title: Design of a Small-Molecule Drug Conjugate for Prostate Cancer Targeted Theranostics.
abstract: Targeted therapy has become an effective strategy of precision medicine for cancer treatment. Based on the success of antibody-drug conjugates (ADCs), here we report a theranostic design of small-molecule drug conjugates (T-SMDCs) for targeted imaging and chemotherapy of prostate cancer. The structure of T-SMDCs built upon a polyethylene glycol (PEG) scaffold consists of (i) a chelating moiety for positron emission tomography (PET) imaging when labeled with (68)Ga, a positron-emitting radioisotope; (ii) a prostate specific membrane antigen (PSMA) specific ligand for prostate cancer targeting; and (iii) a cytotoxic drug (DM1) for chemotherapy. For proof-of-concept, such a T-SMDC, NO3A-DM1-Lys-Urea-Glu, was synthesized and evaluated. The chemical modification of Lys-Urea-Glu for the construction of the conjugate did not compromise its specific binding affinity to PSMA. The PSMA-mediated internalization of (68)Ga-labeled NO3A-DM1-Lys-Urea-Glu displayed a time-dependent manner, allowing the desired drug delivery and release within tumor cells. The antiproliferative activity of the T-SMDC showed a positive correlation with the PSMA expression level. Small animal PET imaging with (68)Ga-labeled NO3A-DM1-Lys-Urea-Glu exhibited significantly higher uptake (p < 0.01) in the PSMA positive PC3-PIP tumors (4.30 ± 0.20%ID/g) at 1 h postinjection than in the PSMA negative PC3-Flu tumors (1.12 ± 0.42%ID/g). Taken together, we have successfully designed and synthesized a T-SMDC system for prostate cancer targeted imaging and therapy.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Tara
authors.initials: T
authors.lastname: Mastren
authors.affiliation: Department of Urology, the First Affiliated Hospital, Medical School of Xi'An Jiaotong University , Xi'An, Shaanxi 710061, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.forename: Guiyang
authors.initials: G
authors.lastname: Hao
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D005710:Gallium Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D008297:Male; D058990:Molecular Targeted Therapy; D011092:Polyethylene Glycols / Q000737:chemistry; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000628:therapy*
chemical_list: D000954:Antigens, Surface; D005710:Gallium Radioisotopes; D018796:Immunoconjugates; D011092:Polyethylene Glycols; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II