Synthesis and evaluation of novel prodrugs of foscarnet and dideoxycytidine with a universal carrier compound comprising a chemiluminescent and a photochromic conjugate.
To facilitate intracellular delivery of hydrophilic drugs, a general lipophilic carrier molecule was designed and synthesized. The carrier comprised a chemiluminescent-photochromic conjugate that potentiates diffusion across cell membranes to enhance intracellular uptake of the drug. The designed mechanism involves activation of the chemiluminescent moiety by intracellular oxygen free radicals and intermolecular energy transfer of the excited state energy to the photochromic moiety to result in release of the drug to allow the desired pharmacological effect to occur. Prodrugs of foscarnet and dideoxycytidine with several carriers caused suppression of a human immunodeficiency virus infection in human cultured macrophages that was up to five times more effective than the drug alone. Successful in vivo efficacy testing of prodrug has been accomplished by demonstrating the suppression of a retroviral infection of Friend leukemia virus in mice. Acute toxicity studies of the carrier indicated that it was nontoxic.
Mills
Randell
R
Luminide Pharmaceutical Corporation, 493 Old Trenton Road, Cranbury, New Jersey 08512, USA. rmills@blacklightpower.com
Wu
Guo Zhang
GZ
D000818:Animals; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017245:Foscarnet / Q000008:administration & dosage / Q000138:chemical synthesis*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D049408:Luminescent Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis*; D016047:Zalcitabine / Q000008:administration & dosage / Q000138:chemical synthesis*
D004337:Drug Carriers; D049408:Luminescent Agents; D011355:Prodrugs; D017245:Foscarnet; D016047:Zalcitabine