Controlled Releases of FGF-2 and Paclitaxel from Chitosan Hydrogels and their Subsequent Effects on Wound Repair, Angiogenesis, and Tumor Growth

Masayuki      Ishihara; Masanori      Fujita; Kiyohaya      Obara; Hidemi      Hattori; Shingo      Nakamura; Masaki      Nambu; Tomoharu      Kiyosawa; Yasuhiro      Kanatani; Bonpei      Takase; Makoto      Kikuchi; Tadaaki      Maehara

Abstract

A photocrosslinkable chitosan (Az-CH-LA) aqueous solution resulted in an insoluble hydrogel like a soft rubber within 30 sec of ultraviolet light (UV)-irradiation. The photocrosslinked chitosan hydrogel showed strong sealing strength and potential use as a new tissue adhesive in surgical application. Paclitaxel, which is an anti-tumor reagent and a vascularization-inhibitor, retained in the photocrosslinked chitosan hydrogel, and were gradually released from the photocrosslinked chitosan hydrogel in vivo upon the degradation of the hydrogel. The paclitaxel-incorporated photocrosslinked chitosan hydrogels effectively inhibited tumor growth and angiogenesis in mice. On the other hand, the fibroblast growth factor (FGF)-2 molecules also retained in both the photocrosslinked chitosan and an injectable chitosan/ IO4-heparin hydrogels, and were gradually released from the hydrogels upon their in vivo biodegradations. The activity of FGF-2 in the hydrogels was stable for long time (more than 14 days). The controlled release of biologically active FGF-2 molecules from the hydrogels caused an induction of the angiogenesis and, possibly, collateral circulation occurred in the healing-impaired diabetic (db/db) mice and the ischemic limbs of rats. The purpose of this review is to describe the effectiveness of the chitosan hydrogels (photocrosslinkable chitosan hydrogel and chitosan/IO4-heparin hydrogel) as a local drug delivery carrier for FGF-2 and paclitaxel to control wound repair, tumor growth, and angiogenesis. It is thus proposed that the chitosan hydrogels may be a promising new local carrier for drugs such as FGF-2 and paclitaxel.

Keywords: Photocrosslinked chitosan hydrogel, Chitosan/IO4-heparin hydrogel, Angiogenesis, Drug delivery carrier, Controlled release, Paclitaxel, Fibroblast growth factor-2 (FGF-2)

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