Grafted copolymer micelles with pH triggered charge reversibility for efficient doxorubicin delivery

Abstract

The instability and premature charge reversal at pH 7.4 have become the major limitations of charge-reversal delivery systems. To address this problem, graft copolymer of poly(butylene succinate)-g-cysteamine-bi-poly(ethylene glycol) (PBS-g-CS-bi-PEG, bi 5 benzoic imine bond) was designed and synthesized through facile thiol-ene click reaction and subsequent Schiff's base reaction. Then, PBS-g-CS-bi-PEG and carboxyl-functionalized polyester of poly(butylene succinate)-g-3-mercaptopropionic acid (PBS-g-MPA) co-assemble in aqueous solution to give PEG shell-sheddable charge-reversal micelles with sizes of 85-103 nm and low polydispersity of 0.11-0.12. Interestingly, the PBS-g-MPA/CS-bi-PEG micelles could sensitively and arbitrarily switch their surface charges between negative and positive status in response to pH fluctuation via reversible protonation and deprotonation of carboxyl and amino groups, which endows the desired stability of coassembly micelles either during long-term storage or under physiological conditions. Doxorubicin (DOX) was loaded into PBS-g-MPA/CS-bi-PEG micelles with a high drug-loading content of 10.2% and entrapment efficiency of 68% as a result of electrostatic attraction. In vitro release studies revealed that less than 25% of DOX was released within 24 h in the environment mimicking the physiological condition, whereas up to 81% of DOX was released in 24 h under weak-acid condition resembling microenvironment in endosome/lysosome. In vitro cytotoxicity study suggested that blank PBS-g-MPA/CS-bi-PEG micelles possessed excellent biocompatibility, while DOXloaded PBS-g-MPA/CS-bi-PEG micelles showed significant cytotoxicity with half-maximal inhibitory concentration (IC 50 ) of 1.55-1.67 lg DOX equiv/mL. This study provides a facile and effective approach for the preparation of novel charge-reversal micelles with switchable charges and excellent biocompatibility, which are highly promising to be used as safe nanocarriers for efficient intracellular drug delivery.

DePEGylation strategies to increase cancer nanomedicine efficacy

“…* this route does not overcome the "PEG dilemma" and the very limited uptake of PEGylated nanoparticles is a major drawback of these systems. [46][47][48][49] Micelles [50] Hydrazone Liposomes [52][53][54] Micelles [55][56][57][58][59][60][61] Acetal Liposomes [62] Micelles [63][64][65][66][67][68][69] β-thiopropionate Micelles [70] Ortho ester Liposomes [71][72][73] Benzoic-imine Micelles [74][75][76] Reduction Glutathione (GSH) (2-10 mM) Liposomes [93] Polymersomes [94,95] Micelles 133] Graphene Oxide [122][123][124] Mesoporous silica nanoparticles (MSN) [125][126][127][128][129][130][131][132] Magnetic nanoparticles [134] Enzymatic Cathepsin B (peptide consensus sequence)…”

“…45 For this, chemical functionalities stable at physiological pH (pH 7.4) but labile at lower pH are required. The most commonly used acid labile chemical groups are vinyl ethers, [46][47][48][49][50] hydrazones, [51][52][53][54][55][56][57][58][59][60][61] acetals, [62][63][64][65][66][67][68][69] β-thiopropionates, 70 ortho esters [71][72][73] and benzoic imines [74][75][76][77][78][79][80][81][82] . Here accompanied by a significant increase in hemolytic activity suggesting partial dePEGylation was sufficient to endow these particles with the desired function.…”

Charge reversal nano-systems for tumor therapy

“…Besides β -carboxylic amides, imine bonds can also be applied to fabricate CR-NDDSs, for example benzoic imine bonds [ 55 , 56 ]. Benzoic imine bonds, which are formed by primary amines and benzaldehyde groups, remain stable at physiological pH environment but can undergo cleavage under acidic condition.…”

Multifunctional redox-responsive and CD44 receptor targeting polymer-drug nanomedicine based curcumin and alendronate: synthesis, characterization and in vitro evaluation

“…The transmission electron microscopy (TEM) was used to observe the morphology of the micelles. As illustrated in Figure 4(A-C), the cur-loaded ALN-oHA-S-S-CUR micelles possessed a spherical shape and the particle size was 80 nm, these results were smaller than the Beckman Coulter Particle Analyzer, these probably because the micelles were dehydrated that made the size contraction, when using the TEM to observe the micelles morphology [28]. On the other, the PI of the cur-loaded ALN-oHA-S-S-CUR micelles was 0.14 smaller than 0.2, showed the uniform of the micelles size, and these results were consistent with TEM.…”