Development of novel small-molecule drug conjugates for imaging and treatment of prostate cancer
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Abstract
Prostate cancer (PCa) is the most frequent cancer in men worldwide, behind only lung cancer. Alt-hough the 5-year survival rate of localized PC is almost 100 %, it drops dramatically to just 30 % for the advanced and metastatic form. This high mortality rate highlights not only the importance of early diagnosis, but also the urgent need for the development of new therapeutic approaches.
The discovery of prostate-specific membrane antigen PSMA as a reliable tumor-associated biomarker for prostate cancer has revolutionized the management of this disease. Several efforts have been done in the last decade to develop selective and sensitive PSMA ligands for PET-imaging and endoradi-otherapy. Among these radiopharmaceuticals [68Ga]Ga-PSMA 11 was the first FDA-approved PSMA-PET radiotracer, followed with its therapeutic counterpart [177Lu]Lu-PSMA 617. In the meantime, sev-eral groups have joined the run for the best PSMA ligand. However, the development of PSMA radio-pharmaceuticals that have both favorable physicochemical properties and a beneficial pharmacokinet-ic profile remains a challenge which still need to be addressed.
In this dissertation, several PSMA ligands with different structural elements were designed and investi-gated for their in vitro and in vivo properties.
Based on preliminary studies, DATA5m.SA.KuE and AAZTA5.SA.KuE were selected to be evaluated more thoroughly. Both PSMA tracers have a hybrid chelator that is easily labeled under mild conditions in addition to beneficial pharmacokinetic properties regarding selectivity and tumor accumulation. Fur-thermore, AAZTA5.SA.KuE has shown promising theranostic potential as it can be labeled with the PET nuclide scandium-44 as well as the therapeutic ß--emitter lutetium-177.
Moreover, a dual-targeted pamidronate-PSMA conjugate was developed to target both PSMA, which is highly expressed in tumor lesions, and the hydroxyapatite structures in bone metastases. This 177Lu-labeled conjugate showed promising results in preclinical studies.
The unique and favorable properties of PSMA make it an optimal target not only in nuclear medicine and radiopharmacy but also in targeted chemotherapy. The advantages of the targeted therapy ap-proach are obvious since the discovery of antibody-drug conjugates (ADCs). However, although ADCs have represented a breakthrough in the treatment of many cancers, efforts to develop PSMA-ADCs have failed due to lack of stability, premature drug release, and high toxicity.
In order to circumvent some of these challenges, small-molecule PSMA binding moieties were used instead of antibodies. The resulting small-molecule drug conjugates (SMDCs) showed some ad-vantages over the ADCs, such as better tumor penetration due to lower molecular weight, fast clear-ance, and cost-effective synthesis.
The SMDCs developed in this dissertation can be divided into two groups. The first group includes di-meric SMDCs consisting of a PSMA binding unit and the antimitotic agent MMAE. Both units are conju-gated to each other via the enzyme-cleavable linker valine-citrulline. The second group consist of tri-meric conjugates (radiolabeled SMDCs) that, in addition to the PSMA-binding moiety and the cytostatic drug, contain a chelator which is able to complex both diagnostic and therapeutic nuclides. Hence, the low-dose 68Ga-labeled SMDC is supposed to be used in the determination of the patient's suitability for therapy. In case of positive response, the patient is then treated with the 177Lu-labeled conjugate. In addition to the thereby implemented personalized medicine approach, the combination of targeted chemotherapy and radiotherapy in a single molecule, may have several advantages, such as circum-venting the development of resistance or enhancing a synergistic effect. Preclinical studies showed the promising potential of this approach in terms of good tolerability and efficacy in vivo. However, further optimization on the molecular structure of these compounds is necessary to enable a translational development.