Christophe Loup

PREPARATION OF WATER-SOLUBLE CATIONIC PHOSPHORUS-CONTAINING DENDRIMERS AS DNA TRANSFECTING AGENTS

P-dendrimers appear to be excellent candidates as transfecting agents after positively charged functions are grafted at their periphery. Five different generations of protonated dendrimers (1-[G1] to 1-[G5]) and the corresponding methylated series (2-[G1] to 2-[G5]) (two examples are shown here) have been examined as transfecting agents of the luciferase gene within 3T3 cells.

Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes

ABSTRACT Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.

Targeting of a hydrophilic photosensitizer by use of internalizing monoclonal antibodies: A new possibility for use in photodynamic therapy.

Coupling of photosensitizers to tumor‐selective monoclonal antibodies ( MAbs ) is an attractive option for improving the selectivity of photodynamic therapy (PDT). For this purpose, hydrophilic sensitizers would be most suitable because of their solubility in water. However, such sensitizers are known to be ineffective in PDT, probably because they cannot readily pass the cell membrane and reach the critical intracellular target. We used the model compound TrisMPyP‐ΦCO2H, a hydrophilic porphyrin derivative, to test the hypothesis that hydrophilic photosensitizers might become of therapeutic value when directed into the tumor cell by use of internalizing MAbs. TrisMPyP‐ΦCO2H was conjugated using a labile ester. Conjugates showed no impairment of integrity on SDS‐PAGE, full stability in serum in vitro, and optimal immunoreactivity when the sensitizer :MAb ratio was ≤3. At higher molar ratios, the solubility of the conjugates decreased. In vitro internalization experiments showed that TrisMPyP‐ΦCONH–125I‐cMAb U36 and TrisMPyPΦCONH–125I‐mMAb 425 conjugates were internalized by A431 cells, in contrast to TrisMPyP‐ΦCONH–125I‐mMAb E48 conjugates. Data on the in vitro efficacy of PDT with MAb‐conjugated TrisMPyP‐ΦCO2H showed that the internalizing cMAb U36 and mMAb 425 conjugates were phototoxic to A431 cells, while the non‐internalizing E48 conjugate and the unconjugated sensitizer were not. Biodistribution data of conjugates with sensitizer:125I‐cMAb U36 ratios varying from 1:1 to 3:1 in tumor‐bearing nude mice revealed selective accumulation in the tumor. Conjugates with higher molar ratios were cleared more rapidly from the blood than the unconjugated 125I‐cMAb U36, resulting in lower tumor uptake but similar tumor‐to‐blood ratios. Our data suggest that hydrophilic photosensitizers might have therapeutic value when targeted to tumors by internalizing MAbs. Int. J. Cancer 88:108–114, 2000.

Trioxaquines and Heme-Artemisinin Adducts Inhibit the In Vitro Formation of Hemozoin Better than Chloroquine

ABSTRACT Trioxaquines, potential antimalarial agents, and heme-artemisinin adducts, resulting from the alkylation of heme by artemisinin, were evaluated as inhibitors of β-hematin formation in 10 M acetate medium at pH 5.

Heme Alkylation by Artesunic Acid and Trioxaquine DU1301, Two Antimalarial Trioxanes

The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug‐resistant Plasmodium falciparum strains, contains a 1,2,4‐trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs.