PEG-Detachable Polymeric Micelles Self-Assembled from Amphiphilic Copolymers for Tumor-Acidity-Triggered Drug Delivery and Controlled Release

Abstract

The development of an intelligent biomaterial system that can efficiently accumulate at the tumor site and release a drug in a controlled way is very important for cancer chemotherapy. PEG is widely selected as a hydrophilic shell to acquire prolonged circulation time and enhanced accumulation at the tumor site, but it also restrains the cellular transport and uptake and leads to insufficient therapeutic efficacy. In this work, a PEG-detachable pH-responsive polymer that forms micelles from copolymer cholesterol grafted poly­(ethylene glycol) methyl ether-Dlabile -poly­(β-amino ester)-Dlabile -poly­(ethylene glycol) methyl ether (MPEG-Dlabile -PAE-g-Chol) is developed to overcome the aforementioned challenges based on pH value changes among normal physiological, extracellular (pHe), and intracellular (pHi) environments. PEGylated doxorubicin (DOX)-loaded polymeric micelles (DOX-PMs) can accumulate at the tumor site via an enhanced permeability and retention effect, and the PEG shell is detachable induced by cleavage of the pHe-labile linker between the PEG segment and the main chain. Meanwhile, the pHi-sensitive poly­(β-amino ester) segment is protonated and has a high positive charge. The detachment of PEG and protonation of PAE facilitate cellular uptake of DOX-PMs by negatively charged tumor cells, along with the escape from endo-/lysosome due to the “proton-sponge” effect. The DOX molecules are controlled release from the carriers at specific pH values. The results demonstrate that DOX-PMs have the capability of showing high therapeutic efficacy and negligible cytotoxicity compared with free DOX in vitro and in vivo. Overall, we anticipate that this PEG-detachable and tumor-acidity-responsive polymeric micelle can mediate effective and biocompatible drug delivery “on demand” with clinical application potential.

Influence of polyethylene glycol molecular weight on the anticancer drug delivery of pH‐sensitive polymeric micelle

“…From the results, the molecular weight of PEG was negatively correlated with the amount of drugs taken up, presumably because the lower molecular weight of PEG affected the size of the micelles, resulting in smaller micelles so that it was easier for cells to uptake. The phenomenon that the drug‐loaded micelle groups were more abundant than the free doxorubicin is not usual in the study of nonactive targeted drug delivery systems, but it has been reported in other literature; however, no specific explanation has been given . As Wang constructed three groups of ∼100 nm nanoparticles with positive, neutral, or negative charge and found that 2.5‐fold higher cellular uptake of cationic PEGylated nanoparticles was responsible for their superior treatment efficacy, we speculated that the slight positive charge of the micelles made itself more easily uptaken by the cells with negatively charged surface, resulting in more intake than in the free doxorubicin group.…”

pH-Responsive hyperbranched polypeptides based on Schiff bases as drug carriers for reducing toxicity of chemotherapy

“…The tumor volume was measured daily. Mice were randomly divided into three groups when tumor volume reached about 100-150 mm 3 (n ¼ 5) to do the following experiment. Free DOX (5 mg kg À1 ), DOX-loaded micelles (DOX 5 mg kg À1 ) and saline were injected intravenously via the tail vein and repeated every 3 days.…”

“…Polymeric micelles are considered as one of the most effective means with a promising prospect to effectively improve the pesticide effect and reduce the side effect to the normal cells. [1][2][3][4][5][6][7] Despite the bright prospects they have, there are still some challenges need to be overcome, such as controllable drug release behavior, degradable in the body and good biocompatibility, and high drug loading capacity. [8][9][10][11][12] Without these characteristics, it is difficult to achieve the ideal therapeutic effect and even possible to cause some side effects in cancer therapy.…”

Polyrotaxane Nanocarriers Can Deliver CRISPR/Cas9 Plasmid to Dystrophic Muscle Cells to Successfully Edit the DMD Gene

“…[7a] Pristine and disulfide 4-arm PRXs exhibited efficient plasmid uptake and were able to escape the lysosome in MB and MT (Figure 2). [23] The disulfide-sensitive linker is expected to enhance plasmid release in vitro resulting in a supramolecular dissociation upon exposure to the intracellular reducing environment. The pristine linear and disulfide linear PRXs demonstrated similar uptake and lysosomal escape as measured by PCC ( Figure S6, Supporting Information).…”