PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice.
There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine-polyethyleneglycol (PEI-PEG) tethered to the PSMA ligand, 2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use.
['Langut|Yael|Y|', 'Talhami|Alaa|A|', 'Mamidi|Samarasimhareddy|S|', 'Shir|Alexei|A|', 'Zigler|Maya|M|', 'Joubran|Salim|S|', 'Sagalov|Anna|A|', 'Flashner-Abramson|Efrat|E|', 'Edinger|Nufar|N|', 'Klein|Shoshana|S|', 'Levitzki|Alexander|A|']
D019264:Adoptive Transfer D000818:Animals D000954:Antigens, Surface D024201:Bystander Effect D045744:Cell Line, Tumor D002470:Cell Survival D004195:Disease Models, Animal D015870:Gene Expression D043425:Glutamate Carboxypeptidase II D006801:Humans D007963:Leukocytes, Mononuclear D008297:Male D051379:Mice D011070:Poly I-C D011471:Prostatic Neoplasms D011485:Protein Binding D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
prostate cancer PSMA PEI-PEG DUPA polyIC