TY - JOUR
T1 - Evaluation of PSMA-Targeted PAMAM Dendrimer Nanoparticles in a Murine Model of Prostate Cancer
AU - Lesniak, Wojciech G.
AU - Boinapally, Srikanth
AU - Banerjee, Sangeeta Ray
AU - Behnam Azad, Babak
AU - Foss, Catherine A.
AU - Shen, Chentian
AU - Lisok, Ala
AU - Wharram, Bryan
AU - Nimmagadda, Sridhar
AU - Pomper, Martin G.
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/3
Y1 - 2019/6/3
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 (Kd) 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 64Cu, [64Cu]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 [64Cu]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 (Kd) 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 64Cu, [64Cu]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 [64Cu]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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U2 - 10.1021/acs.molpharmaceut.9b00181
DO - 10.1021/acs.molpharmaceut.9b00181
M3 - Article
C2 - 31002252
AN - SCOPUS:85065800908
SN - 1543-8384
VL - 16
SP - 2590
EP - 2604
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 6
ER -