Evaluation of PSMA-Targeted PAMAM Dendrimer Nanoparticles in a Murine Model of Prostate Cancer

Wojciech Lesniak, Srikanth Boinapally, Sangeeta Ray, Babak Behnam Azad, Catherine Foss, Chentian Shen, Ala Lisok, Bryan Wharram, Sridhar Nimmagadda, Martin Gilbert Pomper

Research output: Contribution to journalArticle

Abstract

The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant (K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09% injected dose per gram of tissue, %ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1%ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.

Original languageEnglish (US)
JournalMolecular Pharmaceutics
DOIs
StatePublished - Jan 1 2019

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Dendrimers
Nanoparticles
Prostatic Neoplasms
Neoplasms
Poly(amidoamine)
human glutamate carboxypeptidase II
Micelles
Pharmaceutical Preparations

Keywords

  • copper-64
  • molecular imaging
  • polyamidoamine
  • prostate cancer
  • prostate-specific membrane antigen

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

@article{34e79e9d12bd46b084b9ee9d8be95109,
title = "Evaluation of PSMA-Targeted PAMAM Dendrimer Nanoparticles in a Murine Model of Prostate Cancer",
abstract = "The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant (K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09{\%} injected dose per gram of tissue, {\%}ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1{\%}ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.",
keywords = "copper-64, molecular imaging, polyamidoamine, prostate cancer, prostate-specific membrane antigen",
author = "Wojciech Lesniak and Srikanth Boinapally and Sangeeta Ray and {Behnam Azad}, Babak and Catherine Foss and Chentian Shen and Ala Lisok and Bryan Wharram and Sridhar Nimmagadda and Pomper, {Martin Gilbert}",
year = "2019",
month = "1",
day = "1",
doi = "10.1021/acs.molpharmaceut.9b00181",
language = "English (US)",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",

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TY - JOUR

T1 - Evaluation of PSMA-Targeted PAMAM Dendrimer Nanoparticles in a Murine Model of Prostate Cancer

AU - Lesniak, Wojciech

AU - Boinapally, Srikanth

AU - Ray, Sangeeta

AU - Behnam Azad, Babak

AU - Foss, Catherine

AU - Shen, Chentian

AU - Lisok, Ala

AU - Wharram, Bryan

AU - Nimmagadda, Sridhar

AU - Pomper, Martin Gilbert

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant (K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09% injected dose per gram of tissue, %ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1%ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.

AB - The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant (K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09% injected dose per gram of tissue, %ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1%ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.

KW - copper-64

KW - molecular imaging

KW - polyamidoamine

KW - prostate cancer

KW - prostate-specific membrane antigen

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