Circumventing Therapeutic Resistance and the Emergence of Disseminated Breast Cancer Cells Through Non-Invasive Optical Imaging.

摘要

Herein we explore a series of optically distinct near infrared emissive polymersomes (NIREPs; biodegradable polymer vesicles that manifest extraordinarily high irradiances and are ideally suited for in vivo optical imaging), each conjugated to different antibodies for the non-invasive molecular imaging of all breast cancer sites within a patient, including micrometastases. In Year 1, we have taken significant steps to optimize NIREP fabrication protocols to ensure immunoreactive antibodies can be reproducibly conjugated to the surface of NIREPs. We have designed and synthesized the most extensive family of PEO-b- PCL copolymers that vary over the largest range of number-average molecular weights (Mn: 3.6 - 57K), PEO weight fractions (fPEO: 0.08 - 0.33), and PEO chain lengths (0.75 5.8K) reported to date. With these, we have demonstrated using comparative morphology diagrams, that a multiplicity of PEO-b-PCL diblock copolymer compositions are able to give rise to nanoscale vesicles. The broad range of polymersome-forming PEO-b-PCL compositions suggest the ability to construct extensive families of nanoscale vesicles of varied bilayer thickness, providing the ability to tune the timescales of vesicle degradation in vivo. Lastly, we have established four pairs of parental and isogenic matched tamoxifen (tam)-resistant cell lines (MCF7, T47D, MDA-MB-361 and HCC1428), and characterized the changes in cell surface protein expression that occurs with onset of resistance. We have found that members of the HER receptor family (EGFR/HER1; HER2; HER3) are upregulated with the development of tam-resistance; furthermore, differences in receptor expression between ER+ cell lines have been characterized. These reagents are critical for evaluation of the selectivity of a panel of antibody-conjugated NIREPs.