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Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection

  • 2021 CMBE Young Innovators
  • Published:
Cellular and Molecular Bioengineering Aims and scope Submit manuscript

Abstract

Introduction

A major challenge in cancer medicine is the safe and effective delivery of drugs to the right tissue at the right time. Despite being designed for greater target specificity, many drugs still result in side effects and lack of safety in patients following global dissemination. Therefore, to develop new, more effective formulations capable of improving specificity and reducing off-target effects, here we describe formulation of drug crystals, from even a very hydrophobic and otherwise difficult to solubilize small molecule chemical compound, capable of providing constant drug release for weeks following a single injection.

Methods

We chose to utilize the multi-tyrosine kinase inhibitor and multi-modal (anti-angiogenic and tumor cell cytotoxic) agent sorafenib, to combat aberrant angiogenesis and tumor growth which contribute to metastasis, ultimately responsible for poor patient outcomes. We tuned crystal size (surface area:volume ratios), imaged by SEM, to display controllability of drug delivery kinetics in in vitro drug release assays.

Results

Single and powder crystal X-ray diffraction (XRD) established that all crystals were the same polymorph and drug form. When utilized against an orthotopic triple negative breast cancer (TNBC) mouse model (4T1 in syngeneic BALB/c mice), we established anti-tumor activity from a single local, subcutaneous injection of crystalline sorafenib.

Conclusion

From our findings, we support that engineering crystalline drug delivery systems has implications in the treatment of cancer or other diseases where high enough constitutive drug levels are needed to maintain target saturation and inhibition while also preventing emergence of drug resistance, which is a consequence often seen with suboptimal dosing.

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Acknowledgments

This work was supported by the Biomedical Engineering Department at Johns Hopkins University. S.Y.N. and A.R. were both supported by GRFP fellowships from the National Science Foundation. The authors would like to acknowledge the use of resources at Johns Hopkins University School of Medicine Core Facilities for Microscopy, SEM, Histology, and Whole Animal Imaging.

Author Contributions

V.L., S.Y.N., A.R., and J.C.D. designed experiments, analyzed data, and wrote the manuscript. V.L., S.Y.N., A.R., J.P., J.S., S.L., A.S., and J.C.D. performed experiments. V.L., S.Y.N., A.R., J.S., and J.C.D. performed statistical analyses of data sets and aided in the preparation of displays communicating data sets. J.C.D. supervised the study. All authors discussed the results and assisted in the preparation of the manuscript.

Conflict of interest

All authors (Victoria Lai, Sarah Y. Neshat, Amanda Rakoski, James Pitingolo, Johndavid Sabedra, Stephen Li, Aryaman Shodhan, and Joshua C. Doloff) declare they have no conflict of interest.

Ethical Approval

There were no human studies carried out by the authors for this article. For all animal studies, they were carried out in accordance with IACUC-approved protocols at the Johns Hopkins University.

Author information

Author notes

  1. Victoria Lai and Sarah Y. Neshat share co-first authorship.

Authors and Affiliations

  1. Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute/Smith Bldg., Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA

    Victoria Lai, Sarah Y. Neshat, Amanda Rakoski, James Pitingolo, Stephen Li, Aryaman Shodhan & Joshua C. Doloff

  2. Department of Materials Science and Engineering, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD, 21218, USA

    Johndavid Sabedra & Joshua C. Doloff

  3. Institute of NanoBioTechnology, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD, 21218, USA

    Joshua C. Doloff

  4. Department of Oncology, Division of Cancer Immunology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 N. Broadway, Baltimore, MD, 21231, USA

    Joshua C. Doloff

  5. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Joshua C. Doloff

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Corresponding author

Correspondence to Joshua C. Doloff.

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Associate Editor Michael R. King oversaw the review of this article.

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This article is part of the 2021 CMBE Young Innovators special issue.

Joshua C. Doloff is a new Assistant Professor in Biomedical Engineering, Materials Science, and Oncology (Cancer Immunology) at Johns Hopkins University. At the Translational Tissue Engineering Center, his lab focuses on Immunoengineering and Regenerative Medicine, with emphasis on cancer, autoimmunity, and implant/transplantation. Josh earned his undergraduate Bioengineering degree at the University of Pennsylvania, where he carried out biomaterials and tissue engineering research in the Ducheyne Lab. Later, to better understand what happens when deliverables are introduced into the body, Joshua focused his PhD in the Waxman Lab at Boston University on host immune responses to varied therapeutics. Early work on cancer-targeted viral vectors won technology development and University Provost awards. Later work produced insights into chemotherapy-induced anti-tumor immunity. Highlighting his achievements, Joshua was awarded the Frank A. Belamarich Award for Best Doctoral Research in his graduating class. Josh went on to become a Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellow in the Langer and Anderson labs at the Koch Institute at MIT. There, his work on deciphering immune-mediated biomaterial and biomedical device implant rejection contributed to numerous top publications, patents, a lab startup—Sigilon, and awards—including top presentation selections, Immunoengineering prizes, co-chair honors, and a Rising Star Alumni Award.

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Lai, V., Neshat, S.Y., Rakoski, A. et al. Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection. Cel. Mol. Bioeng. 14, 471–486 (2021). https://doi.org/10.1007/s12195-021-00708-6

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