Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer

Niranjan Meher; Gary W Ashley; Kondapa Naidu Bobba; Anju Wadhwa; Anil P Bidkar; Chandrashekhar Dasari; Changhua Mu; Ramya Ambur Sankaranarayanan; Juan A Camara Serrano; Athira Raveendran; David P Bulkley; Rahul Aggarwal; Nancy Y Greenland; Adam Oskowitz; David M Wilson; Youngho Seo; Daniel V Santi; Henry F VanBrocklin; Robert R Flavell

doi:10.1002/adhm.202304618

Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer

Adv Healthc Mater. 2024 May 3:e2304618. doi: 10.1002/adhm.202304618. Online ahead of print.

Authors

Niranjan Meher^{1

2}, Gary W Ashley³, Kondapa Naidu Bobba¹, Anju Wadhwa¹, Anil P Bidkar¹, Chandrashekhar Dasari⁴, Changhua Mu¹, Ramya Ambur Sankaranarayanan¹, Juan A Camara Serrano⁵, Athira Raveendran¹, David P Bulkley⁶, Rahul Aggarwal⁵, Nancy Y Greenland⁷, Adam Oskowitz⁴, David M Wilson^{1

5}, Youngho Seo^{1

5}, Daniel V Santi³, Henry F VanBrocklin^{1

5}, Robert R Flavell^{1

5

8}

Affiliations

¹ Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94143, USA.
² National Institute of Pharmaceutical Education and Research, Raebareli, Lucknow, UP, 226002, India.
³ ProLynx Inc., San Francisco, CA, 94158, USA.
⁴ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143-0981, USA.
⁵ Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA, 94143-0957, USA.
⁶ Department of Pathology, University of California, San Francisco, CA, 94143, USA.
⁷ Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158-2517, USA.
⁸ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, USA.

PMID: 38700450
DOI: 10.1002/adhm.202304618

Abstract

The tumor uptake of large non-targeted nanocarriers primarily occurs through passive extravasation, known as the enhanced permeability and retention (EPR) effect. Prior studies demonstrated improved tumor uptake and retention of 4-arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging by adding prostate-specific membrane antigen (PSMA) targeting small molecule ligands. To test PSMA-targeted delivery and therapeutic efficacy, StarPEG nanodrugs with/without three copies of PSMA-targeting ligands, ACUPA, are designed and synthesized. For single-photon emission computed tomography (SPECT) imaging and therapy, each nanocarrier is labeled with 177Lu using DOTA radiometal chelator. The radiolabeled nanodrugs, [177Lu]PEG-(DOTA)1 and [177Lu]PEG-(DOTA)1(ACUPA)3, are evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers are efficiently radiolabeled with 177Lu with molar activities 10.8-15.8 MBq/nmol. Besides excellent in vitro PSMA binding affinity (kD = 51.7 nM), the targeted nanocarrier, [177Lu]PEG-(DOTA)1(ACUPA)3, demonstrated excellent in vivo SPECT imaging contrast with 21.3% ID/g PC3-Pip tumors uptake at 192 h. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts observed up to 138 days. Along with PSMA-targeted excellent imaging contrast, these results demonstrated high treatment efficacy of [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation.

Keywords: enhanced permeability and retention; polymer nanocarriers; prostate cancer; prostate‐specific membrane antigen (PSMA); radioligand therapy; single photon excited computed tomography (SPECT) imaging.

Abstract

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