Anticancer therapeutic potential of phosphorylated galactosylated chitosan against N-nitrosodiethyl amine-induced hepatocarcinogenesis

Anushree U; Sachin Shetty; Suresh D Kulkarni; Harish Kumar B; K Sreedhara R Pai; Jesil Mathew A; Rajesh Kumar; Sanjay Bharati

doi:10.1016/j.abb.2022.109375

Anticancer therapeutic potential of phosphorylated galactosylated chitosan against N-nitrosodiethyl amine-induced hepatocarcinogenesis

Arch Biochem Biophys. 2022 Oct 15:728:109375. doi: 10.1016/j.abb.2022.109375. Epub 2022 Aug 12.

Authors

Anushree U¹, Sachin Shetty¹, Suresh D Kulkarni², Harish Kumar B³, K Sreedhara R Pai³, Jesil Mathew A⁴, Rajesh Kumar⁵, Sanjay Bharati⁶

Affiliations

¹ Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
² Department of Atomic and Molecular Physics, Manipal Institute of Technology Campus, Manipal Academy of Higher Education, Manipal, Karnataka, India.
³ Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
⁴ Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
⁵ Department of Nuclear Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.
⁶ Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India. Electronic address: sanjay.bharati@manipal.edu.

PMID: 35970414
DOI: 10.1016/j.abb.2022.109375

Abstract

Chitosan is a natural polyfunctional polymer that can be modified to achieve compounds with tailored properties for targeting and treating different cancers. In this study, we report the development and anticancer potential of phosphorylated galactosylated chitosan (PGC). The synthesized compound was characterized by FT-IR, NMR, and mass spectroscopy. The interaction of PGC with asialoglycoprotein receptors (ASGPR) and cellular internalization in HepG2 cells was studied using in silico and uptake studies respectively. PGC was evaluated for its metal chelating, ferric ion reducing, superoxide, and lipid peroxide (LPO) inhibiting potential. Further, anticancer therapeutic potential of PGC was evaluated against N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in a mice model. After development of cancer, PGC was administered to the treatment group (0.5 mg/kg bw, intravenously), once a week for 4 weeks. Characterization studies of PGC revealed successful phosphorylation and galactosylation of chitosan. A strong interaction of PGC with ASGP-receptors was predicted by computational studies and cellular internalization studies demonstrated 98.76 ± 0.53% uptake of PGC in the HepG2 cells. A good metal chelating, ferric ion reducing, and free radical scavenging activity was demonstrated by PGC. The anticancer therapeutic potential of PGC was evident from the observation that PGC treatment increased number of tumor free animals (50%) (6/12) and significantly (p ≤ 0.05) lowered tumor multiplicity as compared to untreated tumor group.

Keywords: ASGPR; Chitosan; Chitosan (PubChem CID 71853); Hepatocellular carcinoma; Lactobionic acid; Lactobionic acid (PubChem CID 7314); Liver cancer; N-Nitrosodiethylamine (PubChem CID 5921); NDEA; Orthophosphoric acid (PubChem CID 1004).

MeSH terms

Amines
Animals
Carcinoma, Hepatocellular*
Chitosan*
Liver Neoplasms*
Mice
Spectroscopy, Fourier Transform Infrared

Substances

Amines
Chitosan