicles (polymersomes) have been exploited extensively as anticancer drug transport vehicles due to their great capability of delivering payloads to tumor regions achieved primarily by the enhanced permeability and retention effects [1,2,3,4,5,6] These nanovehicles show promise in selective delivery of therapeutic agents to target sites, several intractable problems (e.g., the premature drug leakage from carriers and poor intracellular drugrelease property that lead to an insufficient drug bioavailability for killing cancer cells and undesired side effects) have not been completely overcome yet [7,8,9]. In order to meet the basic requirement of the assembly stability in practical drug delivery application without impairing or even with promoting the stimuli-triggered characteristics, several approaches such as covalent crosslinking [19,20,21], mineralization [22,23,24], and surface modification [25,26,27] of nanoparticles have been supplemented to enhance their structural integrity under varying conditions
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