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]

Abstract

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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Acknowledgements

The authors would like to thank Dr. Matt Ross, Department of Basic Sciences, College of Veterinary Medicine at Mississippi State University for allowing access to spectrophotometric instrumentation for the acquisition of UV absorbance measurements.

Funding

Investigations were conducted utilizing extramural sources of funding and support originally allocated for the successful conduction of unrelated research investigations. Research investigations represent a component of an on-going body of research devoted to the design of the molecular structure, and organic chemistry reactions in multi-stage synthesis regimens for covalent biopharmaceutical in the form of immunochemotherapeutic prototypes that possess properties of selective “targeted” antineoplastic cytotoxicity

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LN during the course of a post-doc training program was involved with the execution of laboratory procedures that involved the collection and in some instances the preliminary analysis of data. CPC function as the principal investigator which involved determining the design of the molecular structure and organic chemistry reactions in synthesis regimens for covalent immunopharmaceuticals in addition the performing synthesis methods, collection of data, statistical analysis of results, generation of figure illustrations, identification of relevant references and the composition of the research manuscript.

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Correspondence to Cody P. Coyne.

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Research investigations were conducted while maintaining ethical standards and requirements. Human or animal subjects were not employed during the course of completing any component of the research investigations described. Consequently, statements are therefore not indicated or necessary with regard to human and animal rights, or human consent.

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The conduction of research investigations, analysis of data, interpretation of experimental results, and the reporting and interpretations findings has occurred with compliance to ethical standards.

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Coyne, C.P., Narayanan, L. 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]. J. Pharm. Investig. 49, 173–193 (2019). https://doi.org/10.1007/s40005-018-0401-9

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Keywords

  • Simultaneous dual “targeted” delivery
  • Fludarabine
  • Dexamethasone
  • EGFR
  • IGF-1R
  • Covalent-immunopharmaceutical
  • Anti-neoplastic cytotoxicity