Multimodal dendrimer theranostics targeting aggressive subtypes of prostate cancer

PROJECT SUMMARY Our ultimate goal is to develop a practical, theranostic platform for managing PC. Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Despite a gradually improving trend in outcomes, the current death rate remains unacceptably high, with metastases in 20% of

afflicted men. The American Cancer Society estimates approximately 268,490 new cases and 34,500 deaths from PC in the United States in 2022. Prostate-specific membrane antigen (PSMA) expression has been associated with aggressive PC, and is present in over 90% of metastatic disease. Those features have led to

employing PSMA for PC detection with radionuclide imaging, and for therapies including antibody-drug conjugates, targeted radiotherapeutics and immunotherapeutic approaches. Nearly 450 trials involving PSMA in PC are registered on clinicaltrials.gov. Nevertheless, all of the current therapies show some degree of toxicity

and are not curative. We are well-positioned to develop novel therapies through application of our PSMA- targeted theranostic agents. We have recently synthesized PSMA-targeted poly(amidoamine) (PAMAM) dendrimers that may be used for PC-specific concurrent delivery of imaging and therapy. PAMAM dendrimers

serve as versatile delivery vehicles that can be tailored to different sizes and compositions. Here we propose development of multimodal theranostic agents enabling: (I) highly specific PSMA targeting; (II) application of quantitative positron emission tomography/computed tomography (PET/CT) ultimately for selecting patients for

therapy; (III) incorporation of a potent antimitotic agent; and, (IV) incorporation of optimized chemical exchange saturation transfer (CEST) moieties to enable non-invasive monitoring of PC drug delivery by the clinically ubiquitous imaging modality, magnetic resonance imaging (MRI). As we have shown, CEST is sufficiently

sensitive to enable targeted imaging. When high-frequency salicylate moieties are used there, is a frequency- specific contrast not encumbered by background signal, allowing determination of targeting efficiency. Direct imaging of drug biodistribution provides information needed to understand and improve efficacy. The proposed

PSMA-targeted theranostic agents will be synthesized via consecutive conjugation of PAMAM dendrimer with deferoxamine (DFO, for radiolabeling with 89Zr, enabling PET/CT and evaluation of pharmacokinetics), lysine- urea-glutamate moieties (KEU, for PSMA targeting), and numerous 4-(3-carboxypropanamido)-2-

hydroxybenzoic acid molecules [salicylic acid (SA) derivatives for CEST contrast]. For therapeutic studies, proposed theranostic agents will be additionally equipped with maytansine 1 (DM1) and monomethyl auristatin e (MMAE, both routinely used of formulation of antibody-drug conjugates) via either encapsulation or

conjugation. We will use mice bearing clinically relevant human PC metastatic xenografts for pharmacokinetic studies. Studies will be carried out using state-of-the-art multimodal PET/CT, MRI and optical imaging.