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Targeting Nanomedicines to Prostate Cancer: Evaluation of Specificity of Ligands to Two Different Receptors In Vivo

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Abstract

Purpose

This manuscript utilised in vivo multispectral imaging to demonstrate the efficacy of two different nanomedicine formulations for targeting prostate cancer.

Methods

Pegylated hyperbranched polymers were labelled with fluorescent markers and targeting ligands against two different prostate cancer markers; prostate specific membrane antigen (PSMA) and the protein kinase, EphrinA2 receptor (EphA2). The PSMA targeted nanomedicine utilised a small molecule glutamate urea inhibitor of the protein, while the EphA2 targeted nanomedicine was conjugated to a single-chain variable fragment based on the antibody 4B3 that has shown high affinity to the receptor.

Results

Hyperbranched polymers were synthesised bearing the different targeting ligands. In the case of the EphA2-targeting nanomedicine, significant in vitro uptake was observed in PC3 prostate cancer cells that overexpress the receptor, while low uptake was observed in LNCaP cells (that have minimal expression of this receptor). Conversely, the PSMA-targeted nanomedicine showed high uptake in LNCaP cells, with only minor uptake in the PC3 cells. In a dual-tumour xenograft mouse model, the nanomedicines showed high uptake in tumours in which the receptor was overexpressed, with only minimal non-specific accumulation in the low-expression tumours.

Conclusions

This work highlighted the importance of clearly defining the target of interest in next-generation nanomedicines, and suggests that dual-targeting in such nanomedicines may be a means to achieve greater efficacy.

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Abbreviations

DCM:

Dichloromethane

EGFR:

Epidermal growth factor receptor

EphA2:

EphrinA2

EPR:

Enhanced permeability and retention (effect)

HBP:

Hyperbranched polymer

HER2:

Human epidermal growth factor receptor 2

NMR:

Nuclear magnetic resonance

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate buffered saline

PSMA:

Prostate-specific membrane antigen

scFv:

Single chain variable fragment (of antibody)

SEC-MALS:

Size exclusion chromatography – multiangle laser light scattering

THF:

Tetrahydrofuran

VEGF:

Vascular endothelial growth factor

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ACKNOWLEDGMENTS AND DISCLOSURES

The researchers would like to thank Dr Christopher Howard (Australian Institute for Bioengineering and Nanotechnology, Australia) for the LNCaP cells and EphA2 scFv used in this study. This work was performed in part at the Queensland node of the Australian National Fabrication Facility, a company established under the National Collaborative Research Infrastructure Strategy to provide nano- and micro-fabrication facilities for Australia’s researchers. We acknowledge funding from the National Health and Medical Research Council (APP1099321, KJT), the Australian Research Council (FT110100284 (KJT), DP140100951 (KJT)), and the Australian Commonwealth Government Australian Postgraduate Award (AKP). This research was conducted and funded by the ARC Centre of Excellence in Convergent Bio-Nano Science and Technology (CE140100036).

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Authors and Affiliations

  1. Centre for Advanced Imaging, Australian Institute for Bioengineering and Nanotechnology and the ARC Centre of Excellence in Convergent BioNano Science and Technology, The University of Queensland, Building 57, St Lucia, QLD, 4072, Australia

    Amanda K. Pearce, Adrian V. Fuchs, Nicholas L. Fletcher & Kristofer J. Thurecht

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  1. Amanda K. Pearce
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  2. Adrian V. Fuchs
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  4. Kristofer J. Thurecht
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Correspondence to Kristofer J. Thurecht.

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Pearce, A.K., Fuchs, A.V., Fletcher, N.L. et al. Targeting Nanomedicines to Prostate Cancer: Evaluation of Specificity of Ligands to Two Different Receptors In Vivo . Pharm Res 33, 2388–2399 (2016). https://doi.org/10.1007/s11095-016-1945-x

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  • DOI: https://doi.org/10.1007/s11095-016-1945-x

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