133 Synthetic, Cyclodextrin-Based Polymer Matrix for Local Regional Drug Delivery

Abstract

Various matrices containing both synthetic or natural polymers are currently used for local regional drug delivery to a number of disease locations such as chronic cutaneous wounds, joints, bone, muscle, and nerves. Insert Therapeutics has developed a novel synthetic matrix which consists of a copolymer of β-cyclodextrin and polyethylene-glycol (PEG). Addition of di- or multifunctionalized adamantane-PEG molecules results in noncovalent cross-linking through inclusion complex formation. The resulting hydrogel showed rheological characteristics amenable to topical application or local-regional injection into a variety of tissues (Bellocq et al. (2004) Bioconjug Chem 15(6): 1201–1211). This matrix was shown to be biocompatible, allowing for cellular growth and migration in vitro. It also allowed for efficient delivery of an adenovirus gene therapy vector to dermal fibroblast cells. In vivo, the matrix demonstrated efficient delivery of biotherapeutics such as recombinant adenovirus and non-viral gene therapy vectors after intradermal injection. The matrix was well tolerated and was as efficient as collagen in promoting wound healing when an adenoviral gene therapy vector expressing PDGF-bb was delivered to cutaneous wounds of diabetic mice. The matrix can additionally be modified to incorporate therapeutic small molecules, peptides, or proteins, either through inclusion complex formation or chemical linkage. Using biodegradable linker chemistry, the release rate of covalently attached molecules can be controlled. The cyclodextrin-PEG matrix is therefore an attractive alternative to existing matrices that is biocompatible, biodegradable, tunable with regard to its physicochemical properties, and can be designed to deliver multiple therapeutic agents to a variety of tissues in a controlled fashion.