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Adhesive thermosensitive gels for local delivery of viral vectors.

ABSTRACT: Local delivery of viral vectors can enhance the efficacy of therapies by selectively affecting necessary tissues and reducing the required vector dose. Pluronic F127 is a thermosensitive polymer that undergoes a solution-gelation (sol-gel) transition as temperature increases and can deliver vectors without damaging them. While pluronics can be spread over large areas, such as the surface of an organ, before gelation, they lack sufficient adhesivity to remain attached to some tissues, such as the surface of the heart or mucosal surfaces. Here, we utilized blends of pluronic F127 and polycarbophil (PCB), a mucoadhesive agent, to provide the necessary adhesivity for local delivery of viral vectors to the cardiac muscle. The effects of PCB concentration on adhesive properties, sol-gel temperature transition and cytocompatibility were evaluated. Rheological studies showed that PCB decreased the sol-gel transition temperature at concentrations >1% and increased the adhesive properties of the gel. Furthermore, these gels were able to deliver viral vectors and transduce cells in vitro and in vivo in a neonatal mouse apical resection model. These gels could be a useful platform for delivering viral vectors over the surface of organs where increased adhesivity is required.

SUBMITTER: Caronia JM

PROVIDER: S-EPMC7001463 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Adhesive thermosensitive gels for local delivery of viral vectors.

Caronia Jeanette M JM Sorensen Daniel W DW Leslie Hope M HM van Berlo Jop H JH Azarin Samira M SM

Biotechnology and bioengineering 20190520 9

Local delivery of viral vectors can enhance the efficacy of therapies by selectively affecting necessary tissues and reducing the required vector dose. Pluronic F127 is a thermosensitive polymer that undergoes a solution-gelation (sol-gel) transition as temperature increases and can deliver vectors without damaging them. While pluronics can be spread over large areas, such as the surface of an organ, before gelation, they lack sufficient adhesivity to remain attached to some tissues, such as the ...[more]

PMID: 31038193

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Project description:Limbal stem cell (LSC) transplantation is a promising treatment for ocular surface diseases especially LSC deficiency. Genetic engineering represents an attractive strategy to increase the potential for success in LSC transplantations either by correcting autologous diseased LSCs or by decreasing the immunogenicity of allogeneic LSCs. Therefore, two popular viral vectors, adeno-associated viral (AAV) vector and lentiviral (LV) vector, were compared for gene delivery in human LSCs. Transduction efficiency was evaluated by flow cytometry, quantitation of viral genomes, and fluorescence microscopy after introducing eight self-complementary AAV serotypes or LV carrying a green fluorescent protein (GFP) cassette to fresh limbal epithelial cells, cultivated LSC colonies, or after corneal intrastromal injection into human explant tissue. For fresh limbal epithelial cells, AAV6 showed the highest transduction efficiency, followed by LV and AAV4 at 24?h after vector incubation, which did not directly correlate with internalized genome copy number. The colony formation efficiency, as well as colony size over time, showed no significant differences among AAV serotypes, LV, and nontreated controls. The percentage of GFP+ colonies at 14 days post-seeding was significantly higher in the LV group, which plateaued at 50% GFP+ upon serial passages. Interestingly, AAV6-treated colonies initially showed a variegated transduction phenotype with no GFP+ colonies in serial passages. Quantitative polymerase chain reaction and AAV6 capsid staining revealed that transduction was restricted to differentiated cells of LSC colonies at a post-entry step. Following central intrastromal injection of human corneas, both LV and AAV6 transduced the stroma and endothelial cells, and AAV6 also transduced cells of the epithelia. However, no transduction was observed in derived LSC colonies. The collective results demonstrate the effectiveness of LV for stable human LSC genetic engineering and an unreported phenomenon of AAV6 transduction restriction in multipotent cells derived from the human limbus.

Dataset Information

Adhesive thermosensitive gels for local delivery of viral vectors.

Publications

Adhesive thermosensitive gels for local delivery of viral vectors.

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