Molecular‐Target‐Based Anticancer Photosensitizer: Synthesis and in vitro Photodynamic Activity of Erlotinib–Zinc(II) Phthalocyanine Conjugates

Abstract

Targeted photodynamic therapy is a new promising therapeutic strategy to overcome growing problems in contemporary medicine, such as drug toxicity and drug resistance. A series of erlotinib-zinc(II) phthalocyanine conjugates were designed and synthesized. Compared with unsubstituted zinc(II) phthalocyanine, these conjugates can successfully target EGFR-overexpressing cancer cells owing to the presence of the small molecular-target-based anticancer agent erlotinib. All conjugates were found to be essentially non-cytotoxic in the absence of light (up to 50 μM), but upon illumination, they show significantly high photo-cytotoxicity toward HepG2 cells, with IC50 values as low as 9.61-91.77 nM under a rather low light dose (λ=670 nm, 1.5 J cm(-2) ). Structure-activity relationships for these conjugates were assessed by determining their photophysical/photochemical properties, cellular uptake, and in vitro photodynamic activities. The results show that these conjugates are highly promising antitumor agents for molecular-target-based photodynamic therapy.

Silicon Phthalocyanines Axially Disubstituted with Erlotinib toward Small‐Molecular‐Target‐Based Photodynamic Therapy

“…The dose‐dependent survival curves are shown in Figure . All conjugates essentially had no dark cytotoxicity, and exhibited significantly high photo‐cytotoxicity upon low‐dose light illumination (670 nm, 1.5 J cm −2 , 25 mW cm −2 ) which is usually used in phthalocyanine‐based PDT . The low IC 50 (8–27 n m ) values follow the order SiPc‐3‐E>SiPc‐PEG>SiPc‐2‐E, which is in accordance with their Φ Δ and ROS levels.…”

“…As part of our ongoing interest in the development of targeted PS, we recently developed a “smart” tumor targeted strategy in PDT: PS was conjugated with a small‐molecule target‐based anticancer drug, some of which can target the epidermal growth factor receptor (EGFR) overexpressed in cancer cells . A small‐molecule target‐based anticancer drug with a simple chemical structure and high stability would be a more suitable moiety for conjugation with a photosensitizer to achieve targeted PDT.…”

“…In these systems, we chose erlotinib to conjugate with zinc(II) phthalocyanines (ZnPc) at α‐ or β‐positions via various lengths of oligoethylene glycol spacers. By introducing the erlotinib moiety, these conjugates exhibited high targeting ability to HepG2 cancer cells and A431 tumor tissues, and also maintained high photodynamic efficacy . There are two challenges in clinical PDT applications of ZnPc conjugates: the great tendency to form aggregates, and low purity resulting from isomerization …”

“…[20] As part of our ongoing interest in the development of targeted PS, we recently developed a" smart" tumor targeted strategyi nP DT:P Sw as conjugated with as mall-molecule target-based anticancerd rug, some of which can target the epidermalg rowth factor receptor (EGFR) overexpressed in cancer cells. [21][22][23] As mall-molecule target-based anticancer drug with as imple chemical structure andh igh stabilityw ould be am ore suitablem oiety for conjugation with ap hotosensitizer to achieve targeted PDT.I nt heses ystems, we chose erlotinib to conjugate with zinc(II) phthalocyanines (ZnPc) at a-o r b-positions via various lengths of oligoethylene glycol spacers. By introducing the erlotinib moiety,t hese conjugates exhibited high targetinga bility to HepG2 cancerc ells and A431 tumor tissues,a nd also maintained high photodynamic efficacy.…”

“…By introducing the erlotinib moiety,t hese conjugates exhibited high targetinga bility to HepG2 cancerc ells and A431 tumor tissues,a nd also maintained high photodynamic efficacy. [21][22][23] There are two challenges in clinical PDT applications of ZnPc conjugates:t he great tendency to form aggregates, [8,[24][25][26][27][28][29][30][31][32][33] and low purity resulting from isomerization. [34] As reported, as ilicon centera llows the introductiono ft wo appropriate axial ligands to inhibit the p-p stacking tendency of phthalocyanine (Pc) rings;t hus, axially substituted silicon phthalocyanines (SiPcs)h ave emerged to improve the hydrophilicity and inhibit the self-aggregation of Pcs.…”