On-demand PEGylation and dePEGylation of PLA-based nanocarriers via amphiphilic mPEG-TK-Ce6 for nanoenabled cancer chemotherapy

Abstract

Rationale: PEGylation of nanocarriers could extend blood circulation time and enhance tumor accumulation via the enhanced permeability and retention (EPR) effect. Unfortunately, the PEG moiety suppresses tumor cell internalization of nanocarriers, resulting in limited therapeutic efficiency (known as the PEG dilemma). Designing stimuli-responsive shell-detachable nanocarriers, which could detach the PEG corona from the nanocarriers in desired tumor tissues in response to the local environment, is an appealing approach to overcome the PEG dilemma, but nanocarrier applications are also limited by a lack of universal stimuli for PEG detachment.Methods: In this study, we synthesized red light-responsive, amphiphilic mPEG bridged to the photosensitizer Ce6 via a thioketal (TK) bond (mPEG-TK-Ce6), which was then used to achieve the PEGylation of polylactide (PLA)-based nanoparticles encapsulating the Pt(IV) prodrug. The therapeutic efficacy of the prepared nanoparticles was evaluated in vitro and in vivo.Results: We demonstrated that the amphiphilic mPEG-TK-Ce6 can realize the PEGylation of Pt(IV) prodrug-loaded PLA nanoparticles and consequently enhanced nanoparticle accumulation in tumor tissues. When the tumor tissues were subjected to 660 nm irradiation, reactive oxygen species (ROS) generated by Ce6 induced the rapid degradation of the adjacent TK bond, resulting in PEG detachment and enhanced tumor cell internalization. Therefore, mPEG-TK-Ce6 facilely achieved PEGylation and light-responsive dePEGylation of the nanocarrier for enhanced antitumor efficacy in nanomedicine.Conclusion: Such red light-responsive amphiphilic mPEG-TK-Ce6 facilely achieved PEGylation and dePEGylation of the nanocarrier, providing a facile strategy to overcome PEG dilemma.

Double-PEGylated Cyclopeptidic Photosensitizer Prodrug Improves Drug Uptake from In Vitro to Hen’s Egg Chorioallantoic Membrane Model

“…If one wants to cleave the PEG sidechain before internalizing the drug into the cells, the linker might also be designed to react to ROS produced by a photosensitizer such as Ce6. In a study by Zhu et al [36], the thioketal bond employed to PEGylate PLA nanoparticles was cleaved upon light irradiation after accumulation in the tumor tissue. This idea is quite interesting as one could not only cleave the PEG moieties in order to facilitate the internalization of the drug-loaded nanoparticles, but also initiate death of the cells through the production of ROS.…”

Nanomaterial‐mediated platinum drug‐based combinatorial cancer therapy

“…Additionally, some nanohybrids based on Pt drugs/prodrugs and PSs were also developed by self‐assembly 42 . The well‐defined cavity of a discrete organoplatinum(II) metallacage containing a Pt‐based anticancer drug was employed to encapsulate PS of octaethylporphine (OEP), serving as dual delivery of chemotherapeutic drug and PS for combinatorial therapy 43 .…”

Strategy for Avoiding Protein Corona Inhibition of Targeted Drug Delivery by Linking Recombinant Affibody Scaffold to Magnetosomes

“…15,16 However, some of these strategies were found to inhibit the internalization of NPs by cancer cells, resulting in limited therapeutic effectiveness (eg the "PEG dilemma"). 17 Some groups introduced various types of cleavable bonds and mechanisms in engineered NPs to prolong the exposure of targeting ligands until they reach target sites. 18 However, the above strategies for reducing protein corona effects are generally complicated and not widely used due to the inherent difficulty of in vivo application to diverse types of cancer cells and their external stimuli.…”