Redox and pH-responsive poly (amidoamine) dendrimer–poly (ethylene glycol) conjugates with disulfide linkages for efficient intracellular drug release

Abstract

Nanocarriers with low toxicity, high stability, long circulation in blood and triggered drug release at target sites are extremely needed for cancer therapy. In this study, different molar ratios of poly (ethylene glycol) (PEG) were conjugated to poly (amidoamine) dendrimer (PAMAM) by cleavable disulfide bonds, yielding redox and pH dual-responsive nanocarriers (PSSP). The redox sensitivity of the PSSP conjugates was confirmed by measuring the change in particle size and zeta potential under reductive environment by dynamic light scattering (DLS). Meanwhile, all conjugates showed slight hemolytic ratio and high stability in 10% FBS for 24h. Phagocytosis experiments indicated that the PSSP conjugates could effectively escape the engulfment of macrophage. Doxorubicin (DOX) was loaded into the hydrophobic core of the conjugates with loading content of 10%. In vitro release studies suggested that release rate as well as cumulative release amount of DOX from the PSSP conjugates were pronouncedly enhanced in reductive environment as compared with the non-cleavable counterparts. Besides, all conjugates exhibited excellent acid-triggered release performance. Significantly, PEGylation degree of the conjugates had critical impact on drug release. Cytotoxicity tests displayed that DOX-loaded PSSP conjugates were more potent in killing B16 and A549 tumor cells than the non-cleavable counterparts. Curiously, PSSP conjugate with the highest PEGylation degree showed the best antitumor effect despite the somewhat less cell uptake. Therefore, the dual-responsive PSSP conjugates seem promising candidates for efficient intracellular release of antitumor drugs.