Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin†

doi:10.7503/cjcu20150895

Abstract

Abstract:

Methoxypolyethylene glycol(MPEG)-conjugated hydroxycamptothecin(HCPT), denoted as MPEG-HCPT, was synthesized via etherification reaction between terminal hydroxyl of MPEG and 10-hydroxy of HCPT, and they were characterized via ¹H NMR and FTIR. The effect of MPEG conjugation on the solubility and lactone-ring stability of HCPT was investigated, as well as its aggregation behavior. The mass fraction of HCPT in the derivative was approximately 33% and the solubility of the MPEG-HCPT in buffer solutions of pH 4.8 and 7.2 at 37 ℃ were respectively 5.23 and 7.90 mmol/L, significantly higher than those of pristine HCPT(0.0026 and 0.035 mmol/L). The pK_ah(K_ah, the apparent hydrolysis equilibrium constant) of MPEG-HCPT at 37 ℃ was determined to be approximately 7.12, higher than that of pristine HCPT(ca. 6.67), indicating that the MPEG conjugation could enhance the lactone-ring stability of HCPT. The MPEG-HCPT exhibited obvious surface activity, and could form aggregates in water with a aggregation micelle concentration of 0.46 mmol/L.

Key words: Hydroxycamptothecin, Polyethylene glycol, Solubility, Lactone ring stability

CLC Number:

O648
O629.3

TrendMD:

QIU Chuanlong,LI Chunfang,LI Dongxiang,HOU Wanguo. Synthesis, Characterization and Aggregation Behavior of Polyethylene Glycol-conjugated Hydroxycamptothecin^†[J]. Chem. J. Chinese Universities, 2016, 37(8): 1535.

Figures/Tables 5

Fig.1 Hydrolysis reaction of HCPT

Fig.2 Synthetic route of MPEG-HCPT

Fig.3 1H NMR(A) and FTIR(B) spectra of HCPT(a), MPEG-HCPT(b) and MPEG(c)

Fig.4 UV-Vis spectra of HCPT(A) and MPEG-HCPT(B) in buffer solutions with various pH values and variation of relative percentages of lactone form and carboxylate form vs. pH for HCPT(C) and MPEG-HCPT(D) pH: (A) a—k. 3.5, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9.5; (B) a—j. 4, 5, 6, 6.5, 7, 7.5, 8, 9, 10, 11.

Fig.5 Variation of surface tension(A), I5/I1 value(B), and dynamic radius(Rh)(C) of MPEG-HCPT aggregates vs. concentration with different pH values

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