Synthesis, characterization and augmented anticancer potential of PEG-betulinic acid conjugate.
Betulinic acid (BA), a pentacyclic lupine-type triterpene, is reported to inhibit cell growth in a variety of cancers. However, its efficacy is limited by its poor aqueous solubility and relatively short half-life. In this study, BA-monomethoxy polyethylene glycol (mPEG) conjugate was synthesized by covalent coupling the C-28 carboxylic acid position of BA with amine groups of mPEG, in order to improve its solubility and anticancer efficacy. mPEG-BA conjugate was characterized using various analytical techniques including NMR, FT-IR and MALDI-MS. The mPEG-BA conjugate was cytotoxic, demonstrated internalization and induced cell apoptosis in Hep3B and Huh7 hepatic cancer cells. The western-blot analysis revealed, marked decrease in Bcl-2/Bax ratio, and increase in cleaved-PARP and cleaved-caspase-3 expressions. In vivo studies in Ehrlich ascites tumor (EAT) model following intravenous administration demonstrated significant reduction in tumor volume in case of PEGylated BA as compare to native BA. Furthermore, PEGylated BA treated EAT mice showed no biochemical and histological toxicities. These findings demonstrate the potential of PEGylated BA in cancer therapy, with improved water solubility and efficacy.
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Ankit
A
Saneja
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Love
L
Sharma
Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Ravindra Dhar
RD
Dubey
Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Mubashir Javed
MJ
Mintoo
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Amrinder
A
Singh
PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Amit
A
Kumar
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; Natutal Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Payare Lal
PL
Sangwan
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: stabdullah@iiim.ac.in.
Sheikh Abdullah
SA
Tasaduq
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Gurdarshan
G
Singh
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
Dilip M
DM
Mondhe
Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; Formulation & Drug Delivery Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: pngupta@iiim.ac.in.
Prem N
PN
Gupta
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002286:Carcinoma, Ehrlich Tumor / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004355:Drug Stability; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D053978:Pentacyclic Triterpenes; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D017208:Rats, Wistar; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013347:Subcellular Fractions / Q000378:metabolism; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D015415:Biomarkers; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D011092:Polyethylene Glycols; D000094062:Betulinic Acid
Apoptosis; Betulinic acid; Cytotoxicity; Ehrlich ascites carcinoma; Polyethylene conjugate