Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system

Liqian Ci; Zhigang Huang; Yu Liu; Zhepeng Liu; Gang Wei; Weiyue Lu

doi:10.1016/j.apsb.2017.03.002

Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties: preparation, characterization and application in a vaginal drug delivery system

Acta Pharm Sin B. 2017 Sep;7(5):593-602. doi: 10.1016/j.apsb.2017.03.002. Epub 2017 May 3.

Authors

Liqian Ci¹, Zhigang Huang¹, Yu Liu², Zhepeng Liu¹, Gang Wei², Weiyue Lu²

Affiliations

¹ School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
² Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, China.

Abstract

Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH₂) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH₂-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH₂ is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH₂ and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.

Keywords: ACN, anhydrous acetonitrile; AG, acetate gossypol; AG-loaded FG, F127 gel-loaded with acetate gossypol; AG-loaded NFG, F127-NH2 gel-loaded with acetate gossypol; ANOVA, one-way analysis of variance; Acetate gossypol; Amino group; C6, 6-coumarin; CDI, carbonyl diimidazole; CMC, critical micelle concentration; DAPI, 2-(4-amidinophenyl)-6-indolecarbamindine dihydrochloride; DLS, dynamic light scattering; DPH, 1,6-diphenyl-1,3,5-hexatriene; DTT, dithiothreitol; DiR, 1,1ʹ-dioctadecyl-3,3,3ʹ,3ʹ-tetramethylindotricarbocyanine iodide; EDTA, ethylenediamine tetraacetic acid; EMS, endometriosis; F127, Pluronic F127; FG, F127 gel; FTIR, Fourier transform infrared; H&E, hematoxylin and eosin; ICR, Institute of Cancer Research; In situ hydrogel; Mucoadhesive gel; NF, amino-functionalised poloxamer 407; NFG, aminated poloxamer 407-based temperature sensitive hydrogel; NMR, nuclear magnetic resonance; OCT, optical coherence tomography; PBS, phosphate buffered saline; PDI, polydispersity index; PEO, poly(ethylene oxide); PGM, porcine gastric mucin; PPO, poly(propylene oxide); Poloxamer 407; TEM, transmission electron microscopy; VFS, vaginal fluid stimulant.