Open AccessSynthesis, Tumor Specificity, and Photosensitizing Efficacy of Erlotinib-Conjugated Chlorins and Bacteriochlorins: Identification of a Highly Effective Candidate for Photodynamic Therapy of Cancer
Author(s) -
Ravindra R. Cheruku,
Joseph Cacaccio,
Farukh A. Durrani,
Walter A. Tabaczynski,
Ramona Watson,
Kevin E. Siters,
Joseph R. Missert,
Erin Tracy,
Mykhaylo Dukh,
Khurshid A. Guru,
Richard C. Koya,
Paweł Kaliński,
Heinz Baumann,
Ravindra K. Pandey
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01735
Subject(s) - chemistry , erlotinib , photodynamic therapy , conjugate , cancer research , cell culture , conjugated system , cancer , biochemistry , receptor , epidermal growth factor receptor , medicine , biology , polymer , mathematical analysis , genetics , mathematics , organic chemistry
Erlotinib was covalently linked to 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) and structurally related chlorins and bacteriochlorins at different positions of the tetrapyrrole ring. The functional consequence of each modification was determined by quantifying the uptake and subcellular deposition of the erlotinib conjugates, cellular response to therapeutic light treatment in tissue cultures, and in eliminating of corresponding tumors grown as a xenograft in SCID mice. The experimental human cancer models the established cell lines UMUC3 (bladder), FaDu (hypopharynx), and primary cultures of head and neck tumor cells. The effectiveness of the compounds was compared to that of HPPH. Furthermore, specific functional contribution of the carboxylic acid side group at position 17 2 and the chiral methyl group at 3(1') to the overall activity of the chimeric compounds was assessed. Among the conjugates investigated, the PS 10 was identified as the most effective candidate for achieving tumor cell-specific accumulation and yielding improved long-term tumor control.