Carboxymethyl Chitosan-Modified Polyamidoamine Dendrimer Enables Progressive Drug Targeting of Tumors via pH-Sensitive Charge Inversion

Abstract

Polyamidoamine dendrimers are potential candidates for drug delivery systems due to their remarkable cell-penetrating power that results from their strong positive surface charge. However, the positively charged surfaces always lead to serious cytotoxicity and the rapid clearance of polyamidoamine in vivo, which limit the application of these dendrimers. To overcome these drawbacks, we developed a carboxymethyl chitosan-modified polyamidoamine dendrimer to achieve progressive drug targeting of tumors via pH-sensitive charge inversion. With the shielding of carboxymethyl chitosan, the complex was negatively charged at physiological conditions (pH 7.4) and prone to enrich at tumor sites due to the enhanced permeation and retention effect; however, it regained a positive charge via the removal of the carboxymethyl chitosan coating under tumor-acidic conditions (pH 6.5) and achieved high intracellular uptake in tumor cells through electrostatic adsorptive endocytosis. In this study, these dendrimers exhibited 1.99- and 1.76-times higher cellular uptake efficiencies at pH 7.4 in MCF-7 or A549 cells, respectively, compared with efficiencies at pH 6.5, indicating an effective pH-dependent accumulation; the fluorescence intensities of these cells exposed to the dendrimers at pH 6.5 were also 16.45- and 9.27-fold greater, respectively, than those of free doxorubicin. After intravenous administration in mice bearing H22 tumors, doxorubicin-loaded dendrimers exhibited a 1.50-fold greater antitumor activity and presented no obvious systematic toxicity based on histological analysis compared with free drugs. Overall, a simple decoration of carboxymethyl chitosan demonstrated to be a promising way for cationic nanocarriers to achieve pH-sensitive drug release and charge conversion response to tumor microenvironment pH and enhance the antitumor therapy efficiency of anticancer drugs.

Functionalization of chitosan with carboxylic acids and derivatives of them: Synthesis issues and prospects of practical use: A review

“…It was proven that the maximal adsorption capacity of this cross-linked material with respect to Ni 2+ , Cd 2+ and Cu 2+ exceeded values of this parameter for many known adsorbents of heavy metals cations. In the work [133], 1-O-carboxymethylchitosan with the grafting degree of 65% was utilized for the design of nanocapsules via an interaction of it with polyamidoamine dendrimer (PAMAM). More specifically, the carboxymethylchitosan macromolecules enveloped a PAMAM dendrimer containing doxorubicin as the anti-tumor drug.…”

Mildly Cross-Linked Dendrimer Hydrogel Prepared via Aza-Michael Addition Reaction for Topical Brimonidine Delivery

“…9, 10 Lipids, Hyaluronic acid, PEG, PLGA and chitosan are commonly used polymers as topical drug delivery carriers and have been fabricated into particles and hydrogels. 11–19 In particular, particle-based colloidal drug delivery systems help overcome the cornea barrier and realize prolonged drug release. 20–22 In addition, they do not cause blurriness.…”

Dendrimers: Amazing Platforms for Bioactive Molecule Delivery Systems

“…Dendrimers as DDS can improve key points in transport and biodistribution such as prolongation of the drug circulation time, enhance drug solubility, enhance tumor permeation and retention, protection of the drug from surroundings, and the ability to target diseased tissue, among others. As a strategy to minimize the cytotoxicity of PAMAM dendrimers, the positive surface charge of its surface has been modified with carboxymethyl chitosan (CMCS) [90][91][92]. Considering that, CMCS is an amphoteric polymer, sensitive pH, and taking doxorubicin as a model drug for cancer, it is that the formulation of a nanoparticle between PAMAM dendrimer and CMCS based on electrostatic conjugation, can transport the drug and release it into the target tissue ( Figure 3A).…”