Nano-Targeted Delivery of Toremifene, an Estrogen Receptor-α Blocker in Prostate Cancer

ABSTRACT

Purpose

Estrogen Receptor-α (ERα) expression is increased in prostate cancer and acts as an oncogene. We propose that blocking of estrogen hormone binding to ERα using the ERα blocker toremifene will reduce the tumorigenicity of prostate cancer, and nano-targeted delivery of toremifene will improve anticancer efficacy. We report the synthesis and use in an orthotopic mouse model of PLGA-PEG nanoparticles encapsulating toremifene and nanoparticles encapsulating toremifene that are also conjugated to anti-PSMA for targeted prostate tumor delivery.

Methods

Human prostate cancer cell line PC3M and a nude mouse model were used to test efficacy of nano-targeted and nano-encapsulated toremifene versus free toremifene on the growth and differentiation of tumor cells.

Results

Treatment with free toremifene resulted in a significant reduction in growth of prostate tumor and proliferation, and its nano-targeting resulted in greater reduction of prostate tumor growth, greater toremifene tumor uptake, and enhanced tumor necrosis. Tumors from animals treated with nano-encapsulated toremifene conjugated with anti-PSMA showed about a 15-fold increase of toremifene compared to free toremifene.

Conclusions

Our data provide evidence that blocking ERα by toremifene and targeting prostate cancer tissues with anti-PSMA antibody on the nanoparticles’ surface repressed the tumorigenicity of prostate cancer cells in this mouse model.

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Abbreviations

ERα:

Estrogen receptor alpha

ERβ:

Estrogen receptor beta

HGPIN:

High Grade Prostatic Intraepithelial Hyperplasia

MTT:

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

PEG:

Poly (ethylene glycol)

PLGA:

Poly (lactic-co-glycolic acid)

PSMA:

Prostate specific membrane antigen

SERM:

Selective estrogen receptor modulator

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to express our thanks to Dr. Murat Yalcin (Uludag University, Turkey) and Dr. Hasan Mukhtar (University of Wisconsin, Madison, WI) for their suggestions, and Dr. Kelly Keating (ACPHS) for excellent editing. The authors report no conflicts of interest.

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Corresponding author

Correspondence to Shaker A. Mousa.

Additional information

Waseem Hariri and Thangirala Sudha contributed equally to this work.

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Hariri, W., Sudha, T., Bharali, D.J. et al. Nano-Targeted Delivery of Toremifene, an Estrogen Receptor-α Blocker in Prostate Cancer. Pharm Res 32, 2764–2774 (2015). https://doi.org/10.1007/s11095-015-1662-x

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KEY WORDS

  • anti-PSMA antibody
  • estrogen receptor-α blocker
  • nanomedicine
  • nano-targeted therapy
  • prostate cancer