Novel Porphyrin Conjugates with a Potent Photodynamic Antitumor Effect: Differential Efficacy of Mono‐ and Bis‐β‐cyclodextrin Derivatives In Vifro and In Vivo

Abstract

In the present study we investigated the photosensitizing properties of two novel mono- and bis-cyclodextrin tetrakis (pentafluorophenyl) porphyrin derivatives in several tumor cell lines and in BALB/c mice bearing subcutaneously transplanted syngeneic mouse mammary carcinoma 4T1. Both studied sensitizers were localized mainly in lysosomes and were found to induce cell death by triggering apoptosis in human leukemic cells HL-60. In 4T1 and other cell lines both apoptotic and necrotic modes of cell death occurred depending on drug and light doses. Mono-cyclodextrin porphyrin derivative P(beta-CD)1 exhibited stronger in vitro phototoxic effect than bis-cyclodextrin derivative P(beta-CD)2. However, in vivo P(beta-CD)2 displayed faster tumor uptake with maximal accumulation 6 h after application, leading to complete and prolonged elimination of subcutaneous tumors within 3 days after irradiation (100 J cm(-2)). In contrast, P(beta-CD)1 uptake was slower (48 h) and the reduction of tumor mass was only transient, reaching the maximum at the 12 h interval when a favorable tumor-to-skin ratio appeared. Thus, P(beta-CD)2 represents a new photosensitizing drug displaying fast and selective tumor uptake, strong antitumor activity and fast elimination from the body.

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…Both PSs localized in lysosomes and caused delayed cell death by apoptosis in HL-60 cells compared to 4T1 cell lines which were subject to both apoptotic and necrotic cell death. The mono-cyclodextrin porphyrin derivative 638d showed higher in vitro phototoxicity than the bis-cyclodextrin derivative 638a [351] . Further studies using the β-cyclodextrin conjugates 638a,b,d focused on paclitaxel delivery while the γ-cyclodextrin conjugate 638c was used for doxorubicin transport.…”

“…PDT: 1-500 µM, μM, λ > 600 nm, 3.6 J/cm 2 , 4.6 mW/cm 2 , 24 h incubation post treatment, LD50 = 110 (635b), 219 (635a), 300 (637a), 386 (637b), 428 (637c) > 500 (635c) 635c -inactive @ 500 µM. [324] Human colon adenocarcinoma cells T84 [ 351] mammary carcinoma 4T1 A4-glycochlorins 542a, 543a PDT: @ 0.05 -0.1 μM, 542a > 543a. [354] Mouse colon carcinoma CT26.CL25 Cyclodextrinporphyrins:…”

“…The tetrasubstituted compound 638b was found to be more effective in vitro when tested against 4T1 and K562 cells compared to the same animal model as used before. Best results were obtained with the disubstituted derivatives carrying two β-(638a) or γ-cyclodextrins (638c) which gave very good in vitro and in vivo PDT activity combined with drug complexation at physiological pH conditions and release in cancer cells [351,352] . An alternative method to present carbohydrate units is through strapping of two meso residues.…”

“…The opposite result was obtained in vivo in BALB/c mice bearing subcutaneously transplanted syngeneic mouse mammary carcinoma 4T1. Compound 638a exhibited faster and more selective tumor uptake and caused tumor eradication [351] . Clearly, even within a set study the in vivo activity of PS cannot simply be predicted from in vitro data.…”

Synthesis of Water-Soluble Non-Aggregated Porphyrin-β-Cyclodextrin Tetraconjugate

“…One of these systems intensively studied in the recent years is the conjugates of porphyrins (Por) with cyclodextrins (CD). [1][2][3][4][5][6][7][8][9][10][11][12] The specific biological (tendency to accumulate in cancer tissues) and spectroscopic (high molar absorption, strong fluorescence and good quantum yields) properties of porphyrins predetermine their medical applications mostly focused on photodynamic diagnostic and photodynamic therapy (PDT). [13][14][15][16] The photoactivity of many photosensitizers in PDT is affected by their poor solubility and aggregation, which leads to a decrease in their singlet oxygen production.…”