In vivo fluorescence imaging of the transport of charged chlorin e6 conjugates in a rat orthotopic prostate tumour

Abstract

Summary Polymeric drug conjugates are used in cancer therapy and, varying their molecular size and charge, will affect their in vivo transport and extravasation in tumours. Partitioning between tumour vasculature and tumour tissue will be of particular significance in the case of photosensitizer conjugates used in photodynamic therapy, where this partitioning can lead to different therapeutic effects. Poly-l-lysine chlorin e6 conjugates (derived from polymers of average M r 5000 and 25 000) were prepared both in a cationic state and by poly-succinylation in an anionic state. A fluorescence scanning laser microscope was used to follow the pharmacokinetics of these conjugates in vivo in an orthotopic rat prostate cancer model obtained with MatLyLu cells. Fluorescence was excited with the 454-528 nm group of lines of an argon laser and a 570 nm long pass filter used to isolate the emission. Results showed that the conjugates initially bound to the walls of the vasculature, before extravasating into the tissue, and eventually increasing in fluorescence. The anionic conjugates produced tissue fluorescence faster than the cationic ones, and surprisingly, the larger M r conjugates produced tissue fluorescence faster than the smaller ones with the same charge. These results are consistent with differences in aggregation state between conjugates.

Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells

“…Here, we evaluate a similar approach, but now using DT and ALA-PDT for human prostate cancer cells. Previous work by our group used the LNCaP cell line in PDT studies (Momma et al, 1998;Hamblin et al, 1999) and showed that ALA-induced PpIX formation can be manipulated by androgenic hormones (Momma et al, 1997). Our current work extends that concept by showing that other agents can also alter PpIX levels when used in a short-term course for DT.…”

Photodynamic therapy in the treatment of prostate cancer

“…W komórkach MatLyLu (wariant komórek szczepu Dunning 3327) in vitro większe stężenia osiągały cząsteczki naładowane dodatnio, natomiast w tkankach ortotopowych guzów u szczurów -cząsteczki o ładunku ujemnym, co można wyjaśnić spowolnieniem dyfuzji do tkanki guza cząsteczek naładowanych dodatnio, wskutek ich większego powinowactwa do komórek nabłonka naczyń. Niezależnie od ładunku elektrycznego, molekuły o mniejszej masie cząsteczkowej dyfundowały wolniej do tkanki nowotworowej, co z kolei można wytłumaczyć ich agregacją we krwi [23].…”

Pegylation of charged polymer-photosensitiser conjugates: effects on photodynamic efficacy

“…We have shown that cationic and succinylated pL -c e6 conjugates have differing cellular uptakes and relative phototoxicities in vitro (Soukos et al, 1997) and different biodistributions in vivo (Duska et al, 1997). It was shown that there were also differences in the rate at which these charged polymer -PS conjugates left the tumour vasculature as revealed by in vivo fluorescence microscopy (Hamblin et al, 1999). Polycationic molecules are known to be rapidly and efficiently taken up by cells through endocytosis (Basu et al, 1976), but have the drawback that they are also cleared rapidly from the systemic circulation in vivo (Vorbrodt et al, 1996), and pegylation might increase the serum half-life, thus improving the tumour localising properties of these molecules.…”

“…Our laboratory has studied the conjugation of PS to macromolecular delivery vehicles that are designed to improve their performance by increasing specificity and/or uptake in tumours or other pathological lesions, favourably altering pharmacokinetics or biodistribution (i.e. less skin photosensitivity) or decreasing phototoxicity to normal tissue (Hamblin et al, 1996(Hamblin et al, , 1999Duska et al, 1997;Del Governatore et al, 2000a, b;Molpus et al, 2000). The physical properties of macromolecular -PS conjugates such as size, ionic charge, hydrophobicity can be easily altered (Soukos et al, 1997), while keeping the same PS molecule joined to the conjugate that may or may not have a specific recognition site for a target (Hamblin et al, 1996).…”