Actively Targeted and Redox Responsive Delivery of Anticancer Drug by Chitosan Nanoparticles.

Elisabetta Mazzotta,Selene De Benedittis,Antonio Qualtieri,Rita Muzzalupo

doi:10.3390/pharmaceutics12010026

Elisabetta Mazzotta, Selene De Benedittis + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics12010026

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Abstract

The clinical efficacy of methotrexate (MTX) is limited by its poor water solubility, its low bioavailability, and the development of resistance in cancer cells. Herein, we developed novel folate redox-responsive chitosan (FTC) nanoparticles for intracellular MTX delivery. l-Cysteine and folic acid molecules were selected to be covalently linked to chitosan in order to confer it redox responsiveness and active targeting of folate receptors (FRs). NPs based on these novel polymers could possess tumor specificity and a controlled drug release due to the overexpression of FRs and high concentration of reductive agents in the microenvironment of cancer cells. Nanoparticles (NPs) were prepared using an ionotropic gelation technique and characterized in terms of size, morphology, and loading capacity. In vitro drug release profiles exhibited a glutathione (GSH) dependence. In the normal physiological environment, NPs maintained good stability, whereas, in a reducing environment similar to tumor cells, the encapsulated MTX was promptly released. The anticancer activity of MTX-loaded FTC-NPs was also studied by incubating HeLa cells with formulations for various time and concentration intervals. A significant reduction in viability was observed in a dose- and time-dependent manner. In particular, FTC-NPs showed a better inhibition effect on HeLa cancer cell proliferation compared to non-target chitosan-based NPs used as control. The selective cellular uptake of FTC-NPs via FRs was evaluated and confirmed by fluorescence microscopy. Overall, the designed NPs provide an attractive strategy and potential platform for efficient intracellular anticancer drug delivery.

Highlights

The specific, effective, and safe intratumoral delivery of active drugs is one of the key issues in cancer therapy
The common method used for NP preparation is the ionic gelation technique, an easy method based on the electrostatic interaction between the positively charged chitosan chains and anionic crosslinking agents such as glutaraldehyde, tripolyphosphate, and polyaspartic acid sodium salt [4]
Nanocarriers responsive to the reductive conditions are appealing for intracellular drug delivery applications in cancer therapy

Summary

Introduction

The specific, effective, and safe intratumoral delivery of active drugs is one of the key issues in cancer therapy. The excellent features of NPs include prolonged systemic circulation, high preferential accumulation at the tumor sites via an enhanced permeation and retention effect (EPR), and the ability to overcome P-glycoprotein-mediated multidrug resistance of cancer cells [2]. CHT is a naturally occurring biopolysaccharide that was extensively explored in pharmaceutical and biomedical fields due to its unique biological activities including antioxidant, anti-inflammatory, antifungal, and antimicrobial activity. This polysaccharide provides a profitable tool for the design of innovative delivery systems due to its biocompatibility, biodegradability, non-toxicity, and mucoadhesivity [3]. The cationic nature of chitosan makes it a promising material for drug delivery systems. The presence of reactive functional groups gives huge opportunities for chemical modifications with a wide range of molecules in order to improve its targeting tumor ability

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