A novel photosensitizer: An l-glutamide lipid conjugate with improved properties for photodynamic therapy

Abstract

Photosensitizers (PS) are used in photodynamic therapy to treat several cancers. The efficacy of photodynamic therapy (PDT) could be further improved by overcoming aggregation-dependent quenching of PS and by improving the biodistribution of the PS. In this work we attempted to overcome these issues by conjugating a PS with a lipid molecule and tested the liposomes prepared with this PS conjugated lipid for PDT. A novel lipid-porphyrin conjugate (1 : 1) was synthesized by attaching a PS, 5-(4-methoxycarbonylphenyl)-10,15,20-triphenyl-H,H-porphine, to the head group of a glutamide lipid. Two liposomal preparations, with egg phosphatidylcholine as the bulk lipid, were prepared viz. liposomes with PS conjugated lipid (LPSL) and PS entrapped in liposomes (PSL). At equimolar concentrations of the PS, both liposomal preparations were found to generate comparable amounts of reactive oxygen species as free PS upon light exposure. Electron micrographs and dynamic light scattering measurements indicated uniform and circular liposomes of 150 nm in size and near neutral zeta potential. Uptake of these liposomes by the human ovarian carcinoma cell line, SK-OV-3, was shown by FACS and confocal microscopy. Upon light exposure, the LPSL, i.e., with the conjugate lipid, have shown a substantial decrease (>4 times) in the PS requirement compared to PSL or free PS in its ability to cause light mediated cell death of SK-OV-3 cells. The light mediate cell death by LPSL was shown to be not dependent on the bulk properties of the lipid. Our data suggest a potential benefit of conjugating PS with a lipid in improving the efficiency of PDT.

Impacting Pancreatic Cancer Therapy in Heterotypic in Vitro Organoids and in Vivo Tumors with Specificity-Tuned, NIR-Activable Photoimmunonanoconjugates: Towards Conquering Desmoplasia?

“…Without the stable membrane insertion of BPD into the nanoconstruct, attempts at antibody targeted delivery of BPD become futile. Lipidic bilayered nanovesicles formed of lipidated porphyrins, first reported in 2002, 49 have been previously prepared by the conjugation of porphyrins to phospholipid acyl chains, 49 glycerol moieties, 48,50,51 phosphate head groups, 52,53 and PEG chains. 48,54 Recent studies by Zheng and Lovell have demonstrated the unique properties of lipidated porphyrin constituents of nanomedicines and nanotheranostics.…”

“…Without the stable membrane insertion of BPD into the nanoconstruct, attempts at antibody targeted delivery of BPD become futile. Lipidic bilayered nanovesicles formed of lipidated porphyrins, first reported in 2002, have been previously prepared by the conjugation of porphyrins to phospholipid acyl chains, glycerol moieties, ,, phosphate head groups, , and PEG chains. , Recent studies by Zheng and Lovell have demonstrated the unique properties of lipidated porphyrin constituents of nanomedicines and nanotheranostics. , We thus synthesized a panel of liposomal nanoformulations of BPD and its lipidated variants conjugated to 16:0 lyso PC, 20:0 lyso PC, and cholesterol through Steglich esterification or to DSPE-PEG 2000 -NH 2 by EDC-amide coupling . Cholesterol was selected as a classical membrane anchor, 16:0 lyso PC and 20 lyso PC were compared for their varying acyl chain length, and DSPE-PEG 2000 -NH 2 was selected for its double acyl chain membrane anchors.…”

Recent advances in porphyrin-based nanocomposites for effective targeted imaging and therapy

“…Hence, the DOX drug will be released, and the fluorescence of the porphyrin will be recovered. Nathan et al [96] have also shown that the modification of porphyrins using a L-glutamide lipid chain led to the formation of porphysomes with better PDT efficiency compared to the usual liposomal formulations.…”