Cancer Therapy: Preclinical Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation

نویسندگان

  • Masanori Hasegawa
  • Raj Kumar Sinha
  • Manoj Kumar
  • Maroof Alam
  • Li Yin
  • Deepak Raina
  • Akriti Kharbanda
  • Govind Panchamoorthy
  • Dikshi Gupta
  • Harpal Singh
  • Surender Kharbanda
  • Donald Kufe
چکیده

Purpose: 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. Experimental Design: Encapsulation of theMUC1-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 ofMUC1-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 tumorswas associatedwith regressions thatwere 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. Clin Cancer Res; 1–10. 2015 AACR.

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Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.

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تاریخ انتشار 2015