title: EGFR-targeted stearoyl gemcitabine nanoparticles show enhanced anti-tumor activity.
abstract: Previously, it was shown that a novel 4-(N)-stearoyl gemcitabine nanoparticle formulation was more effective than gemcitabine hydrochloride in controlling the growth of model mouse or human tumors pre-established in mice. In the present study, the feasibility of targeting the stearoyl gemcitabine nanoparticles (GemC18-NPs) into tumor cells that over-express epidermal growth factor receptor (EGFR) to more effectively control tumor growth was evaluated. EGFR is over-expressed in a variety of tumor cells, and EGF is a known natural ligand of EGFR. Recombinant murine EGF was conjugated onto the GemC18-NPs. The ability of the EGF to target the GemC18-NPs to human breast adenocarcinoma cells that expressed different levels of EGFR was evaluated in vitro and in vivo. In culture, the extent to which the EGF-conjugated GemC18-NPs were taken up by tumor cells was correlated to the EGFR density on the tumor cells, whereas the uptake of untargeted GemC18-NPs exhibited no difference among those same cell lines. The relative cytotoxicity of the EGF-conjugated GemC18-NPs to tumor cells in culture was correlated to EGFR expression as well. In vivo, EGFR-over-expressing MDA-MB-468 tumors in mice treated with the EGF-conjugated GemC18-NPs grew significantly slower than in mice treated with untargeted GemC18-NPs, likely due to that the EGF-GemC18-NPs were more anti-proliferative, anti-angiogenic, and pro-apoptotic. Fluorescence intensity data from ex vivo imaging showed that the EGF on the nanoparticles helped increase the accumulation of the GemC18-NPs into MDA-MB-468 tumors pre-established in mice by more than 2-fold as compared to the un-targeted GemC18-NPs. In conclusion, active targeting of the GemC18-NPs into EGFR-over-expressed tumors can further enhance their anti-tumor activity.
authors.affiliation: Pharmaceutics Division, The University of Texas at Austin, College of Pharmacy, Austin, Texas 78712, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandoval
authors.forename: Brian R
authors.initials: BR
authors.lastname: Sloat
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: B Leticia
authors.initials: BL
authors.lastname: Rodriguez
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kiguchi
authors.forename: John
authors.initials: J
authors.lastname: Digiovanni
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010047:Ovalbumin / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D004815:Epidermal Growth Factor; D010047:Ovalbumin; D066246:ErbB Receptors; D000093542:Gemcitabine