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Impact of tumor HER2/ERBB2 expression level on HER2-targeted liposomal doxorubicin-mediated drug delivery: multiple

Bart S Hendriks1, Stephan G Klinz, Joseph G Reynolds

  • 1Corresponding Author: Bart Hendriks, Merrimack Pharmaceuticals, 1 Kendall Square, Suite B7201, Cambridge, MA 02139. bhendriks@merrimackpharma.com.

Molecular Cancer Therapeutics
|June 1, 2013
PubMed

Insights

HER2-targeted liposomal doxorubicin delivery to tumor cell nuclei increases with higher HER2 expression, showing a threshold effect. This suggests potential treatment for tumors with lower HER2 levels, expanding patient eligibility.

Area of Science:

  • Oncology
  • Nanomedicine
  • Pharmacology

Background:

  • Targeted nanotherapeutics show promise for solid tumors, but cellular heterogeneity's impact on nanoparticle interaction is understudied.
  • Heterogeneous antigen expression (e.g., HER2/ERBB2) across patients and tumors complicates targeted therapy efficacy and requires understanding.
  • Optimizing the therapeutic window is crucial due to antigen expression in non-target tissues.

Purpose of the Study:

  • To quantitatively investigate the impact of HER2 expression levels on the nuclear delivery of doxorubicin from HER2-targeted liposomes.
  • To determine the relationship between HER2 receptor density on cells and the efficacy of targeted nanoparticle drug delivery.
  • To explore the potential for HER2-targeted nanotherapeutics in patient populations with varying HER2 expression levels.

Main Methods:

  • Utilized HER2-targeted liposomal doxorubicin as a model system to study nanoparticle-cell interactions.
  • Quantitatively assessed doxorubicin delivery to the nucleus in relation to varying HER2 expression levels.
  • Employed kinetic modeling to elucidate the mechanisms underlying the observed effects of HER2 expression.

Main Results:

  • Demonstrated a quantitative increase in nuclear doxorubicin delivery with rising HER2 expression levels.
  • Identified a threshold effect for nuclear doxorubicin delivery at approximately 2 × 10(5) HER2 receptors/cell.
  • Observed minimal uptake in human cardiomyocytes with HER2 levels below the identified threshold, consistent with safety profiles.

Conclusions:

  • The threshold effect in nuclear doxorubicin delivery is attributed to multiple low-affinity interactions between the targeted liposome and HER2.
  • HER2-targeted liposomal doxorubicin may effectively treat tumors with HER2 expression below traditional positive thresholds.
  • These findings suggest a broader patient population could benefit from HER2-targeted nanotherapeutics, expanding treatment possibilities.

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