Oligo(Lactic Acid)8-Rapamycin Prodrug-Loaded Poly(Ethylene Glycol)-block-Poly(Lactic Acid) Micelles for Injection

  • Yu Tong Tam
  • Lauren Repp
  • Zhi-Xiong Ma
  • John B. Feltenberger
  • Glen S. KwonEmail author
Research Paper
Part of the following topical collections:
  1. Nanomedicines in Cancer



To prepare an oligo(lactic acid)8-rapamycin prodrug (o(LA)8-RAP)-loaded poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelle for injection and characterize its compatibility and performance versus a RAP-loaded PEG-b-PLA micelle for injection in vitro and in vivo.


Monodisperse o(LA)8 was coupled on RAP at the C-40 via DCC/DMAP chemistry, and conversion of o(LA)8-RAP prodrug into RAP was characterized in vitro. Physicochemical properties of o(LA)8-RAP- and RAP-loaded PEG-b-PLA micelles and their antitumor efficacies in a syngeneic 4 T1 breast tumor model were compared.


Synthesis of o(LA)8-RAP prodrug was confirmed by 1H NMR and mass spectroscopy. The o(LA)8-RAP prodrug underwent conversion in PBS and rat plasma by backbiting and esterase-mediated cleavage, respectively. O(LA)8-RAP-loaded PEG-b-PLA micelles increased water solubility of RAP equivalent to 3.3 mg/ml with no signs of precipitation. Further, o(LA)8-RAP was released more slowly than RAP from PEG-b-PLA micelles. With added physical stability, o(LA)8-RAP-loaded PEG-b-PLA micelles significantly inhibited tumor growth relative to RAP-loaded PEG-b-PLA micelles in 4 T1 breast tumor-bearing mice without signs of acute toxicity.


An o(LA)8-RAP-loaded PEG-b-PLA micelle for injection is more stable than a RAP-loaded PEG-b-PLA micelle for injection, and o(LA)8-RAP converts into RAP rapidly in rat plasma (t1/2 = 1 h), resulting in antitumor efficacy in a syngeneic 4 T1 breast tumor model.


block copolymer mTOR oligo(lactic acid) polymeric micelle prodrug sirolimus 







Methylene chloride






Ethyl acetate


Hydrogen fluoride/pyridine


Mammalian target of rapamycin


Sodium sulphate


Sodium bicarbonate


Oligo(lactic acid)n


Oligo(lactic acid)n-rapamycin


Phosphate buffered saline


Palladium on carbon


Poly(ethylene glycol)-block-poly(lactic acid)






Triethylsilyl ether




Thin layer chromatography


Supplementary material

11095_2019_2600_MOESM1_ESM.docx (566 kb)
ESM 1 (DOCX 565 kb)


