A Theranostic Small-Molecule Prodrug Conjugate for Neuroendocrine Prostate Cancer

Abstract

After androgen deprivation therapy, a significant number of prostate cancer cases progress with a therapy-resistant neuroendocrine phenotype (NEPC). This represents a challenge for diagnosis and treatment. Based on our previously reported design of theranostic small-molecule prodrug conjugates (T-SMPDCs), herein we report a T-SMPDC tailored for targeted positron emission tomography (PET) imaging and chemotherapy of NEPC. The T-SMPDC is built upon a triazine core (TZ) to present three functionalities: (1) a chelating moiety (DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for PET imaging when labeled with 68Ga (t1/2 = 68 min) or other relevant radiometals; (2) an octreotide (Octr) that targets the somatostatin receptor 2 (SSTR2), which is overexpressed in the innervated tumor microenvironment (TME); and (3) fingolimod, FTY720—an antagonist of sphingosine kinase 1 that is an intracellular enzyme upregulated in NEPC. Polyethylene glycol (PEG) chains were incorporated via conventional conjugation methods or a click chemistry reaction forming a 1,4-disubstituted 1,2,3-triazole (Trz) linkage for the optimization of in vivo kinetics as necessary. The T-SMPDC, DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 (PEGn: PEG with n repeating ethyleneoxy units (n = 2, 3, or 4); Val: valine; Cit: citrulline; pABOC: p-amino-benzyloxycarbonyl), showed selective SSTR2 binding and mediated internalization of the molecule in SSTR2 high cells. Release of FTY720 was observed when the T-SMPDC was exposed to cathepsin B, and the released FTY720 exerted cytotoxicity in cells. In vivo PET imaging showed significantly higher accumulation (2.1 ± 0.3 %ID/g; p = 0.02) of [68Ga]Ga-DOTA-PEG3-TZ(PEG4-Octr)-PEG2-Trz-PEG3-Val-Cit-pABOC-FTY720 in SSTR2high prostate cancer xenografts than in the SSTR2low xenografts (1.5 ± 0.4 %ID/g) at 13 min post-injection (p.i.) with a rapid excretion through the kidneys. Taken together, these proof-of-concept results validate the design concept of the T-SMPDC, which may hold a great potential for targeted diagnosis and therapy of NEPC.

PET/CT and Conventional Imaging for the Assessment of Neuroendocrine Prostate Cancer: A Systematic Review

“…In this scenario, it has been proposed that specific forms of NEPC, depending on their origin, can be imaged with different radiopharmaceuticals based on preclinical evidence [41,43,46,47]. Moreover, new tracers able to evaluate the presence of NEPC or its progression from CRPC are continuously developed and hopefully will help in the assessment of the disease [34,[48][49][50]. Lastly, some interesting insights on the role of these new radiopharmaceuticals for the evaluation of treatment response with innovative drugs specific to NEPC have been reported [51].…”

Targeting Sphingosine 1-Phosphate Metabolism as a Therapeutic Avenue for Prostate Cancer

“…Interestingly, when fingolimod was encapsulated, it was unable to induce lymphopenia in mice [155]. Furthermore, fingolimod has been recently included as a theragnostic small-molecule prodrug conjugate, which can be eventually used as a therapy for mCRPC patients [156].…”

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways

“…Peptide receptor radionuclide therapy (PRRT) is an innovative therapeutic option traditionally used as a second-line treatment for advanced (metastatic or inoperable) neuroendocrine tumors (NETs), characterized by the expression of the SSTRs, especially the SSTR2 [111,112]. The applicability of such treatment is closely related to the expression of somatostatin receptors, which can be evaluated through functional imaging such as 68Ga-DOTA peptide PET/CT, octreoscan, 111In-octreotide-scintigraphy, or 99m-EDDA-HYNIC-tyr3-octreotide scintigraphy [10,[113][114][115][116][117][118][119][120][121][122][123][124].…”