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

被引：7

作者：

Meher, Niranjan ^{[1
,2
]}

Ashley, Gary W. ^{[3
]}

Bobba, Kondapa Naidu ^{[1
]}

Wadhwa, Anju ^{[1
]}

Bidkar, Anil P. ^{[1
]}

Dasari, Chandrashekhar ^{[4
]}

Mu, Changhua ^{[1
]}

Sankaranarayanan, Ramya Ambur ^{[1
]}

Serrano, Juan A. Camara ^{[5
]}

Raveendran, Athira ^{[1
]}

Bulkley, David P. ^{[6
]}

Aggarwal, Rahul ^{[5
]}

Greenland, Nancy Y. ^{[7
]}

Oskowitz, Adam ^{[4
]}

Wilson, David M. ^{[1
,5
]}

Seo, Youngho ^{[1
,5
]}

Santi, Daniel V. ^{[3
]}

Vanbrocklin, Henry F. ^{[1
,5
]}

Flavell, Robert R. ^{[1
,5
,8
]}

机构：

[1] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA

[2] Natl Inst Pharmaceut Educ & Res, Lucknow 226002, Uttar Pradesh, India

[3] ProLynx Inc, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Div Vasc & Endovasc Surg, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

来源：

ADVANCED HEALTHCARE MATERIALS | 2024年 / 13卷 / 19期

关键词：

enhanced permeability and retention; polymer nanocarriers; prostate cancer; prostate-specific membrane antigen (PSMA); radioligand therapy; single photon excited computed tomography (SPECT) imaging; ENHANCED PERMEABILITY; PSMA; INHIBITORS; TUMORS;

D O I：

10.1002/adhm.202304618

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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. The multivalent StarPEG nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 (ACUPA is ((S)-2-(3- ((S)-5-amino-1- carboxypentyl) ureido) pentanedioic acid) exhibits high prostate-specific membrane antigen (PSMA) targeted delivery of the therapeutic isotope 177Lu with superior imaging contrast and therapeutic efficacy in prostate cancer. In preclinical models, single-dose administration of the targeted nanocarrier shows a notable improvement in therapeutic efficacy compared to [177Lu]PSMA-617, suggesting potential for clinical translation in the future. image

引用

页数：15

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