pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery

Abstract

To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000(DSPE-PEG2000), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG3400 (DSPE-PEG3400-2C5), and poly(ethylene glycol)-coupled poly(l-histidine) (PHIS-PEG2000). The structure of PHIS-PEG2000 was confirmed by 1H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50wt% of PHIS-PEG2000 showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG2000. At pH around 5.5, about 75–95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome- specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG2000/DSPE-PEG3400-2C5/PHIS-PEG2000) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy.

Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

“…20 First, the micellar solutions at varied concentrations ranging from 0.5 to 100 μg/mL were mixed with pyrene. The mixed solutions were sonicated for 30 minutes and placed at room temperature for 1 hour.…”

“…13, 18 Wu et al designed a pH-sensitive mixed micelle based on 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG 2000 (DSPE-PEG 2000 ) for cytosolic drug delivery, where DSPE-PEG 2000 was an US Food and Drug Administration (FDA)-approved excipient being widely used in drug formulations. 19,20 The mixed micelle exhibited a strong enhancement on tumor-specific internalization and anticancer efficacy in drug-sensitive tumors. 20 Stimulated by these former research ideas, this study is aimed at utilizing and further modifying the PHIS-PEG 2000 /DSPE-PEG 2000 micellar system to counter the MDR effect, an investigation that so far has not been attempted by other research groups.…”

“…19,20 The mixed micelle exhibited a strong enhancement on tumor-specific internalization and anticancer efficacy in drug-sensitive tumors. 20 Stimulated by these former research ideas, this study is aimed at utilizing and further modifying the PHIS-PEG 2000 /DSPE-PEG 2000 micellar system to counter the MDR effect, an investigation that so far has not been attempted by other research groups.…”

“…The synthesis of PHIS-PEG 2000 was according to previous reports. 20 PHIS 3000 (30 mg) was dissolved in 2 mL of DMSO and stirred for 12 hours at 30°C. An excess amount of mPEG 2000 -NHS (1.2:1, mol/mol) was added dropwise to the above solution.…”

Efficient Synthesis and Characterization of Monoprotected Symmetrical Poly(Ethylene Glycol) Diamine

“…[1][2][3] It has been reported that PEGylation improves the quality of various kinds of materials used for biomedical application in such way of increasing protein/peptide stability, promoting efficient drug delivery, and increasing biocompatibility toward nonfouling medical devices. [4][5][6][7] Versatile functional groups at the terminal sites of PEG polymers enable the attachment of various biomolecules such as proteins, nucleic acids, and carbohydrates. [8][9][10][11] Of the numerous functional PEG polymers, heterobifunctional PEG derivatives are often used as cross-linkers or spacers between two biomolecules.…”