The influence of modified pluronic F127 copolymers with higher phase transition temperature on arsenic trioxide-releasing properties and toxicity in a subcutaneous model of rats

Abstract

Pluronic F127 (PF-127) shows thermoreversible property, which is of the utmost interest in optimizing drug formulation and delivery. However, its hitherto unresolved drawback of a low phase transition temperature (T (tr)) has limited its application in injectable drug delivery systems. We have recently synthesized a new type of PF-127 copolymers with higher T (tr) using a simple oxidative method. Here, we have investigated the drug-releasing feature of oxidized PF-127 and oxidized PF-127-containing silver nanoparticles (SNPs), carrying arsenic trioxide (ATO), in a subcutaneous model of rats. Injectable hydrogels prepared with oxidized PF-127s were less viscous and easier to inject, at the same concentration, than their precursor. Addition of SNPs further elevated T (tr), resulting in even lower viscosity of the injectable hydrogel prepared from SNP-containing oxidized PF-127. The oxidized PF-127 copolymers did not differ significantly in ATO-releasing ability, compared with parental PF-127, but the addition of SNPs altered the ATO-releasing feature of oxidized PF-127 to some extent. ATO-carrying oxidized PF-127s had similar toxicity, but the addition of SNPs enhanced the hepatotoxicity of ATO, as evidenced by elevated serum levels of alanine aminotransferase and aspartate aminotransferase and histological alterations, compared to parental PF-127. The results presented herein warrant further investigation of the modified PF-127 copolymers to deliver ATO or other drugs in the form of injectable hydrogels.

Fig. 1

Molecular structures of PF-127 polymers. The parental PF-127 polymer (S0) and oxidized PF-127 polymers (S1 and S2, prepared at 48 or 72 h of oxidation time, respectively) are shown in a, b, and c, respectively

Fig. 2

Serum levels of ATO. Rats were subcutaneously injected with the control ATO solution or hydrogels containing ATO formulated in S0, S1, S2, or S3. The blood samples were collected at the indicated time points, and sera were harvested to measure the serum levels of ATO. Single asterisk indicates a significant higher level of ATO from the four hydrogel groups 12 h after injection. Double asterisks: A significant higher level from the other three hydrogel groups. Dagger: A significant higher level from the S0 group. Double dagger: A significant lower level from the four hydrogel groups, at the respective time points

Fig. 3

Serum levels of AST, ALT, BUN, and Cr. The rats were killed 120 h after injection of the control ATO solution or hydrogels containing ATO formulated in S0, S1, S2, or S3, and blood samples were collected via cardiac puncture. The serum levels of AST and ALT (a) and BUN and Cr (b) were measured. Results are expressed as mean ± SD (n = 6). A significant increase from the control group is denoted by an asterisk and a significant increase from the S1 or S2 groups by a dagger

Fig. 4

Histological analysis of liver, kidney, and heart. a Representative photographs (×400 magnification) were taken from the sections of livers, kidneys, and hearts from the rats subcutaneously injected with the control ATO solution or hydrogels containing ATO formulated in S0, S1, S2, or S3, 120 h earlier. b Histological scoring was performed as described in “Materials and Methods” section. Data were represented by mean ± SD (n = 6). A significant increase from the control group is denoted by an asterisk (P < 0.05)