Synthesis and in Vitro Evaluation of BBB Permeability, Tumor Cell Uptake, and Cytotoxicity of a Series of Carboranylporphyrin Conjugates

Abstract

A series of tri[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin conjugates of linear and branched polyamines, glucose, arginine, tri(ethylene glycol), and Tyr-d-Arg-Phe-β-Ala (YRFA) peptide were synthesized. These conjugates were investigated for their BBB permeability in human hCMEC/D3 brain endothelial cells, and their cytotoxicity and uptake were assessed using human glioma T98G cells. For comparison purposes, a symmetric tetra[(p-carboranylmethylthio)tetrafluorophenyl]porphyrin was also synthesized, and its crystal structure was obtained. All porphyrin conjugates show low dark cytotoxicity (IC50 > 400 μM) and low phototoxicity (IC50 > 100 μM at 1.5 J/cm2) toward T98G cells. All conjugates were efficiently taken up by T98G cells, particularly the cationic polyamine and arginine conjugates, and were localized in multiple cellular organelles, including mitochondria and lysosomes. All compounds showed relatively low in vitro BBB permeability compared with that of lucifer yellow because of their higher molecular weight, hydrophobicity, and tendency for aggregation in solution. Within this series, the branched polyamine and YRFA conjugates showed the highest permeability coefficient, whereas the glucose conjugate showed the lowest permeability coefficient.

Fluorinated porphyrinoids as efficient platforms for new photonic materials, sensors, and therapeutics

“…12) were reported. 41,46 Symmetric tetra substituted porphyrin– p -carborane was obtained in quantitative yields. The PEG derivative was further conjugated to peptide (YRFA) and amino acid (lysine) via an amide coupling reaction.…”

“…By controlling the stoichiometry and reaction conditions, the TPPF 20 , CF 20 , IF 20 and BF 20 platforms can be appended with 1–4 groups. 33,41 Note that asymmetric moieties appended onto the CF 20 , IF 20 and BF 20 platforms result in diastereomers at the bridge head positions. Because of the orthogonal geometry of the aryl groups and the barrier to rotation, substitution of more than one m -position results in atropisomers.…”

“…41,43–47 There are few examples where more than one biomolecular motif ( e.g . cell targeting, hydrophilic, or chemotherapeutic) can be appended to a dye but the molecular topology of the porphyrinoids allows a range of substitutions.…”

“…cell targeting, hydrophilic, or chemotherapeutic) can be appended to a dye but the molecular topology of the porphyrinoids allows a range of substitutions. 41,46 For biotargeting and bio-sensing, the multiple valence significantly increases binding to the target. Other strategies that exploit the topological richness of the porphyrinoids are as drug carriers, e.g .…”

Synthesis and properties of a series of carboranyl-BODIPYs

“…Tight junctions limit paracellular diffusion of molecules and fluid into and out of the brain, preventing diseases and viruses from attacking the sensitive brain tissue. The investigation of several types of molecules, including peptides, sugars, liposomes and porphyrins, using hCMEC/D3 cell monolayers as BBB model [7–9], has shown that several structural and physical factors play a role in their ability to permeate the BBB, including size, conformation, lipophilicity, and molecular weight [10–12]. …”