Cooling-induced, localized release of cytotoxic peptides from engineered polymer nanoparticles in living mice for cancer therapy

Abstract

Temperature-responsive polymers are often characterized by an abrupt change in the degree of swelling brought about by small changes in temperature. Polymers with a lower critical solution temperature (LCST) in particular, are important as drug and gene delivery vehicles. Drug molecules are taken up by the polymer in their solvent swollen state below their LCST. Increasing the temperature above the LCST, typically physiological temperatures, results in desolvation of polymer chains and microstructure collapse. The trapped drug is released slowly by passive diffusion through the collapsed polymer network. Since diffusion is dependent on many variables, localizing and control of the drug delivery rate can be challenging. Here, we report a fundamentally different approach for the rapid (seconds) tumor-specific delivery of a biomacromolecular drug. A copolymer nanoparticle (NP) was engineered with affinity for melittin, a peptide with potent anti-cancer activity, at physiological temperature. Intravenous injection of the NP-melittin complex results in its accumulation in organs and at the tumor. We demonstrate that by local cooling of the tumor the melittin is rapidly released from the NP-melittin complex. The release occurs only at the cooled tumor site. Importantly, tumor growth was significantly suppressed using this technique demonstrating therapeutically useful quantities of the drug can be delivered. This work reports the first example of an in vivo site-specific release of a macromolecular drug by local cooling for cancer therapy. In view of the increasing number of cryotherapeutic devices for in vivo applications, this work has the potential to stimulate cryotherapy for in vivo drug delivery.

Keywords: Lower critical solution temperature; Nanogel; Protein-protein interaction; Stimuli-responsive; cancer therapy.