Cytosolic Delivery Mediated via Electrostatic Surface Binding of Protein, Virus, or siRNA Cargos to pH-Responsive Core−Shell Gel Particles

• Published in: Biomacromolecules 2009-04, Vol.10 (4), p.756-765
• Main Authors: Hu, Yuhua, Atukorale, Prabhani U, Lu, James J, Moon, James J, Um, Soong Ho, Cho, Eun Chol, Wang, Yana, Chen, Jianzhu, Irvine, Darrell J
• Format: Article
• Language: English
• Subjects: Animals; Applied sciences; Biological and medical sciences; Bone Marrow - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - metabolism; Composites; Cytosol - chemistry; Dendritic Cells - physiology; Dendritic Cells - virology; Drug Delivery Systems - methods; Endosomes - physiology; Endosomes - virology; Exact sciences and technology; Female; Forms of application and semi-finished materials; Gels - chemistry; Gene Knockdown Techniques; General pharmacology; Hydrogen-Ion Concentration; Influenza A virus - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Monocytes - cytology; Monocytes - metabolism; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Ovalbumin - metabolism; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymer industry, paints, wood; Receptors, Antigen, T-Cell - physiology; RNA, Small Interfering - pharmacology; Static Electricity; Surface Properties; Technology of polymers
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm801199z

We recently described a strategy for intracellular delivery of macromolecules, utilizing pH-responsive “core−shell” structured gel particles. These cross-linked hydrogel particles disrupt endosomes with low toxicity by virtue of physical sequestration of an endosome-disrupting “proton sponge” core inside a nontoxic hydrophilic shell. Here we tested the efficacy of this system for cytosolic delivery of a broad range of macromolecular cargos, and demonstrate the delivery of proteins, whole viral particles, or siRNA oligonucleotides into the cytosol of dendritic cells and epithelial cells via core−shell particles. We assessed the functional impact of particle delivery for vaccine applications and found that cytosolic delivery of protein antigens in dendritic cells via the core−shell particles promotes priming of CD8+ T-cells at 100-fold lower doses than soluble protein. Functional gene knockdown following delivery of siRNA using the particles was demonstrated in epithelial cells. Based on these findings, these materials may be of interest for a broad range of biomedical applications.