Dynamic micelles with detachable PEGylation at tumoral extracellular pH for enhanced chemotherapy

Abstract

Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo , it also blocks uptake by tumor cells. This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times. Herein, the amphiphilic graft copolymers with pH-sensitive ortho ester-linked mPEG in side chains and polyurethanes in backbone, can self-assemble into the free and doxorubicin (DOX)-loaded micelles. The pH-sensitive micelles could undergo several characteristics as follows: (i) PEGylated shells for stability in sodium dodecyl sulfonate (SDS) solution; (ii) DePEGylation via degradation of ortho ester linkages at tumoral extracellular pH (6.5) for gradually dynamic size changes and effective release of DOX; and (iii) enhanced cellular uptake and cytotoxicity via positive DOX. Moreover, the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5Y multicellular spheroids (MCs) and strongly inhibit tumor growth in vitro and in vivo , and might be considered as promising and effective drug carriers in tumor therapy.

Drug Delivery Systems with a “Tumor-Triggered” Targeting or Intracellular Drug Release Property Based on DePEGylation

“…Ortho ester is another kind of pH-sensitive bond that can be broken in a slightly acidic environment and used for DePEGylation and controlled drug release [ 93 ]. Based on ortho ester, amphiphilic graft copolymer dynamic micelles with polyurethanes or poly(disulfide)s backbones and PEG hydrophilic side chains were reported [ 94 , 95 ]. The ortho ester-linked PEG could be stripped at pH 6.5, resulting in the size changes of the micelles, which allowed the micelles to penetrate the centers of SH-SY5Y multicellular spheroids quickly for controlled intracellular drug release and enhanced chemotherapy.…”

pH-Sensitive Nanodrug Self-Assembled from Aliphatic 5-Fluorouracil Derivative and Doxorubicin for Synergistic Cancer Therapy

“…16,17 Ortho ester linkages (OE) have been demonstrated with superior response to tumoral intracellular pH in comparison with other acidiclabile linkages. 18,19 Therefore, it is a feasible strategy to improve tumor selectivity of 5FU via chemically connecting 5FUAC and SA using an ortho ester linkage instead of the ester linkage (Scheme 1). Additionally, such a hydrophobic 5FU derivative could easily self-assemble into pH-responsive SMNs (SA-OE-5FU-NPs) through O/W emulsion solvent evaporation method.…”

“…Intrinsic hypoxic hypoxia endows the mildly acidic microenvironment with obvious pH gradient distribution among extracellular (pH = 6.5–7.0), endosomal (pH = 5.0–6.0), and lysosomal (pH = 4.0–5.0) space in tumor tissues. Hence, pH responsiveness is an effective means to enhance tumor selectivity for programmable drug release. , Ortho ester linkages (OE) have been demonstrated with superior response to tumoral intracellular pH in comparison with other acidic-labile linkages. , Therefore, it is a feasible strategy to improve tumor selectivity of 5FU via chemically connecting 5FUAC and SA using an ortho ester linkage instead of the ester linkage (Scheme ). Additionally, such a hydrophobic 5FU derivative could easily self-assemble into pH-responsive SMNs (SA-OE-5FU-NPs) through O/W emulsion solvent evaporation method .…”