  1. 1.
    Zoncu R, Efeyan A, Sabatini DM. MTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.PubMedCrossRefGoogle Scholar
  2. 2.
    Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol. 2010;7:209–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Zheng Y, Jiang Y. mTOR inhibitors at a glance. Mol Cell Pharmacol. 2015;7(2):15–20.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Lin T, Leung C, Nguyen K, Figlin RA. Mammalian target of rapamycin (mTOR) inhibitors in solid tumours. Cinical Pharm. 2016;8(3):1–23.Google Scholar
  5. 5.
    Forrest ML, Won CY, Malick AW, Kwon GS. In vitro release of the mTOR inhibitor rapamycin from poly(ethylene glycol)-b-poly(ε-caprolactone) micelles. J Control Release. 2006;110(2):370–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Yatscoff RW, Wang P, Chan K, Hicks D, Zimmerman J. Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations. Ther Drug Monit. 1995;17:666–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82(4):381–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Rini BI. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res. 2008;14(5):1286–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Iacovelli R, Santoni M, Verzoni E, Grassi P, Testa I, De Braud F, et al. Everolimus and temsirolimus are not the same second-line in metastatic renal cell carcinoma. A systematic review and meta-analysis of literature data. Clin Genitourin Cancer. 2015;13(2):137–41.PubMedCrossRefGoogle Scholar
  10. 10.
    Soefje SA, Karnad A, Brenner AJ. Common toxicities of mammalian target of rapamycin inhibitors. Target Oncol. 2011;6(2):125–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004;22(12):2336–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Yáñez JA, Forrest ML, Ohgami Y, Kwon GS, Davies NM. Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(ε- caprolactone) micelles of rapamycin. Cancer Chemother Pharmacol. 2008;61(1):133–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Xu W, Ling P, Zhang T. Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv. 2013;2013:1–15.CrossRefGoogle Scholar
  14. 14.
    Houdaihed L, Evans JC, Allen C. Overcoming the road blocks: advancement of block copolymer micelles for cancer therapy in the clinic. Mol Pharm. 2017;14(8):2503–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Shin DH, Tam YT, Kwon GS. Polymeric micelle nanocarriers in cancer research. Front Chem Sci Eng. 2016;10(3):348–59.CrossRefGoogle Scholar
  16. 16.
    Cho H, Gao J, Kwon GS. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol–gels for drug delivery. J Control Release. 2016;240:191–201.PubMedCrossRefGoogle Scholar
  17. 17.
    Chandler D. Interfaces and the driving force of hydrophobic assembly. Nature. 2005;437(7059):640–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Riley T, Stolnik S, Heald CR, Xiong CD, Garnett MC, Illum L, et al. Physicochemical evaluation of nanoparticles assembled from poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) block copolymers as drug delivery vehicles. Langmuir. 2001;17(11):3168–74.CrossRefGoogle Scholar
  19. 19.
    Owen SC, Chan DPY, Shoichet MS. Polymeric micelle stability. Nano Today. 2012;7(1):53–65.CrossRefGoogle Scholar
  20. 20.
    Cabral H, Miyata K, Osada K, Kataoka K. Block copolymer micelles in nanomedicine applications. Chem Rev. 2018;118(14):6844–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Tam YT, Gao J, Kwon GS. Oligo(lactic acid)n-paclitaxel prodrugs for poly(ethylene glycol)-block-poly(lactic acid) micelles: loading, release, and backbiting conversion for anticancer activity. J Am Chem Soc. 2016;138(28):8674–7.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Tam YT, Huang C, Poellmann M, Kwon GS. Stereocomplex prodrugs of oligo(lactic acid)n-gemcitabine in poly(ethylene glycol)- block-poly(d, l -lactic acid) micelles for improved physical stability and enhanced antitumor efficacy. ACS Nano. 2018;12(7):7406–14.PubMedCrossRefGoogle Scholar
  23. 23.
    De Jong SJ, Van Dijk-Wolthuis WNE, Kettenes-Van Den Bosch JJ, PJW S, Hennink WE. Monodisperse enantiomeric lactic acid oligomers: preparation, characterization, and stereocomplex formation. Macromolecules. 1998;31(19):6397–402.CrossRefGoogle Scholar
  24. 24.
    Takizawa K, Nulwala H, Hu J, Yoshinaga K, Hawker CJ. Molecularly defined (L)-lactic acid oligomers and polymers: synthesis and characterization. J Poly Sci. 2008;46:5977–90.CrossRefGoogle Scholar
  25. 25.
    Kaihara S, Matsumura S, Mikos AG, Fisher JP. Synthesis of poly(L-lactide) and polyglycolide by ring-opening polymerization. Nat Protoc. 2007;2(11):2667–71.CrossRefGoogle Scholar
  26. 26.
    Van Nostrum CF, Veldhuis TFJ, Bos GW, Hennink WE. Hydrolytic degradation of oligo(lactic acid): a kinetic and mechanistic study. Polymer. 2004;45(20):6779–87.CrossRefGoogle Scholar
  27. 27.
    Wang H, Zheng X, Cai Z, Yu O, Zheng S, Zhu T. Synthesis and evaluation of an injectable everolimus prodrug. Bioorganic Med Chem Lett. 2017;27(5):1175–8.CrossRefGoogle Scholar
  28. 28.
    Tai W, Chen Z, Barve A, Peng Z, Cheng K. A novel rapamycin-polymer conjugate based on a new poly(ethylene glycol) multiblock copolymer. Pharm Res. 2014;31(3):706–19.PubMedCrossRefGoogle Scholar
  29. 29.
    Woo HN, Chung HK, Ju EJ, Jung J, Kang H-W, Lee S-W, et al. Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy. Int J Nanomedicine. 2012;7:2197–208.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Meng LH, Zheng XS. Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin. 2015;36(10):1163–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Liederer BM, Borchardt RT. Enzymes involved in the bioconversion of ester-based prodrugs. J Pharm Sci. 2006;95(6):1177–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Tam YT, Shin DH, Chen KE, Kwon GS. Poly(ethylene glycol)-block-poly(D,L-lactic acid) micelles containing oligo (lactic acid)8-paclitaxel prodrug: in vivo conversion and antitumor efficacy. J Control Release. 2019;298:186–93.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pharmaceutical Sciences DivisionUniversity of Wisconsin-MadisonMadisonUSA
  2. 2.Discovery Pharmaceutical Sciences Merck Research LaboratoriesCaliforniaUSA
  3. 3.Medicinal Chemistry Center, School of PharmacyUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations