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 7 mg/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.

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