Design of a Small-molecule Drug Conjugate for Prostate Cancer Targeted Theranostics.

Targeted therapy has become an effective strategy of precision medicine for cancer treatment. Based on the success of an-tibody-drug conjugates (ADCs), here we report a theranostic design of small-molecule drug conjugates (T-SMDCs) for tar-geted 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 68Ga, a posi-tron-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 com-promise its specific binding affinity to PSMA. The PSMA-mediated internalization of 68Ga-labeled NO3A-DM1-Lys-Urea-Glu displayed a time-dependent manner, allowing the desired drug delivery and release within tumor cells. The anti-proliferative activity of the T-SMDC showed a positive correlation with the PSMA expression level. Small animal PET imag-ing with 68Ga-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 hour post-injection 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.

Bioconjugate chemistry. 2016 Jun 01 [Epub ahead of print]

Amit Kumar, Tara Elise Mastren, Bin Wang, Jer-Tsong Hsieh, Guiyang Hao, Xiankai Sun


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