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KMID : 1146920190490010173
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Journal of Pharmaceutical Investigation
2019 Volume.49 No. 1 p.173 ~ p.193
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Anti-neoplastic cytotoxicity by complementary simultaneous selective “targeted” delivery for pulmonary adenocarcinoma: fludarabine-(5′-phosphoramidate)-[anti-IGF-1R] in dual-combination with dexamethasone-(C21-phosphoramidate)-[anti-EGFR]
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Coyne Cody P.
Narayanan Lakshmi
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Abstract
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Selective “targeted” delivery of chemotherapeutic agents represents a molecular strategy for achieving enhanced margins-of-safety and greater potency compared to conventional small-molecular weight chemotherapeutics. Greater margins-of-safety are possible because extensive un-intentional diffusion of therapeutics across intact cell membranes of normal healthy cells residing within tissues and organ systems is minimized or avoided. Simultaneous, independent “targeted” delivery of one or more therapeutics at multiple sites on the external surface membrane of neoplastic cells has not been described extensively. Fludarabine-(5′-phosphoramidate)-[anti-IGF-1R] and dexamethasone-(C21-phosphoramidate)-[anti-EGFR] were synthesized by reacting fludarabine or dexamethasone-C21-monophosphate with a carbodiimide reagent and imidazole for synthesis of covalent fludarabine-(5′-phosphoramidate)-[anti-IGF-1R] and dexamethasone-(C21-phosphoramidate)-[anti-EGFR] immunopharmaceuticals. The pharmaceutical molar-incorporation-indexes for fludarabine-(C5-phosphoramidate)-[anti-IGF-1R] and dexamethasone-(C21-phosphoramidate)-[anti-EGFR] were 3.67:1 and 6.95:1 respectively. Simultaneous dual-combination selective “targeted” delivery with fludarabine-(5′-phosphoramidate)-[anti-IGF-1R] with dexamethasone-(C21-phosphoramidate)-[anti-EGFR] produced the most profound enhancement in anti-neoplastic cytotoxitity at the pharmaceutical-equivalent concentations of 10??9 M (14.7% ±?0.80 SE) and 10??8 M (54.0% ±?0.9 SE) respectively. Simultaneous dual “targeted” anti-neoplastic cytotoxicity can potentially be evoked ex-vivo and in-vivo with fludarabine-(5′-phosphoramidate)-[anti-IGF-1R] and dexamethasone-(C21-phosphoramidate)-[anti-EGFR] through the synergistic and additive efficacy achieved through the combined mechanisms-of-actions associated with; (1) covalently bound therapeutic moieties; (2) anti-trophic receptor IgG-immunoglobulin; and (3) activation of three host immune responses.
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KEYWORD
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Simultaneous dual “targeted” delivery, Fludarabine, Dexamethasone, EGFR, IGF-1R, Covalent-immunopharmaceutical, Anti-neoplastic cytotoxicity
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