PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

Abstract

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of "PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa". The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed.

Keywords: enhanced permeability and retention (EPR) effect; nanocarriers; nanoparticle; positron emission tomography (PET); prostate cancer theranostics; prostate-specific membrane antigen (PSMA); radioligand theranostics; radiopharmaceutical therapy; small-molecule PSMA inhibitors.

Figure 4

Imaging of PSMA-labelled iron oxide nanoparticles in prostate cancer murine models. (A) In vivo PET imaging of a mouse model bearing PSMA+ 22rv1 and PSMA—PC3 tumors at 1 h post-injection of PSMA-targeted iron oxide NPs encapsulated with DOTA- and ACUPA-conjugated PEGs. Reprinted with permission from Ref [40]. Copyright 2016, Elsevier. (B) In vivo SPECT-CT imaging of PSMA-targeted iron oxide NPs in mouse model bearing PSMA+ PC3-Pip and PSMA- PC3-Flu tumors over 4 days. Reprinted with permission from Ref [42]. Copyright 2015, Royal Society of Chemistry.

Figure 1

Summary of PSMA-targeted nanocarriers for radioligand imaging and treatment of PCa.

Figure 2

Chemical structures of main classes of small molecule-based PSMA-targeting ligands.

Figure 3

Summary of various physical and biological parameters associated with nanocarrier systems, like (A) size, (B) shape, (C) surface charge, (D) tumor phenotype, and (E) targeting ligand density, that potentially influence their in vivo pharmacokinetics and should be considered carefully when designing nanotheranostic systems.

Figure 5

Development of PSMA-targeted amphiphilic block copolymers using aptamers as a targeting ligand. (A) Quantification of aptamer ligand density on the PLGA-b-PEG nanoparticle surface. (B) Cell uptake assay of ³H-labelled NPs in LNCaP and PC3 cells. (C,D) Ex vivo biodistribution of NPs with different % of aptamer conjugated PLGA-b-PEG polymer in LNCaP tumor-bearing mice administered by retro-orbital injection. Reprinted with permission from Ref [50]. Copyright 2008, National Academy of Science.

Figure 6

Development of PSMA-targeted PLA-PEG NPs for imaging of prostate cancer in mouse models. (A) Representative structure of the PSMA-targeted PLA-PEG NPs. (B) In vivo SPECT-CT of ¹¹¹In-labelled PSMA-targeted and non-targeted NPs in PSMA expressing PC3-Pip (red circles) and PSMA negative PC3-Flu (yellow circles) tumor-bearing mice model up to 96 h. White arrows show prominent spleen uptake. Reprinted with permission from Ref [51]. Copyright 2017, American Chemical Society.

Figure 7

Design and preliminary evaluation of carborane-loaded, PSMA-targeted PLGA–PEG NPs for imaging and treatment of prostate cancer using BNCT. (A) Graphical presentation of carborane-loaded PLGA–PEG NPs radiolabeled with ⁸⁹Zr for targeted boron delivery. (B) Axial μPET/CT imaging of mice bearing dual xenografts of PC3-Pip and PC3-Flu at different time points. Reprinted with permission from Ref [57]. Copyright 2021, American Chemical Society.

Figure 8

Imaging and treatment of prostate cancer in mouse models using PSMA-targeted liposome-like texaphyrin NPs. (A) Synthetic scheme showing chelation of lutetium with texaphyrin−lipid. (B) Formulation and representation of nanotexaphyrin self-assembly. (C) Radiolabeling conditions and schematic representation of ¹¹¹In/Lu-labelled nanotexaphyrin. (D) Schematic representation of PSMA-targeting ligand (ACUPA) conjugated ¹¹¹In/Lu–nanotexaphyrin. (E) mSPECT/CT images of a mouse model bearing dual xenografts of PC3-Pip and PC3-Flu. Reprinted with permission from Ref [61]. Copyright 2022, American Chemical Society.

Figure 9

Treatment of prostate cancer using PSMA-targeted, ²²⁵Ac-labelled liposomes. Immunofluorescent images of g-H2AX foci (green) in cell nuclei (blue) upon treatment with Ab-targeted vesicles (A), urea-targeted vesicles (B), and radiolabeled Abs (C). Scale bar, 40 mm. Reprinted with permission from Ref [63]. Copyright 2016, American Association of Cancer Research.

Figure 10

Representative constructs for scFv-conjugated lipid vesicles. Reprinted with permission from Ref [64]. Copyright 2017, Elsevier.

Figure 11

PSMA-targeted nanoplex for combined imaging and treatment of PCa using a prodrug enzyme strategy and siRNA. (A) Schematic representation of the PSMA-targeted nanoplex 1 and 2. (B) Transaxial mSPECT/CT images of the targeted ¹¹¹In-labelled nanoplex 1 at 48 h post-injection in SCID mouse bearing PC3-PIP and PC3-Flu tumors. (C) ROI on tumors and muscle at 48 h post-injection (n = 4, * p < 0.05). Reprinted with permission from Ref [67]. Copyright 2012, American Chemical Society.

Figure 12

Representative chemical structures of (A) PSMA-targeted G4(MP-KEU) and (B) control G4(Ctrl) dendrimers. (C) Volume-rendered mPET/CT images of NOD-SCID mice model bearing dual xenografts of PC3-Pip and PC3-flu. Reprinted with permission from Ref [68]. Copyright 2019 American Chemical Society.

Figure 13

Representative chemical structures of triazine dendrimers conjugated with PSMA-targeting DUPA ligands and radiometal chelator DOTA. Reprinted with permission from Ref [5] Copyright 2019, MDPI.

Figure 14

Development of PSMA-targeted starPEG nanocarriers for prostate cancer imaging. (A) Representative chemical structures of ⁸⁹Zr-labelled PEG nanocarriers without and with different numbers of PSMA-targeting ACUPA ligands. (B) Maximum intensity projection (MIP) μPET/CT, axial μPET/CT, and axial CT images obtained at 216 h following administration of ⁸⁹Zr-labelled nanocarriers in mice model bearing PC3-Pip and PC3-Flu dual xenografts. (C) Autoradiography images of tumor slices were collected after 216 h post-injection of the ⁸⁹Zr-labelled nanocarriers. Reprinted with permission from Ref [69]. Copyright 2022, American Chemical Society.