Advances in prostate-specific membrane antigen-targeted theranostics: from radionuclides to near-infrared fluorescence technology

Abstract

Prostate-Specific Membrane Antigen (PSMA) is a highly expressed and structurally unique target specific to prostate cancer (PCa). Diagnostic and therapeutic approaches in nuclear medicine, coupling PSMA ligands with radionuclides, have shown significant clinical success. PSMA-PET/CT effectively identifies tumors and metastatic lymph nodes for imaging purposes, while ^177Lu-PSMA-617 (Pluvicto) has received FDA approval for treating metastatic castration-resistant PCa (mCRPC). Despite their success, radionuclide-based diagnostic and therapeutic methods face limitations such as high costs and significant side effects. Recently, near-infrared (NIR) fluorescence imaging and phototherapy have advanced significantly in biomedical applications. It's benefits, such as deep tissue penetration, real-time precision, and minimal side effects, have driven broader clinical adoption, especially in fluorescence-guided surgery (FGS). This review suggests combining NIR dyes with PSMA ligands to enable targeted, high-resolution imaging with superior signal-to-background ratios, facilitating precise FGS. NIR techniques can also aid pathological diagnosis in ex vivo specimens. Furthermore, combining photosensitizers with PSMA ligands allows localized photothermal (PTT) or photodynamic therapy (PDT) under NIR irradiation, producing heat or reactive oxygen species (ROS) to treat PCa. This review aims to extend the clinical success of radionuclide-based PSMA targeting by exploring advances in NIR-based FGS and phototherapy, presenting a promising new diagnostic and therapeutic approach.

Keywords: fluorescence-guided surgery (FGS); near-infrared/shortwave infrared (NIR/SWIR); photodynamic therapy (PDT); photothermal therapy (PTT); prostate cancer (PCa); prostate-specific membrane antigen (PSMA); radioligand therapy (RLT); targeted imaging.

Figure 1

Comprehensive Theranostics of Prostate Cancer (PCa) Targeting PSMA: Bridging Radionuclides and Near-Infrared. (A) PSMA structure: The intracellular domain of PSMA consists of 19 amino acids, the transmembrane domain is composed of 24 amino acids, and the extracellular domain contains 707 amino acids. (B) Radionuclide Theranostics: PSMA inhibitors (PSMAi) leverage the enzymatic activity of PSMA's extracellular domain to target PCa. It can be labeled with ⁶⁸Ga and ¹⁷F for imaging, and with ¹⁷⁷Lu and ²⁵⁵Ac for therapy. Notably, ¹⁷⁷Lu-PSMA-617. Near-Infrared (NIR) Theranostics: NIR dyes, including small molecule dyes (SMDs), are conjugated with PSMAi for PSMA-targeted NIR fluorescence imaging. Photosensitizers in nanoparticles (NPs) linked to PSMAi enable targeted photothermal therapy (PTT) and photodynamic therapy (PDT), generating heat and reactive oxygen species (ROS) to combat cancer cells, respectively.

Figure 2

Targeted PSMA NIR Applications: Fluorescence-guided surgery and in vitro tissue assessment. (A) In Vivo Fluorescence-Guided Surgery: PSMA-specific fluorescent probes are designed for NIR imaging. Post-injection, these probes target tumor sites and are visualized using a NIR laser, particularly in the NIR-II region. (B) In vitro targeted imaging: In the context of PCa, needle biopsy samples from preoperative patients are incubated with PSMA-targeted probes, washed, and imaged. Additionally, this technique can be applied to intraoperative and postoperative specimens to define tumor margins, informing surgical and prognostic assessments.