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Fabrication of thermo-sensitive complex micelles for reversible cell targeting

  • Biomaterials Synthesis and Characterization
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Abstract

To ideally solve the contradiction between enhanced cellular uptake and prolonged blood circulation, reversible targeting polymeric micelles based on the expanding and shrinking behavior of a temperature-responsive polymer were developed. The micelle contained a hydrophobic PCL core and a mixed shell consisting of poly(N-isopropylacrylamide) (PNIPAAm) and biotin-terminated poly(ethylene glycol) (Biotin-PEG), and its targeting ability could be switched on/off by temperature. The cellular uptake of the complex polymeric micelles was studied. The results from a quantitative enzyme-linked immunosorbent assay (ELISA) indicated that the surface biotin content increased by as much as 11.6-fold when the temperature increased above the lower critical solution temperature (LCST). More importantly, the ELISA confirmed that biotin-mediated targeting on the surface was reversibly switched on and off for at least five cycles. In addition, the results from quantitative flow cytometry and confocal spectroscopy indicated that the cellular uptake of the targeted micelles at temperatures above the LCST was much higher than that at temperatures below the LCST. This complex polymeric micelle with reversible targeting property could be a promising alternative for drug delivery.

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References

  1. Maeda H, Bharate GYY, Daruwalla J. Polymeric drugs for efficient tumor-targeted drug delivery based on EPR-effect. Eur J Pharm Biopharm. 2009;71:409–19. doi:10.1016/j.ejpb.2008.11.010.

    Article  Google Scholar 

  2. Kwon IK, Lee SC, Han B, Park K. Analysis on the current status of targeted drug delivery to tumors. J Control Release. 2012;164:108–14. doi:10.1016/j.jconrel.2012.07.010.

    Article  Google Scholar 

  3. Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63:136–51. doi:10.1016/j.addr.2010.04.009.

    Article  Google Scholar 

  4. Manuscript A, Targeting D, Heterogeneity T, Bae YH. Drug targeting and tumor heterogeneity. J Control Release. 2009;133:2–3. doi:10.1016/j.jconrel.2008.09.074.

    Article  Google Scholar 

  5. Chen CC, Borden MA. The role of poly(ethylene glycol) brush architecture in complement activation on targeted microbubble surfaces. Biomaterials. 2011;32:6579–87. doi:10.1016/j.biomaterials.2011.05.027.

    Article  Google Scholar 

  6. McNeeley KM, Karathanasis E, Annapragada AV, Bellamkonda RV. Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors. Biomaterials. 2009;30:3986–95. doi:10.1016/j.biomaterials.2009.04.012.

    Article  Google Scholar 

  7. Gullotti E, Yeo Y. Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm. 2009;6:1041–51. doi:10.1021/mp900090z.

    Article  Google Scholar 

  8. Low PS. The optimal strategy for drug targeting. Mol Pharm. 2007;4:629–30. doi:10.1021/mp700111w.

    Article  Google Scholar 

  9. Fan N-C, Cheng F-Y, Ho JA, Yeh C-S. Photocontrolled targeted drug delivery: photocaged biologically active folic acid as a light-responsive tumor-targeting molecule. Angew Chem Int Ed Engl. 2012;51:8806–10. doi:10.1002/anie.201203339.

    Article  Google Scholar 

  10. Chen Y, Gao D-Y, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2014;. doi:10.1016/j.addr.2014.05.009.

    Google Scholar 

  11. Niu Y, Yu M, Hartono SB, Yang J, Xu H, Zhang H, et al. Nanoparticles mimicking viral surface topography for enhanced cellular delivery. Adv Mater. 2013;25:6232–3. doi:10.1002/adma.201302737.

    Article  Google Scholar 

  12. Yao X, Peng R, Ding J. Cell-material interactions revealed via material techniques of surface patterning. Adv Mater. 2013;25(37):5257–86. doi:10.1002/adma.201301762.

