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Journal of Pharmaceutical Investigation

, Volume 49, Issue 1, pp 173–193 | Cite as

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]

  • Cody P. CoyneEmail author
  • Lakshmi Narayanan
Original Article
  • 45 Downloads

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.

Keywords

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

Notes

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.

Author contributions

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.

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

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest exists.

Statement of human and animal rights

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.

Ethical standards

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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© The Korean Society of Pharmaceutical Sciences and Technology 2018

Authors and Affiliations

  1. 1.Department of Basic SciencesCollege of Veterinary MedicineMississippiUSA
  2. 2.College of Veterinary Medicine, Wise CenterMississippi State UniversityMississippi StateUSA
  3. 3.Department of Sustainable Bioproducts, Forest and Wildlife Research Center, College of Forestry, Division of Agriculture, ForestryWildlife and Veterinary Medicine, Mississippi State UniversityMississippi StateUSA

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