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Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation
Masanori Hasegawa1, Raj Kumar Sinha2, Manoj Kumar2
1Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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.
Insights
Novel polymeric nanoparticles effectively deliver the MUC1-C inhibitor GO-203, improving cancer cell targeting and reducing tumor growth in mice with less frequent dosing.
Area of Science:
- Oncology
- Nanotechnology
- Drug Delivery
Background:
- The MUC1-C oncoprotein is a targetable cancer driver.
- Peptide drug development faces challenges with pharmacokinetics and cell penetration.
Purpose of the Study:
- To encapsulate the MUC1-C inhibitor GO-203 into polymeric nanoparticles.
- To evaluate the nanoparticles' efficacy in targeting MUC1-C signaling and function.
Main Methods:
- GO-203 was loaded into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers.
- In vitro cancer cell studies assessed GO-203 release, MUC1-C inhibition, and cancer cell self-renewal.
- In vivo studies in mice evaluated tumor regression with weekly nanoparticle administration.
Main Results:
- Nanoparticle encapsulation enhanced GO-203 delivery and controlled its release for over 7 days.
- GO-203/nanoparticle treatment showed superior efficacy in cancer cells compared to free GO-203, with less frequent dosing.
- In vivo studies demonstrated significant tumor regression with weekly GO-203/nanoparticle administration, comparable to daily free GO-203 dosing.
Conclusions:
- Polymeric nanoparticles provide a sustained delivery system for the MUC1-C inhibitor GO-203.
- This nanoparticle approach shows potential for improved cancer peptide drug delivery and efficacy.
