Abstract
Over 800 G-protein-coupled receptors (GPCRs) are encoded by the human genome and many are overexpressed in tumors. GPCRs are triggered by ligand molecules outside the cell and activate internal signal transduction pathways driving cellular responses. The receptor signals are desensitized by receptor internalization and this mechanism can be exploited for the specific delivery of ligand-linked drug molecules directly into cells. Detailed expression analysis in cancer tissue can inform the design of GPCR-ligand decorated drug carriers for active tumor cell targeting. The active targeting process utilizes ligand receptor interactions leading to binding and in most cases internalization of the ligand-attached drug carrier resulting in effective targeting of cancer cells. In this report public microarray data from the Gene Expression Omnibus (GEO) repository was used to identify overexpressed GPCRs in prostate and breast cancer tissues. The analyzed data confirmed previously known cancer receptor associations and identified novel candidates for potential active targeting. Prioritization of the identified targeting receptors is also presented based on high expression levels and frequencies in cancer samples but low expression in healthy tissue. Finally, some selected examples were used in ligand docking studies to assess the feasibility for chemical conjugation to drug nanocarriers without interference of receptor binding and activation. The presented data demonstrate a large untapped potential to improve efficacy and safety of current and future anti-cancer compounds through active targeting of GPCRs on cancer cells.
Highlights
More than 14 million cancer-related deaths were reported in 2012 and this annual burden is expected to grow to approximately 22 million by 2030 (World Cancer Report 2014, Stewart BW, Wild CW, ISBN 978-92-832-0443-5)
Our findings reveal a large untapped potential for G-protein-coupled receptor (GPCR) targeting in cancer treatment with engineered drug carriers
A list of 755 GPCR genes was compiled from 21 Protein Family (Pfam) domains (7tm and GPCR) within the protein family database and 437 GPCR genes were identified on the GPL570 platform
Summary
More than 14 million cancer-related deaths were reported in 2012 and this annual burden is expected to grow to approximately 22 million by 2030 (World Cancer Report 2014, Stewart BW, Wild CW, ISBN 978-92-832-0443-5). The majority www.oncotarget.com of clinically available anti-cancer nano-formulations use passive targeting, exploiting the Enhanced Permeability and Retention Effect (EPR) [2] In this case, passive diffusion through endothelial fenestrations of tumor tissue lead to a local build-up of nanoparticle concentrations, an effect further enhanced by the lack of efficient lymphatic drainage. Nanoparticles accumulate in various organs, mainly liver and spleen, by vascular escape through endothelial fenestrations [3] To minimize this effect, drug carriers can be functionalized with ligands or antibodies for active targeting of receptors which show overexpression on cancer cells in comparison to healthy tissue. Drug carriers can be functionalized with ligands or antibodies for active targeting of receptors which show overexpression on cancer cells in comparison to healthy tissue This can both further enhance the anti-cancer potency on solid tumors and reduce toxic side effects on healthy cells
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