Effect of chirality on cellular uptake, imaging and photodynamic therapy of photosensitizers derived from chlorophyll-a

Abstract

We have previously shown that the 124I-analog of methyl 3-(1’-m-iodobenzyloxy) ethyl-3-devinyl-pyropheophorbide-a derived as racemic mixture from chlorophyll-a can be used for PET (positron emission tomography) -imaging in animal tumor models. On the other hand, as a non-radioactive analog, it showed excellent fluorescence and photodynamic therapy (PDT) efficacy. Thus, a single agent in a mixture of radioactive (124I-) and non-radioactive (127I) material can be used for both dual-imaging and PDT of cancer. Before advancing to Phase I human clinical trials, we evaluated the activity of the individual isomers as well as the impact of a chiral center at position-31 in directing in vitro/in vivo cellular uptake, intracellular localization, epithelial tumor cell-specific retention, fluorescence/PET imaging, and photosensitizing ability. The results indicate that both isomers (racemates), either as methyl ester or carboxylic acid, were equally effective. However, the methyl ester analogs, due to subcellular deposition into vesicular structures, were preferentially retained. All derivatives containing carboxylic acid at the position-172 were noted to be substrate for the ABCG2 (a member of the ATP binding cassette transporters) protein explaining their low retention in lung tumor cells expressing this transporter. The compounds in which the chirality at position-3 has been substituted by a non-chiral functionality showed reduced cellular uptake, retention and lower PDT efficacy in mice bearing murine Colon26 tumors.

Cell‐specific Retention and Action of Pheophorbide‐based Photosensitizers in Human Lung Cancer Cells

“…Depending upon their structural and physicochemical properties, pheophorbides exhibit two basic modes of cellular uptake: (1) by transmembrane diffusion into intracellular compartment with preferential accumulation in the ER and the outer membrane of mitochondria as noted for HPPH, or (2) by binding to the cell surface followed by endocytosis and deposition in lysosomes as found with HPPH-Lac (8,17). We confirmed that the two distinct uptake mechanisms applied to cultures of lung tumor ECs (Figure S1A).…”

Surface-anchored poly(acryloyl-L(D)-valine) with enhanced chirality-selective effect on cellular uptake of gold nanoparticles

“…In fact, the investigation on the interaction between surface chiral molecules ( e.g . peptides with different chiral amino acid groups) and cells has not found chirality-dependent cell receptors so far 32 34 35 36 . Hence, some other factors or biomolecules in the cells may take the role on the chirality-dependent cellular uptake.…”

Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma

“…Similarly, although the same amount of PS is injected for each patient, PS accumulation in each lesion can vary depending on the physiologic parameters such as lesion vascularity, drug delivery, and cellular retention. 59,60 DOS techniques can provide local PDT-related parameters such as tissue optical properties, blood flow, oxygenation, and PS content. Thus, assessing these parameters locally with DOS can provide useful feedback for PDT planning for improved PDT efficacy.…”