    Article  Google Scholar 

  13. Poon Z, Chen S, Engler AC, Lee HI, Atas E, von Maltzahn G, et al. Ligand-clustered “patchy” nanoparticles for modulated cellular uptake and in vivo tumor targeting. Angew Chemie Int Ed. 2010;49:7266–70. doi:10.1002/anie.201003445.

    Article  Google Scholar 

  14. Ashley CE, Carnes EC, Phillips GK, Padilla D, Durfee PN, Brown PA, et al. The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nat Mater. 2011;10:389–97. doi:10.1038/NMAT2992.

    Article  Google Scholar 

  15. Kim C, Lee Y, Kim JS, Jeong JH, Park TG. Thermally triggered cellular uptake of quantum dots immobilized with poly(N-isopropylacrylamide) and cell penetrating peptide. Langmuir. 2010;26:14965–9. doi:10.1021/la102632m.

    Article  Google Scholar 

  16. Moradi E, Vllasaliu D, Garnett M, Falcone F, Stolnik S. Ligand density and clustering effects on endocytosis of folate modified nanoparticles. RSC Adv. 2012;2:3025. doi:10.1039/c2ra01168a.

    Article  Google Scholar 

  17. Sansone F, Casnati A. Multivalent glycocalixarenes for recognition of biological macromolecules: glycocalyx mimics capable of multitasking. Chem Soc Rev. 2013;42:4623–39. doi:10.1039/c2cs35437c.

    Article  Google Scholar 

  18. Zhang Z, Ali MM, Eckert MA, Kang D-KD-K, Chen YY, Sender LS, et al. A polyvalent aptamer system for targeted drug delivery. Biomaterials. 2013;34:9728–35. doi:10.1016/j.biomaterials.2013.08.079.

    Article  Google Scholar 

  19. Mastrotto F, Caliceti P, Amendola V, Bersani S, Magnusson JP, Meneghetti M, et al. Polymer control of ligand display on gold nanoparticles for multimodal switchable cell targeting. Chem Commun. 2011;47:9846–8. doi:10.1039/c1cc12654g.

    Article  Google Scholar 

  20. Macewan SR, Chilkoti A. Digital switching of local arginine density in a genetically encoded self-assembled polypeptide nanoparticle controls cellular uptake. Nano Lett. 2012;12:3322–8. doi:10.1021/nl301529p.

    Article  Google Scholar 

  21. Lin Q, Bao C, Yang Y, Liang Q, Zhang D, Cheng S, et al. Highly discriminating photorelease of anticancer drugs based on hypoxia activatable phototrigger conjugated chitosan nanoparticles. Adv Mater. 2013;25:1981–6. doi:10.1002/adma.201204455.

    Article  Google Scholar 

  22. Borden MA, Zhang H, Gillies RJ, Dayton PA, Ferrara KW. A stimulus-responsive contrast agent for ultrasound molecular imaging. Biomaterials. 2008;29:597–606. doi:10.1016/j.biomaterials.2007.10.011.

    Article  Google Scholar 

  23. Lee ES, Gao Z, Bae YH, Manuscript A. Recent progress in tumor pH targeting nanotechnology. J Control Release. 2008;132:164–70. doi:10.1016/j.jconrel.2008.05.003.

    Article  Google Scholar 

  24. Sethuraman VA, Bae YH. TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors. J Control Release. 2007;118:216–24. doi:10.1016/j.jconrel.2006.12.008.

    Article  Google Scholar 

  25. Quan C-Y, Chen J-X, Wang H-Y, Li C, Chang C, Zhang X, et al. Core-shell nanosized assemblies mediated by the alpha-beta cyclodextrin dimer with a tumor-triggered targeting property. ACS Nano. 2010;4:4211–9. doi:10.1021/nn100534q.

    Article  Google Scholar 

  26. Gao H, Cheng T, Liu J, Liu J, Yang C, Chu L, et al. Self-regulated multifunctional collaboration of targeted nanocarriers for enhanced tumor therapy. Biomacromolecules. 2014;15:3634–42. doi:10.1021/bm5009348.

    Article  Google Scholar 

  27. Tian Z, Yang C, Wang W, Yuan Z. Shieldable tumor targeting based on pH responsive self-assembly/disassembly of gold nanoparticles. ACS Appl Mater Interfaces. 2014;. doi:10.1021/am5045339.

