PEGylation alleviates the non-specific toxicities of Alpha-Momorcharin and preserves its antitumor efficacy in vivo.
Alpha-Momorcharin (α-MMC) is a ribosome inactivating protein from Momordica charantia with anti-tumor activity. Previously, we had observed that modification of α-MMC with polyethylene glycol (PEG) could reduce toxicity, but it also reduces its anti-tumor activity in vitro. This study aims to investigate whether the metabolism-extended properties of α-MMC resulting from PEGylation could preserve its anti-tumor efficacy in vivo through pharmacokinetics and antitumor experiments. The pharmacokinetics experiments were conducted in rats using the TCA (Trichloroacetic Acid) method. Antitumor activity in vivo was investigated in murine mammary carcinoma (EMT-6) and human mammary carcinoma (MDA-MB-231) transplanted tumor mouse models. The results showed that PEGylation increased the plasma half-life of α-MMC in rats from 6.2-7.5 h to 52-87 h. When administered at 1 mg/kg, α-MMC-PEG and α-MMC showed similar anti-tumor activities in vivo, with a T/C% of 38.56% for α-MMC versus 35.43% for α-MMC-PEG in the EMT-6 tumor model and 36.30% for α-MMC versus 39.88% for α-MMC-PEG in the MDA-MB-231 tumor model (p > 0.05). Importantly, at the dose of 3 mg/kg, all the animals treated with α-MMC died while the animals treated with α-MMC-PEG exhibited only moderate toxic reactions, and α-MMC-PEG exhibited improved anti-tumor efficacy with a T/C% (relative tumor growth rate) of 25.18% and 21.07% in the EMT-6 and MDA-MB-231 tumor models, respectively. The present study demonstrates that PEGylation extends the half-life of α-MMC and alleviates non-specific toxicity, thereby preserving its antitumor efficacy in vivo, and a higher lever of dosage can be used to achieve better therapeutic efficacy.
a Department of Immunology , College of Preclinical and Forensic Medicine, Sichuan University , Chengdu , PR China .|b School of Medical Laboratory Science, Chengdu Medical College , Chengdu , PR China .
Nian-hua
NH
Deng
b School of Medical Laboratory Science, Chengdu Medical College , Chengdu , PR China .
Ling
L
Wang
c Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA , and.
Qian-chuan
QC
He
b School of Medical Laboratory Science, Chengdu Medical College , Chengdu , PR China .
Jue-cun
JC
Zheng
b School of Medical Laboratory Science, Chengdu Medical College , Chengdu , PR China .
Yao
Y
Meng
d Key Laboratory of Bio-Resources and Eco-Environment Ministry of Education/Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province , College of Life Science, Sichuan University , Chengdu , PR China.
Yan-Fa
YF
Meng
a Department of Immunology , College of Preclinical and Forensic Medicine, Sichuan University , Chengdu , PR China .
Chong-Jie
CJ
Zhang
b School of Medical Laboratory Science, Chengdu Medical College , Chengdu , PR China .
Fu-bing
FB
Shen
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054788:Ribosome Inactivating Proteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D011092:Polyethylene Glycols; C039582:MMC protein, Momordica charantia; D054788:Ribosome Inactivating Proteins
PEGylation; anti-tumor activity; pharmacokinetics; α-MMC; α-MMC-PEG