A chitosan-based cascade-responsive drug delivery system for triple-negative breast cancer therapy

Abstract

Background It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. Results In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. Conclusions The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.

Natural Ingredient-Based Polymeric Nanoparticles for Cancer Treatment

“…The cell-penetrating peptide facilitated the formulation to accumulate at the tumor site after administration. The DDS demonstrated stronger tumor inhibition in the xenograft mouse model with less off-target effects and lower systemic toxicity than treatment with doxorubicin alone [47].…”

“… Materials Composition of Nanoparticles Significances Ref. Chitosan Ascorbic acid, pentasodium tripolyphosphate Antioxidative; reduced viability of cervical cancer cells; nontoxic to human normal cells [ 40 ] EGFR binding peptide, PEG2000, Mad2 siRNA Selective uptake by NSCLC cells; stronger tumor inhibition in a drug-resistant model [ 41 , 42 ] Folate, curcumin Targeted folate receptors; enhanced toxicity to breast cancer cells; controlled release in acidic environments [ 43 ] Glycyrrhetinic acid, doxorubicin Enhanced cellular uptake and cytotoxicity of doxorubicin [ 45 ] PNVCL, cell-penetrating peptide, doxorubicin Controlled in acidic and hyperpyrexic conditions; selective cellular uptake; stronger tumor inhibition and lower systemic toxicity [ 47 ] Hyaluronic acid Cisplatin, siRNA, near IR dye indocyanine green (ICG), various fatty amines or cationic polyamines Targeted CD44 receptors; effective in combination treatments against resistant cancers [ 48 , 49 ] L-lysine methyl ester, lipoic acid, doxorubicin Controlled release of doxorubicin triggered by GSH; targeted CD44 receptors [ 50 ] PEGylated cationic quaternary amine, ...…”

Chitosan-Based Nanoparticles of Targeted Drug Delivery System in Breast Cancer Treatment

“…Under the in vivo enzyme, CS will break down into water and carbon dioxide and become an endogenous species, ensuring no harmful effects from the products of degradation. Due to its increased solubility at slightly acidic pHs, such as those present in the microenvironment of the tumor, CS is generally used to develop pH-sensitive DDS [ 45 ].…”

“…The four major benefits of such approaches to nanotechnology are helping solubilize hydrophobic drugs, prolonged drug in system circulation, it can passively target tumour cells through the EPR effect, allow stimulus-responsive materials to ensure provide drug at the target cells, and functionalized targeting ligands to achieve specific tumor cell binding and uptake, thus minimizing off-target side effects [ 45 ].…”

Nebulised surface-active hybrid nanoparticles of voriconazole for pulmonary Aspergillosis demonstrate clathrin-mediated cellular uptake, improved antifungal efficacy and lung retention

“…Accordingly, we herein investigate nebulized DPPC coated chitosan (CH) nanoparticles (NPs) for the pulmonary delivery of voriconazole. CH, a natural polysaccharide, has shown immense potential and acceptance in the inhalational drug delivery due to its biodegradable, mucoadhesive, permeation-enhancing and controlled release characteristics [ 25 – 27 ]. The presence of DPPC coating on NPs surface enhance its biocompatibility as well as increase its interaction with the pulmonary surfactant monolayers (PSM), which line the inner epithelial surface of lung alveoli at the air–liquid interface [ 21 , 23 ].…”