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Design, Synthesis, and Biological Evaluation of Polyaminocarboxylate Ligand‐Based Theranostic Conjugates for Antibody‐Targeted Cancer Therapy and Near‐Infrared Optical Imaging
Author(s) -
Ren Siyuan,
Sun Xiang,
Wang Haixing,
Nguyen Trung Hai,
Sadeghipour Negar,
Xu Xiaochun,
Kang Chi Soo,
Liu Yujie,
Xu Hua,
Wu Ningjie,
Chen Yanda,
Tichauer Kenneth,
Minh David D. L.,
Chong HyunSoon
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800598
Subject(s) - conjugate , biodistribution , epidermal growth factor receptor , cancer research , in vivo , fluorescence lifetime imaging microscopy , chemistry , cancer cell , targeted therapy , cancer , imaging agent , chelation , a431 cells , ligand (biochemistry) , fluorescence , in vitro , cell , medicine , receptor , biochemistry , cell cycle , biology , mathematical analysis , molecular medicine , mathematics , microbiology and biotechnology , quantum mechanics , physics , organic chemistry
We report the design, synthesis, and evaluation of polyaminocarboxylate ligand‐based antibody conjugates for potential application in targeted cancer therapy and near‐infrared (NIR) fluorescence imaging. We synthesized a new polyaminocarboxylate chelate (CAB‐NE3TA) as a potential anticancer agent. CAB‐NE3TA displayed potent inhibitory activities against various cancer cell lines. We then designed a multifunctional theranostic platform (CAB‐NE3TA‐PAN‐IR800) constructed on an epidermal growth factor receptor (EGFR)‐targeted antibody (panitumumab, PAN) labeled with a NIR fluorescent dye. We also built the first atomistic model of the EGFR–PAN complex and loaded it with the cytotoxic CAB‐NE3TA and the NIR dye. The therapeutic (CAB‐NE3TA‐PAN) and theranostic (CAB‐NE3TA‐PAN‐IR800) conjugates were evaluated using an EGFR‐positive A431 (human skin cancer) cell xenograft mouse model. Biodistribution studies using NIR fluorescence imaging demonstrated that the CAB‐NE3TA‐PAN labeled with the IR800 dye selectively targeted the A431 tumors in mice and resulted in prolonged retention in the tumor tissue and displayed excellent clearance in blood and normal organs. The therapeutic conjugate was capable of significantly inhibiting tumor growth, leading to nearly complete disappearance of tumors in the mice. The results of our pilot in vivo studies support further evaluation of the novel ligand‐based therapeutic and theranostic conjugates for targeted iron chelation cancer therapy and imaging applications.