title: Reformulating Tylocrebrine in Epidermal Growth Factor Receptor Targeted Polymeric Nanoparticles Improves Its Therapeutic Index.
abstract: Several promising anticancer drug candidates have been sidelined owing to their poor physicochemical properties or unfavorable pharmacokinetics, resulting in high overall cost of drug discovery and development. Use of alternative formulation strategies that alleviate these issues can help advance new molecules to the clinic at a significantly lower cost. Tylocrebrine is a natural product with potent anticancer activity. Its clinical trial was discontinued following the discovery of severe central nervous system toxicities. To improve the safety and potency of tylocrebrine, we formulated the drug in polymeric nanoparticles targeted to the epidermal growth factor receptor (EGFR) overexpressed on several types of tumors. Through in vitro studies in different cancer cell lines, we found that EGFR targeted nanoparticles were significantly more effective in killing tumor cells than the free drug. In vivo pharmacokinetic studies revealed that encapsulation in nanoparticles resulted in lower brain penetration and enhanced tumor accumulation of the drug. Further, targeted nanoparticles were characterized by significantly enhanced tumor growth inhibitory activity in a mouse xenograft model of epidermoid cancer. These results suggest that the therapeutic index of drugs that were previously considered unusable could be significantly improved by reformulation. Application of novel formulation strategies to previously abandoned drugs provides an opportunity to advance new molecules to the clinic at a lower cost. This can significantly increase the repertoire of treatment options available to cancer patients.
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Ameya R
authors.initials: AR
authors.lastname: Kirtane
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Wong
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Bharath Raja
authors.initials: BR
authors.lastname: Guru
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Lev G
authors.initials: LG
authors.lastname: Lis
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Vadim J
authors.initials: VJ
authors.lastname: Gurvich
authors.affiliation: †Department of Pharmaceutics, ‡Institute of Therapeutics Discovery and Development, §Department of Medicinal Chemistry, and ⊥Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010616:Phenanthrenes / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010616:Phenanthrenes; D011108:Polymers; D044005:Tetrahydroisoquinolines; C100148:tylocrebrine; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: PLGA nanoparticles; chemotherapy; drug targeting; therapeutic index; tylocrebrine