Diplatinum(II) Catecholate of Photoactive Boron-Dipyrromethene for Lysosome-Targeted Photodynamic Therapy in Red Light

Abstract

The binuclear platinum(II) boron-dipyrromethene (BODIPY) complex [{Pt(dach)} 2 (μ-Dcrb)] (DP), where dach is 1,2-diaminocyclohexane and H 4 Dcrb is a morpholine-conjugated BODIPY-linked dicatechol bridging ligand, was prepared for lysosome organelle targeting and near-IR (NIR) light (600−720 nm) induced photocytotoxic activity. The platinum complex [Pt(dach)(cat)] (CP), where H 2 cat is catechol, was synthesized and used as a control complex without bearing the BODIPY unit. The complex DP displayed a band at 660 nm (ε = 2.1 × 10 4 M −1 cm −1 ) in the red region of the UV−visible spectrum recorded in 10% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (DMSO/DMEM, pH 7.2). The complex DP and the BODIPY ligand displayed emission in 10% DMSO−DMEM (pH 7.2) giving an λ em value of 668 nm (λ ex = 650 nm) with a Φ F value of 0.02 for DP and 0.16 for H 4 Dcrb (Φ F , fluorescence quantum yield). Titration experiments using 1,3-diphenylisobenzofuran (DPBF) indicated that the complex DP and H 4 Dcrb on irradiation with near-IR light of 600−720 nm generated singlet oxygen ( 1 O 2 ) as the ROS (reactive oxygen species). The complex DP showed significant lysosomal localization and remarkable apoptotic photodynamic therapy (PDT) effects, giving half-maximal inhibitory concentration values (IC 50 ) within 0.6−3.4 μM in HeLa cervical cancer, A549 lung cancer, and MDA-MB231 multidrug resistant cancer cells, while being essentially nontoxic in the dark and in the HPL1D immortalized lung epithelial normal cells. The acridine orange assay using A549 cells showed lysosomal membrane permeabilization by the complex DP under near-IR light (600−720 nm). This complex on near-IR light (600−720 nm) activation in A549 cells induced apoptotic cell death, as observed from an Annexin-V FITC assay.

Studying the cellular distribution of highly phototoxic platinated metalloporphyrins using isotope labelling

“…a cisplatin analogue. 2 While this approach normally renders the conjugate more toxic 3 , it might diminish one of the main advantages of PDT, namely the special selectivity by the applied light source. Previously, we have reported about a series of easily accessible tetrapyridyl-porphyrins (tPt-H24PyP, cPt-H24PyP, dPt-H24PyP) that were coordinated by four platinum(II) complexes to yield highly phototoxic agents ( Figure 1).…”

Lysosome Specific Platinum(II) Catecholates with Photoactive BODIPY for Imaging and Photodynamic Therapy in Near‐IR Light

“…Ligands, 4‐(2‐(5,5‐difluoro‐1,7,9‐trimethyl‐10‐(4‐(morpholinomethyl)phenyl)‐dipyrrolo[1,3,2]diazaborinin‐3‐yl)vinyl)benzene‐1,2‐diol (H 2 ML ) and 4‐(2‐(5,5‐difluoro‐2,8‐diiodo‐1,7,9‐trimethyl‐10‐(4‐(morpholinomethyl)phenyl)‐dipyrrolo[1,3,2]diazaborinin‐3yl)vinyl)benzene‐1,2‐diol (H 2 IML ), were synthesised following reported literature procedure and the synthetic strategy employed is provided in supporting information as Scheme S1 [40,41] . The platinum complexes, namely, [Pt(dach)( ML )] ( MP ) and [Pt(dach)( IML )] ( IMP ) were synthesised as provided in scheme S2 in supporting information following literature methods [16,39] . The procedure followed for the synthesis of the ligands and the complexes are provided below with the characterization data.…”

“…Lysosomes containing various hydrolytic enzymes functioning to digest the cellular components are now been developed as an attractive target for organelle targeted anticancer therapy. On the drug action, if the lysosomal damage leads to lysosomal membrane disruption, various caspases and cathepsins release into the cell and initiate apoptosis to cause cell death eventually [14–16] . The presence of higher number of lysosomes in cancer cells over non‐cancerous cells induces higher accumulation of lysosome specific drug molecule to accumulate inside cancer cells preferentially over the non‐cancerous cells, thus rendering specificity of the drug and minimizing the possible side effects [17]…”

“…On the drug action, if the lysosomal damage leads to lysosomal membrane disruption, various caspases and cathepsins release into the cell and initiate apoptosis to cause cell death eventually. [14][15][16] The presence of higher number of lysosomes in cancer cells over non-cancerous cells induces higher accumulation of lysosome specific drug molecule to accumulate inside cancer cells preferentially over the non-cancerous cells, thus rendering specificity of the drug and minimizing the possible side effects. [17] Recently, metal complexes as mitochondria, endoplasmic reticulum, cytomembrane, lysosomes targeting drugs are developed and analyzed as photodynamic therapy (PDT) agents.…”

Studying the Cellular Distribution of Highly Phototoxic Platinated Metalloporphyrins Using Isotope Labelling

“…1 A number of publications have reported about PSs conjugated with a chemotoxic unit, e.g., a cisplatin analogue. 2 While this approach normally renders the conjugate more toxic, 3 it might diminish one of the main advantages of PDT, namely the special selectivity by the applied light source.…”