Melbourne Medical School Collected Works - Research Publications
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ItemNanobiotechnology approaches for cardiovascular diseases: site-specific targeting of drugs and nanoparticles for atherothrombosis(BMC, 2022-02-08)Atherosclerosis and atherothrombosis, the major contributors to cardiovascular diseases (CVDs), represent the leading cause of death worldwide. Current pharmacological therapies have been associated with side effects or are insufficient at halting atherosclerotic progression effectively. Pioneering work harnessing the passive diffusion or endocytosis properties of nanoparticles and advanced biotechnologies in creating recombinant proteins for site-specific delivery have been utilized to overcome these limitations. Since CVDs are complex diseases, the most challenging aspect of developing site-specific therapies is the identification of an individual and unique antigenic epitope that is only expressed in lesions or diseased areas. This review focuses on the pathological mechanism of atherothrombosis and discusses the unique targets that are important during disease progression. We review recent advances in site-specific therapy using novel targeted drug-delivery and nanoparticle-carrier systems. Furthermore, we explore the limitations and future perspectives of site-specific therapy for CVDs.
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ItemActivated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases(IVYSPRING INT PUBL, 2019-01-01)Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results: In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.