title: Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.
abstract: OBJECTIVE
  The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.
  
  
  METHODS
  Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.
  
  
  RESULTS
  Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C-positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO-203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203.
  
  
  CONCLUSIONS
  These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Sinha
authors.affiliation: Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Genus Oncology, Boston, Massachusetts.
authors.forename: Deepak
authors.initials: D
authors.lastname: Raina
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Akriti
authors.initials: A
authors.lastname: Kharbanda
authors.affiliation: Genus Oncology, Boston, Massachusetts.
authors.forename: Govind
authors.initials: G
authors.lastname: Panchamoorthy
authors.affiliation: Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India.
authors.forename: Dikshi
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India. donald_kufe@dfci.harvard.edu harpal2000@yahoo.com.
authors.forename: Harpal
authors.initials: H
authors.lastname: Singh
authors.affiliation: Genus Oncology, Boston, Massachusetts.
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. donald_kufe@dfci.harvard.edu harpal2000@yahoo.com.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004339:Drug Compounding; D006801:Humans; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D018396:Mucin-1 / Q000378:metabolism*; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D010084:Oxidation-Reduction; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D055503:Protein Multimerization; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; D000970:Antineoplastic Agents; C060192:MUC1 protein, human; D018396:Mucin-1; D053769:Nanocapsules; D010455:Peptides