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

  • Clin Cancer Res. 2015 May 15;21(10):2338-47. doi: 10.1158/1078-0432.CCR-14-3000.
Masanori Hasegawa  1 ,  Raj Kumar Sinha  2 ,  Manoj Kumar  2 ,  Maroof Alam  1 ,  Li Yin  1 ,  Deepak Raina  3 ,  Akriti Kharbanda  1 ,  Govind Panchamoorthy  3 ,  Dikshi Gupta  2 ,  Harpal Singh  4 ,  Surender Kharbanda  3 ,  Donald Kufe  5
Affiliations
  • 1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 2. Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India.
  • 3. Genus Oncology, Boston, Massachusetts.
  • 4. Center for Biomedical Engineering, Indian Institute of Technology, New Delhi, India. [email protected] [email protected].
  • 5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. [email protected] [email protected].
PMID: 25712682 DOI: 10.1158/1078-0432.CCR-14-3000
Abstract

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 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.

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