In vivo pharmacokinetics, biodistribution and antitumor effect of amphiphilic poly(L-amino acids) micelles loaded with a novel all-trans retinoic acid derivative.
Poly(amino acid)s are well-known as biodegradable and environmentally acceptable materials. In this study, a series of poly(L-aspartic acid)-b-poly(L-phenylalanine) (PAA-PPA) compounds with different degrees of polymerization were used to prepare copolymer micelles for a poorly water-soluble drug 4-amino-2-trifluoromethyl-phenyl retinate (ATPR, a novel all-trans retinoic acid derivative) and in vivo pharmacokinetics, biodistribution and antitumor efficacy of ATPR delivered by PAA-PPA micelles were evaluated. The area under the plasma concentration time curve AUC0→∞ of ATPR-loaded PAA20PPA20 micelles was 2.23 and 1.97 times higher than that of ATPR solution and ATPR CrmEL solution, respectively; In addition, the mean residence time (MRT) was increased 1.67 and 1.97-fold, respectively and the total body clearance (CL) was reduced 2.25 and 1.98-fold, respectively. The biodistribution study indicated that most of the ATPR in the ATPR-M group was distributed in the liver and there was delayed liver aggregation compared with the ATPR solution and ATPR CrmEL solution groups. Furthermore, the antitumor efficacy of ATPR-loaded PAA20PPA20 micelles was demonstrated in in vivo antitumor models involving mice inoculated with the human gastric cancer cell line SGC-7901. At the same dose of 7mg/kg, the ATPR-loaded micelles group demonstrated a better tumor growth inhibition and induced differentiation than the groups given ATPR solution and ATPR CrmEL solution. Therefore, the ATPR-loaded PAA-PPA micelles appear to be a potentially useful drug delivery system for ATPR and suitable for the chemotherapy of gastric cancer.
College of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China. Electronic address: flying.99@163.com.
Jihui
J
Tang
Xinqun
X
Wang
Ting
T
Wang
Feihu
F
Chen
Jianping
J
Zhou
D000596:Amino Acids / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001224:Aspartic Acid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D010649:Phenylalanine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012176:Retinoids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D014018:Tissue Distribution / Q000502:physiology; D014212:Tretinoin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
C585745:4-amino-2-trifluoromethyl-phenyl retinate; D000596:Amino Acids; D000970:Antineoplastic Agents; D008823:Micelles; D011108:Polymers; D012176:Retinoids; D001224:Aspartic Acid; D010649:Phenylalanine; D014212:Tretinoin
4-Amino-2-trifluoromethyl-phenyl retinate (ATPR); Antitumor effect; Biodistribution; Micelles; Pharmacokinetics; Poly(l-amino acids)