title: Tunable diblock copolypeptide hydrogel depots for local delivery of hydrophobic molecules in healthy and injured central nervous system.
abstract: Many hydrophobic small molecules are available to regulate gene expression and other cellular functions. Locally restricted application of such molecules in the central nervous system (CNS) would be desirable in many experimental and therapeutic settings, but is limited by a lack of innocuous vehicles able to load and easily deliver hydrophobic cargo. Here, we tested the potential for diblock copolypeptide hydrogels (DCH) to serve as such vehicles. In vitro tests on loading and release were conducted with cholesterol and the anti-cancer agent, temozolomide (TMZ). Loading of hydrophobic cargo modified DCH physical properties such as stiffness and viscosity, but these could readily be tuned to desired ranges by modifying DCH concentration, amino acid composition or chain lengths. Different DCH formulations exhibited different loading capacities and different rates of release. For example, comparison of different DCH with increasing alanine contents showed corresponding increases in both cargo loading capacity and time for cargo release. In vivo tests were conducted with tamoxifen, a small synthetic hydrophobic molecule widely used to regulate transgene expression. Tamoxifen released from DCH depots injected into healthy or injured CNS efficiently activated reporter gene expression in a locally restricted manner in transgenic mice. These findings demonstrate the facile and predictable tunability of DCH to achieve a wide range of loading capacities and release profiles of hydrophobic cargos while retaining CNS compatible physical properties. In addition, the findings show that DCH depots injected into the CNS can efficiently deliver small hydrophobic molecules that regulate gene expression in local cells.
authors: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095-1569, USA.
authors: Shanshan
authors: S
authors: Zhang
authors: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA.
authors: Mark A
authors: MA
authors: Anderson
authors: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA.
authors: Yan
authors: Y
authors: Ao
authors: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA; Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1751, USA.
authors: Baljit S
authors: BS
authors: Khakh
authors: Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095-1600, USA.
authors: Jessica
authors: J
authors: Fan
authors: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095-1569, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095-1600, USA. Electronic address: demingt@seas.ucla.edu.
authors: Timothy J
authors: TJ
authors: Deming
authors: Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1763, USA. Electronic address: sofroniew@mednet.ucla.edu.
authors: Michael V
authors: MV
authors: Sofroniew
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000737:chemistry; D016503:Drug Delivery Systems; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008822:Mice, Transgenic; D008962:Models, Theoretical; D010455:Peptides / Q000737:chemistry*; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D010455:Peptides; D013629:Tamoxifen; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D002784:Cholesterol
keywords: Anti-cancer drugs; Brain; Hydrogels; Neural stem cells; Reactive astrocytes; Spinal cord