Nucleic Acid Therapeutics: Concepts for Targeted Delivery to Solid Tumors

Abstract

Solid tumors form a heterogeneous group of diseases, although common features such as hyperproliferation, overexpression of certain growth factor receptors and deregulated vessel formation including leaky vasculature give the opportunity to target macromolecular drug and nucleic acid carriers to tumor tissue. Similar to other macromolecular drugs, nucleic acid carriers have to be designed to enable tumor targeting after systemic injection. Chemical modification of nucleic acids makes them resistant towards enzymatic degradation. Cationic lipids or polycations condense nucleic acids into small, virus-like structures and the surface modification with hydrophilic polymers allows passive accumulation in tumor tissue; tumor cell binding ligands allow cellular targeting. To avoid toxic side effects, biodegradable and biocompatible carriers were designed. The design of thermoresponsive gene carriers allowed their selective tumor accumulation by locoregional hyperthermia. As a therapeutic concept, tumor-specific delivery of antitumoral RNA was realized in an orthotopic brain tumor model. The combination of gene- and radio-therapy enabled selective accumulation of radionuclides in tumors and boosted antitumoral effects. Hence, combining a smart delivery concept for nucleic acids with a suitable therapeutic strategy will allow successful treatment of otherwise incurable malignant diseases.

Acknowledgements

The majority of this work was carried out at the Chair of Pharmaceutical Biotechnology led by Ernst Wagner, who pioneered work on artificial gene delivery systems. The author is particularly thankful to all people participating in this work, especially to all current and former member of the ‘Vectorology‘ group. Special thanks go to Alexander Levitzki and Christine Spitzweg. Alexander Levitzki has initiated and supervised the pIC study described in the ‘Delivery of immune stimulatory RNA‘ section and Christine Spitzweg the NIS/radiotherapy studies in the ‘Combined radio-gene therapy‘ section. The author would also like to thank Lars Lindner and Rolf Issels for the very fruitful collaboration on hyperthermia-targeted gene delivery.

Financial & competing interests disclosure

Financial support was granted by the German research foundation (DFG) within the research programs SPP1230, SFB486, SFB824 and NIM (Nanosystems Initiative Munich), the Helmholtz Gemeinschaft (VH-VI-140, Clinical Hyperthermia and Related Technology) and the European Union (GIANT network). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.