Biotinylated Platinum(II) Ferrocenylterpyridine Complexes for Targeted Photoinduced Cytotoxicity

Abstract

Biotinylated platinum(II) ferrocenylterpyridine (Fc-tpy) complexes [Pt(Fc-tpy)(L(1))]Cl (1) and [Pt(Fc-tpy)(L(2))]Cl (2), where HL(1) and HL(2) are biotin-containing ligands, were prepared, and their targeted photoinduced cytotoxic effect in cancer cells over normal cells was studied. A nonbiotinylated complex, [Pt(Fc-tpy)(L(3))]Cl (3), was prepared as a control to study the role of the biotin moiety in cellular uptake properties of the complexes. Three platinum(II) phenylterpyridine (Ph-tpy) complexes, viz., [Pt(Ph-tpy)(L(1))]Cl (4), [Pt(Ph-tpy)(L(2))]Cl (5), and [Pt(Ph-tpy)(L(3))]Cl (6), were synthesized and explored to understand the role of a metal-bound Fc-tpy ligand over Ph-tpy as a photoinitiator. The Fc-tpy complexes displayed an intense absorption band near 640 nm, which was absent in their Ph-tpy analogues. The Fc-tpy complexes (1 mM in 0.1 M TBAP) showed an irreversible cyclic voltammetric anodic response of the Fc/Fc(+) couple near 0.25 V. The Fc-tpy complexes displayed photodegradation in red light of 647 nm involving the formation of a ferrocenium ion (Fc(+)) and reactive oxygen species (ROS). Photoinduced release of the biotinylated ligands was observed from spectral measurements, and this possibly led to the controlled generation of an active platinum(II) species, which binds to the calf-thymus DNA used for this study. The biotinylated photoactive Fc-tpy complexes showed significant photoinduced cytotoxicity, giving a IC50 value of ∼7 μM in visible light of 400-700 nm with selective uptake in BT474 cancer cells over HBL-100 normal cells. Furthermore, ferrocenyl complexes resulted in light-induced ROS-mediated apoptosis, as indicated by DCFDA, annexin V/FITC staining, and sub-G1 DNA content determined by fluorescent activated cell sorting analysis. The phenyl analogues 4 and 5 were photostable, served as DNA intercalators, and demonstrated selective cytotoxicity in the cancer cells, giving IC50 values of ∼4 μM.

Gold and platinum alkynyl complexes for biomedical applications

“…12) have been reported for targeted photo-induced cytotoxicity. 93 In this occasion a biotinylated alkynyl was used as ancillary ligand in order to target specifically cancer cells. Biotinylated derivatives are known to display cancer cell-specific uptake.…”

Photoactivatable Platinum-Based Anticancer Drugs: Mode of Photoactivation and Mechanism of Action

“…The complexes will be divided into groups based on their mechanisms of action, including photoreduction, photo-uncaging, and photodissociation. In addition to these types of photoactivatable platinum drugs, dual-action platinum drugs built by a conjugation of PDT agents with platinum drugs also showed enhanced cytotoxicity under irradiation compared with that in the darkness [20][21][22][23][24][25]. This kind of complex will not be discussed in this review, as this review will focus on the platinum complexes that could generate an active form of Pt(II) species upon irradiation.…”

Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization

“…Thus, biotin conjugates may be favourably captured by the tumour tissue, and this concept has been extensively used for the targeting of drugs (including drug nanocarriers) to tumours . Several classes of biotin containing metal compounds have been investigated for their anticancer potential, including complexes based on Re(I) and Ru(II), Zn(II)‐phthalocyanine, Au(III)‐NHC, Pt(II) and Pt(IV), and ferrocene derivatives . In general, such biotinylated species successfully display enhanced cellular uptake and selectivity, and the cytotoxicity and the cellular uptake are reduced when the in vitro cell medium culture is enriched with biotin or the cells are pre‐treated with biotin.…”