Introduction: Genetic materials offer an exciting potential as anti-cancer therapeutics[1]. Yet, this potential has not been realized in the clinic. One of the most challenging barriers to clinical translation is the tremendous heterogeneity of tumor lesions. Although many biomaterial platforms have been developed for systemic delivery of therapeutic genes, most platforms fail to deliver consistent in vivo performance. A large part of the in vivo inconsistency is contributed by inter-tumor variability that leads to unpredictable biological response to therapy[2],[3]. Thus, success of cancer gene therapies would ultimately depend on the ability to monitor therapeutic response. Development of theranostic platforms that could not only mediate gene delivery but also assist in early identification of therapy responders via imaging is of utmost significance in this context. We have developed an ultrasound-visible gene microplatform (MagMB) that enhances gene delivery under magneto-acoustic actuation[4]. Here we assess the plausibility of leveraging this microplatform for concurrent in vivo gene therapy and ultrasonographic assessment of response to therapy.
Materials and Methods: The micro-platform comprised of microbubbles and magnetic nanoparticles (MagMB). The feasibility of the in vivo magneto-acoustic gene therapy and image monitoring of therapeutic response was tested in tumor-harboring Balb/c mice using a cytokine-encoding gene as a model drug. The echogenicity of the micro-platform and its’ plausibility for non-invasive monitoring of tumor response to therapy was explored using B-mode ultrasound imaging. Following intravenous administration of the micro-platform, the tumor was monitored with ultrasonography and then subjected to magneto-acoustic induction of gene transfer. Image sets were acquired before, during and sequentially after therapy. The fractional area of contrast enhancement (FACE) was estimated within the tumor region of interest[5]. Treatment-induced change in FACE (dFACE) was calculated to assess response to therapy.
Results and Discussion: Micro-platform characterization revealed high echogenicity in addition to strong magnetic and acoustic responsiveness. In vivo, intravenous administration of 107 MagMB enhanced the renal artery signal by a 12.3 dB on the B-mode ultrasound scans. This high echogenicity suggested suitability of the micro-platform for non-invasive monitoring of tumor perfusion as a surrogate measure of response to therapy. Magneto-acoustic tumor delivery of therapeutic cytokine-encoding genes resulted in a 40% extension of the animal median survival as compared to magnetic, acoustic or non-modulated gene delivery controls. Within the magneto-acoustically targeted group, 70% of mice responded to gene therapy exhibiting extended survival times while other 30% did not respond to therapy. Interestingly, as early as day 7 post-treatment the image-derived mean dFACE of the therapy-responding subgroup was found to be significantly lower than that of the non-treated controls (p<0.01), indicating marked reduction in perfusion in response to therapy. In contrast, no significant difference in dFACE values was found between the non-responding treated subgroup and the non-treated controls (p=0.45). Therefore, dFACE mapping via echogenic multifunctional MagMB provides a gateway for early identification of gene therapy responders.
Conclusions: Results presented reveal that the magneto-acoustic gene platform MagMB allowed concurrent gene therapy and early assessment of response to therapy. This versatile micro-platform, thereby, offers a far-reaching potential to harness the value of genetic therapeutics for combating cancer.
References:
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[4] Chertok, B., Langer, B. & Anderson, D.G. Microplatform for Magneto-Ultrasonic, Spatially-selective Enhancement of Systemic Gene Delivery. In submission.
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