Smart polymeric nanocarriers functionalized with tumor-acidity-triggered surface charge transition for enhanced cellular uptake

摘要

Introduction: A tailor-made nanoparticulate drug delivery system capable of altering its surface charge in response to external pH change for enhanced intracellular therapeutic delivery was developed in this work. Materials and Methods: N-Acetyl-histidine conjugated D-α-Tocopheryl polyethylene glycol succinate (NAcHis-TPGS) was prepared from the coupling reaction of TPGS and N-acetyl-histidine in DMSO using N,N'-dicyclohexylcarbodiimide as a coupling reagent. To obtain the drug-loaded nanoparticles (NPs), the anticancer drug, doxorubicin (DOX, free base form), and the biodegradable copolymer, poly(lactic-co-glycolic acid) (PLGA), were dissolved in DMSO and subsequently dropped into an aqueous solution containing NAcHis-TPGS. After dialysis to remove the unloaded payloads, the DOX-loaded NAcHis-TPGS/PLGA NPs (NHTPNs) used in this work were attained. For comparison, the DOX-loaded PLGA/TPGS nanoparticles (DOX-loaded TPNs) serving as a control sample incapable of undergoing pH response in charge transition were also prepared. Characterizations of the NPs with respect to particle size and surface charge variation in aqueous solutions of different pH were conducted on a Malvem zetasizer. The therapeutic uptake by cancer cells (HeLa cells) was quantitatively evaluated using fluorescence spectrometer. Results and Discussion: The DOX-loaded NHTPNs and TPNs exhibit a similar particle size distribution (polydispersity index 0.144) with a range 40～45 nm in hydrodynamic diameter. The drug loading content and efficiency was ca 8.0 wt% and 77.2 % for both NHTPNs and TPNs. With medium pH being adjusted from 7.4 to 5.0, the DOX-loaded NHTPNs demonstrated a dramatic surface charge transition from -15 to +10 mV, while TPNs only underwent a negligible response to the same pH variation. The surface charge variation is attributed to the protonation of imidazole groups at the end of NAcHis-TPGS chain segments coated on the surfaces of NHTPNs under the acidic conditions. The data of NP uptake by HeLa cells indicate that such a pH-triggered surface charge transition enables NHTPNs to be engulfed ca 7-fold more at pH 6.0 than that at pH 7.4 while only a 2-fold increase was observed for TPNs in response to the pH variation. Conclusions: The DOX-loaded NHTPNs developed in these work exhibit desirable properties, including the high drug loading efficiency and the tumor-acidity-triggered surface charge transition for enhanced intracellular NP delivery. The delivery system thus shows great potency to promote the therapeutic efficacy of chemotherapy by enhanced NP accumulation in tumor cells.