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Preservation of Anticancer and Immunosuppressive Properties of Rapamycin Achieved Through Controlled Releasing Particles

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Abstract

Rapamycin is commonly used in chemotherapy and posttransplantation rejection suppression, where sustained release is preferred. Conventionally, rapamycin has to be administered in excess due to its poor solubility, and this often leads to cytotoxicity and undesirable side effects. In addition, rapamycin has been shown to be hydrolytically unstable, losing its bioactivity within a few hours. The use of drug delivery systems is hypothesized to preserve the bioactivity of rapamycin, while providing controlled release of this otherwise potent drug. This paper reports on the use of microparticles (MP) as a means to tune and sustain the delivery of bioactive rapamycin for up to 30 days. Rapamycin was encapsulated (100% efficiency) in poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or a mixture of both via an emulsion method. The use of different polymer types and mixture was shown to achieve a variety of release kinetics and profile. Released rapamycin was subsequently evaluated against breast cancer cell (MCF-7) and human lymphocyte cell (Jurkat). Inhibition of cell proliferation was in good agreement with in vitro release profiles, which confirmed the intact bioactivity of rapamycin. For Jurkat cells, the suppression of cell growth was proven to be effective up to 20 days, a duration significantly longer than free rapamycin. Taken together, these results demonstrate the ability to tune, sustain, and preserve the bioactivity of rapamycin using MP formulations. The sustained delivery of rapamycin could lead to better therapeutic effects than bolus dosage, at the same time improving patient compliance due to its long-acting duration.

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Acknowledgments

The authors would like to acknowledge the financial support from the Singapore Centre on Environmental Life Sciences Engineering (SCELSE) (M4330001.C70.703012), the School of Materials Science and Engineering (M020070110), the NTU-National Healthcare Group (NTU-NHG) grant (ARG/14012), Lee Kong Chian School of Medicine Postdoctoral Fellowship support for Han Wei Hou and the Lee Kong Chian School of Medicine, Nanyang Technological University start-up grant for Per-Olof Berggren.

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Authors and Affiliations

  1. Nanyang Institute of Technology in Health & Medicine, Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore

    Yan Liang Fan

  2. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    Han Wei Hou, Hui Min Tay & Per-Olof Berggren

  3. The Agency for Science, Technology and Research, Biotransformation Innovation Platform, Singapore, Singapore

    Wei Mei Guo

  4. School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore, 639798, Singapore

    Yan Liang Fan & Say Chye Joachim Loo

  5. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden

    Per-Olof Berggren

  6. Singapore Centre for Environmental Life Sciences Engineering, Singapore, Singapore

    Say Chye Joachim Loo

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  1. Yan Liang Fan
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  2. Han Wei Hou
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  3. Hui Min Tay
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  6. Say Chye Joachim Loo
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Correspondence to Say Chye Joachim Loo.

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Fan, Y.L., Hou, H.W., Tay, H.M. et al. Preservation of Anticancer and Immunosuppressive Properties of Rapamycin Achieved Through Controlled Releasing Particles. AAPS PharmSciTech 18, 2648–2657 (2017). https://doi.org/10.1208/s12249-017-0745-x

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