Hyperthermia-Induced Targeting of Thermosensitive Gene Carriers to Tumors

Abstract

Locoregional hyperthermia (HT) can be used for site-directed activation of macromolecular drug delivery systems. We have developed a gene delivery system based on thermosensitive block copolymers (TSCs) with a phase transition temperature of 42 degrees C [Zintchenko, A., Ogris, M., and Wagner, E. (2006). Bioconjug. Chem. 17, 766-772], in which the statistical copolymer of vinylpyrrolidinone and N-isopropylacryamide is grafted on polyethylenimine (PEI). Here we applied polyplexes consisting of plasmid DNA and TSCs systemically in A/J mice bearing a syngeneic Neuro2A neuroblastoma tumor subcutaneously in each hind limb. One limb was selectively treated by HT at 42 degrees C, at the same time that polyplexes were injected via the tail vein. Hyperthermia led to increased accumulation of thermosensitive polymer and aggregation of thermosensitive polyplexes in HT-treated tumors, resulting in up to 10-fold increased DNA deposition compared with non-HT-treated tumor. The level of transgene expression induced by TSC polyplexes in HT-treated tumors was significantly higher and selective for tumor tissue. With nonthermosensitive PEI polyplexes HT did not influence transgene deposition or expression in tumor.

Responsive polyelectrolyte complexes for triggered release of nucleic acid therapeutics

“…3). 28 26 Changes in DNA-binding affinity of the sets of block co-polymers were observed across the temperature ranges in gel retardation assays, while NMR and neutron scattering studies further supported a mechanism in which supramolecular architectures of the polymers changed across LCST.…”

Intelligent nucleic acid delivery systems based on stimuli-responsive polymers

“…In recent years, a number of other thermoresponsive cationic polymers were prepared and studied as gene carriers. 183 This work implies that other nucleic acids such as siRNA can also be sitespecifically delivered by a combination of hyperthermia and thermoresponsive polymers. 178 Park et al reported another temperature-sensitive gene delivery system.…”

Functional Polymers for Targeted Delivery of Nucleic Acid Drugs

“…The poly(NIPAM-VP)-block-PEI delivered a 10-fold higher amount of plasmid DNA to tumor tissue under the hyperthermia condition than branched PEI (25 kDa) in a mouse model. [70] Moreover, hyperthermia induced gene delivery by poly(NIPAM-VP)-block-PEI, which significantly reduced non-specific delivery of plasmid DNA to normal tissues such as lung, heart, liver and kidney.…”