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Published on: January 20, 2019
Bioorthogonal two-component drug delivery in HER2(+) breast cancer mouse models
Sudath Hapuarachchige1, Yoshinori Kato1,2,3, Dmitri Artemov1,2
1Division of Cancer Imaging Research, Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
The HER2 receptor is overexpressed in approximately 20% of breast cancers and is associated with tumorigenesis, metastasis, and a poor prognosis. Trastuzumab is a first-line targeted drug used against HER2(+) breast cancers; however, at least 50% of HER2(+) tumors develop resistance to trastuzumab. To treat these patients, trastuzumab-based antibody-drug conjugates (ACDs) have been developed and are currently used in the clinic. Despite their high efficacy, the long circulation half-life and non-specific binding of cytotoxic ADCs can result in systemic toxicity. In addition, standard ADCs do not provide an image-guided mode of administration. Here, we have developed a two-component, two-step, pre-targeting drug delivery system integrated with image guidance to circumvent these issues. In this strategy, HER2 receptors are pre-labeled with a functionalized trastuzumab antibody followed by the delivery of drug-loaded nanocarriers. Both components are cross-linked by multiple bioorthogonal click reactions in situ on the surface of the target cell and internalized as nanoclusters. We have explored the efficacy of this delivery strategy in HER2(+) human breast cancer models. Our therapeutic study confirms the high therapeutic efficacy of the new delivery system, with no significant toxicity.
Insights
A novel pre-targeting drug delivery system enhances HER2-positive breast cancer treatment by reducing toxicity and enabling image-guided administration. This innovative approach improves therapeutic efficacy for patients resistant to trastuzumab.
Area of Science:
- Oncology
- Biomedical Engineering
- Drug Delivery Systems
Background:
- HER2 receptor overexpression in 20% of breast cancers drives poor prognosis.
- Trastuzumab resistance develops in over 50% of HER2-positive tumors.
- Current antibody-drug conjugates (ADCs) face challenges with systemic toxicity and lack image guidance.
Purpose of the Study:
- To develop a two-component, image-guided pre-targeting drug delivery system for HER2-positive breast cancer.
- To overcome trastuzumab resistance and reduce systemic toxicity associated with ADCs.
- To investigate the therapeutic efficacy and safety of the novel system in preclinical models.
Main Methods:
- Pre-targeting strategy using functionalized trastuzumab for HER2 receptor labeling.
- Delivery of drug-loaded nanocarriers.
- In situ bioorthogonal click chemistry for nanocluster formation and internalization.
- Evaluation in HER2-positive human breast cancer models.
Main Results:
- Demonstrated high therapeutic efficacy in HER2-positive breast cancer models.
- The novel system showed no significant systemic toxicity.
- Successful pre-targeting and in situ nanocluster formation were achieved.
Conclusions:
- The developed pre-targeting system offers a promising alternative for treating HER2-positive breast cancer, especially in cases of trastuzumab resistance.
- Image-guided administration and reduced toxicity represent significant advantages over standard ADCs.
- This strategy warrants further investigation for clinical translation.
