Association of anti-HER2 antibody with graphene oxide for curative treatment of osteosarcoma
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Published on: June 13, 2014
Lan Li1, Chengke Luo2, Zhenwei Song3
1Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China; University of Utah, Department of Pathology and ARUP Laboratories, Salt Lake City, UT, USA.
Abstract:
The finding of HER2 overexpression in osteosarcoma (OS) makes HER2 a potential therapeutic target. However, studies indicate OS cells are nonresponsive to anti-HER2 antibody trastuzumab (TRA) therapy. We established stable, non-covalent association of TRA with nanomaterial graphene oxide (GO) to generated multivalent TRA/GO complexes that demonstrated markedly enhanced HER2-binding activity and capacity to rapidly kill OS cells. TRA/GO simultaneously induced oxidative stress and HER2 signaling in the target cells, leading to rapid depletion of the cellular inhibitors of apoptosis protein (cIAP) and caspase-8, formation of RIP1/RIPK3/MLKL necroptosome and necroptosis of the OS cells. Intravenous administration of TRA/GO eradicated established xenograft the OS in immunodeficient mice, resulting in indefinite survival of the animals, whereas TRA in its original form failed to do so. No appreciable side effects were observed with TRA/GO therapy. The results demonstrate a novel, nontoxic, curative therapy for a HER2pos cancer in a preclinical animal model.
Insights
Graphene oxide enhanced trastuzumab therapy for HER2-positive osteosarcoma. This novel TRA/GO complex effectively kills cancer cells and eradicates tumors in mice, offering a potential new treatment.
Area of Science:
- Oncology
- Nanomedicine
- Biotechnology
Background:
- HER2 overexpression presents a therapeutic target in osteosarcoma (OS).
- Standard anti-HER2 antibody trastuzumab (TRA) shows limited efficacy in OS.
- Need for enhanced delivery and efficacy of HER2-targeted therapies in OS.
Purpose of the Study:
- To develop a novel therapeutic complex for HER2-positive osteosarcoma.
- To enhance the anti-cancer activity of trastuzumab using graphene oxide.
- To evaluate the efficacy and safety of the TRA/GO complex in preclinical models.
Main Methods:
- Stable non-covalent association of trastuzumab (TRA) with graphene oxide (GO) to form multivalent TRA/GO complexes.
- In vitro assessment of HER2-binding activity and cancer cell killing capacity.
- In vivo evaluation of TRA/GO efficacy in established xenograft osteosarcoma mouse models.
Main Results:
- TRA/GO complexes exhibited significantly enhanced HER2-binding and rapid OS cell killing.
- TRA/GO induced oxidative stress, necroptosis, and apoptosis in cancer cells.
- Intravenous administration of TRA/GO eradicated tumors and led to indefinite survival in mice, unlike TRA alone.
Conclusions:
- Multivalent TRA/GO complexes represent a potent and effective therapeutic strategy for HER2-positive osteosarcoma.
- This novel nanomedicine approach overcomes resistance to conventional trastuzumab therapy.
- TRA/GO demonstrates a promising, nontoxic, and curative potential for osteosarcoma in preclinical settings.
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