Poly(2-ethyl-2-oxazoline)–Doxorubicin Conjugate-Based Dual Endosomal pH-Sensitive Micelles with Enhanced Antitumor Efficacy

Abstract

Dual endosomal pH-sensitive micelles were designed and fabricated to deliver doxorubicin (DOX) for treating breast cancer based on a poly(2-ethyl-2-oxazoline) (PEOz)-DOX (PEOz-hyd-DOX) conjugate. PEOz-hyd-DOX was successfully synthesized by connecting DOX to PEOz via an acid cleavable hydrazone linker and self-assembled into nanosized micelles, which further physically encapsulated DOX. The conjugate and DOX-loaded conjugate micelles displayed faster release of DOX at pH 5.0 than at pH 7.4. This pH-dependent release behavior might assist the quick diffusion of DOX from acidic endosomes or lysosomes and the intracellular transfer into the nucleus after internalization, which was confirmed by confocal laser scanning microscopy images. As expected, PEOz-hyd-DOX conjugate and DOX-loaded conjugate micelles maintained cytotoxicity of DOX. In addition, the dual endosomal pH-sensitive micelles were found to substantially enhance antitumor efficacy and reduce side effects compared with free DOX. Therefore, PEOz-hyd-DOX conjugate-based micelles might be potential drug delivery vehicles of DOX for safe and effective breast cancer therapy.

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

“…When the pH was lowered to 6.5, the drug release rate after the same time period increased to 86%, while at pH 5.0 almost 100% of the loaded drug was released within 4 h. By contrast, the dox release profiles of PEG‐platesome‐dox remained relatively stable under these conditions; the total drug release after 10 h did not exceed 62% at any of the pH levels tested. In addition, when incubated at acidic pH (5.0 or 6.5) for 1 h, the size of PEOz‐platesome‐dox, as measured by dynamic light scattering, significantly increased; after several hours, the size became much smaller than the particles kept at pH 7.4 (Figure S4, Supporting Information), likely reflecting the disassembly process of platesome triggered by the acidic environment . These results affirmed that the incorporation of the pH‐sensitive lipid DSPE‐PEOz successfully enabled PEOz‐platesome‐dox to release their cargo pH‐dependently, which facilitated the release of dox in the slightly acidic tumor microenvironment and especially the lysosomal compartments within tumor cells (pH 4.5–5.0).…”

Surface spermidine functionalized PEGylated poly(lactide-co-glycolide) nanoparticles for tumor-targeted drug delivery

“…Notably, the size of DOX-loaded NPs determined by TEM was slightly smaller than that measured by DLS, which could be ascribed to the swelling or stretching of the SPD-PEG chain in solution for DLS measurement, while shrinking and crimping on the copper grid surface during drying and vacuumizing for TEM characterization. 32,33 The zeta potential of DOX-NPs was observed to be about À5.2 mV. Aer SPD modication, the zeta potential of SPD-DOX-NPs was characterized to be nearly À2.4 mV.…”

Stimuli‐responsive liposomes for drug delivery

“…Poly(2‐ethyl‐2‐oxazoline) (PEOz) is water soluble, biocompatible, nontoxic, and nonimmunogenic pH‐sensitive polymer . It has been approved for use as a food additive by the US Food and Drug Administration and possesses broad application prospects in drug delivery systems . The ionizable group, NR 3+ , is the key motif involved in driving hydration changes from water‐solubilized hydrophilic interactions to hydrophobic water‐insoluble states upon protonation/deprotonation reactions as a function of pH.…”