Development of nano-based drug-delivering carriers for colorectal and breast cancer targeting

Abstract

This study aimed to develop three types of nanocarriers for targeted delivery of chemotherapeutic drugs to colorectal and breast cancers: Polyethylene glycol diacrylate/polyacrylic acid nanoparticles (PEGDA/AA NPs), trastuzumab (Tras)-decorated liposomes (Tras-Lip), and Tras-decorated maleimide-conjugated chitosan/cysteine-conjugated alginate nanoparticles (Tras-CHI-Mal/Alg-Cys NPs). Doxorubicin (Dox) and curcumin were selected as model compounds. PEGDA/AA NPs were prepared by surfactant-free emulsion polymerization using V50 azo initiator and bisacrylamide crosslinker. Tras-Lip formulations were prepared by thin-film hydration method followed by coating with iodoacetamide grafted chitosan (CHI-IA) and conjugated with Tras. Tras-CHI-Mal/Alg-Cys NPs were prepared by ionic gelation and click reaction between the polymers and followed by conjugation with Tras by the thiol-maleimide reaction. The structural characterization was performed using proton nuclear magnetic resonance (1H-NMR), attenuated total reflection Fourier transform infrared (ATR-FTIR) and inductively coupled plasma mass spectrometers (ICP-MS). Their physicochemical properties, morphology, drug content/release, antibody content, and cytotoxicity on normal and cancer cells were investigated. The cellular uptake and apoptosis mechanism of the nanocarriers on colorectal and HER2-positive breast cancer cells were also determined. All nanocarriers were successfully developed with desirable sizes, good polydispersity index, and presented a spherical shape. The zeta potential of PEGDA/AA NPs and CHI-Mal/Alg-Cys NPs were negative charges, while that of Tras-Lip was positive. Dox was encapsulated in the nanocarriers with a % loading efficiency (%LE) of 45.8 ± 0.23 % in PEGDA/AA NPs and 84.6 ± 5.2 % in Tras-CHI-IA coated liposome. Dox was released completely from PEGDA/AA NPs and 78.0 ± 1.8 % from Tras-CHI-IA coated liposome within 24 h at tumor pH. Curcumin was incorporated with a high %LE of 74 ± 3.2% in CHI-Mal/Alg-Cys NPs and released completely within 7 days in tumor pH. The nanocarriers showed potent cytotoxic effects with relatively low IC50 values against HT-29 and SK-BR-3 cells while being non-toxic to Caco-2 and HGF cells . Dox-PEGDA/AA NPs were able to be accumulated passively inside colorectal cancer cells and induce apoptosis, while Tras-CHI-IA coated liposomes and curcumin-CHI-Mal/Alg-Cys NPs demonstrated greater cell toxicity towards breast cancer cells via ligand-receptor mediated endocytosis. Our findings suggest that these nanocarriers could be promising carriers for delivering therapeutic anti-cancer drugs by both passive and active targeting strategies.

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