    Google Scholar 

  28. Mok H, Bae KH, Ahn C-H, Park TG. PEGylated and MMP-2 specifically dePEGylated quantum dots: comparative evaluation of cellular uptake. Langmuir. 2009;25:1645–50. doi:10.1021/la803542v.

    Article  Google Scholar 

  29. Deng C, Jiang Y, Cheng R, Meng F, Zhong Z. Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: promises, progress and prospects. Nano Today. 2012;7:467–80. doi:10.1016/j.nantod.2012.08.005.

    Article  Google Scholar 

  30. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12:991–1003. doi:10.1038/nmat3776.

    Article  Google Scholar 

  31. Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002;43:33–56. doi:10.1016/s1040-8428(01)00179-2.

    Article  Google Scholar 

  32. Mcdaniel JR, Macewan SR, Dewhirst M, Chilkoti A. Doxorubicin-conjugated chimeric polypeptide nanoparticles that respond to mild hyperthermia. J Control Release. 2012;159:362–7. doi:10.1016/j.jconrel.2012.02.030.

    Article  Google Scholar 

  33. McDaniel JR, Dewhirst MW, Chilkoti A. Actively targeting solid tumours with thermoresponsive drug delivery systems that respond to mild hyperthermia. Int J Hyperth. 2013;29:501–10. doi:10.3109/02656736.2013.819999.

    Article  Google Scholar 

  34. Miyata K, Christie RJ, Kataoka K. Polymeric micelles for nano-scale drug delivery. React Funct Polym. 2011;71:227–34. doi:10.1016/j.reactfunctpolym.2010.10.009.

    Article  Google Scholar 

  35. Li C, Ge Z, Fang J, Liu S. Synthesis and self-assembly of coil–rod double hydrophilic diblock copolymer with dually responsive asymmetric centipede-shaped polymer brush as the rod segment. Macromolecules. 2009;42:2916–24. doi:10.1021/ma900165z.

    Article  Google Scholar 

  36. Li W, Li J, Gao J, Li B, Xia Y, Meng Y, et al. The fine-tuning of thermosensitive and degradable polymer micelles for enhancing intracellular uptake and drug release in tumors. Biomaterials. 2011;32:3832–44. doi:10.1016/j.biomaterials.2011.01.075.

    Article  Google Scholar 

  37. Akimoto J, Nakayama M, Sakai K, Okano T. Temperature-induced intracellular uptake of thermoresponsive polymeric micelles. Biomacromolecules. 2009;10:1331–6. doi:10.1021/bm900032r.

    Article  Google Scholar 

  38. Sawant RM, Hurley JP, Salmaso S, Kale A, Tolcheva E, Levchenko TS, et al. “SMART” drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers. Bioconjug. Chem. 2006;17:943–9. doi:10.1021/bc060080h.

    Article  Google Scholar 

  39. Lee F, Chung JE, Kurisawa M. An injectable hyaluronic acid-tyramine hydrogel system for protein delivery. J Control Release. 2009;134:186–93. doi:10.1016/j.jconrel.2008.11.028.

    Article  Google Scholar 

  40. Huang W, Wang W, Wang P, Tian Q, Zhang C, Wang C, et al. Glycyrrhetinic acid-modified poly(ethylene glycol)-b-poly(gamma-benzyl L-glutamate) micelles for liver targeting therapy. Acta Biomater. 2010;6:3927–35. doi:10.1016/j.actbio.2010.04.021.

    Article  Google Scholar 

  41. Ho K, Lapitsky Y, Shi M, Shoichet MS. Tunable immunonanoparticle binding to cancer cells: thermodynamic analysis of targeted drug delivery vehicles. Soft Matter. 2009;5:1074. doi:10.1039/b814204a.

    Article  Google Scholar 

  42. Glavas L, Olsén P, Odelius K, Albertsson AC. Achieving micelle control through core crystallinity. Biomacromolecules. 2013;14:4150–6. doi:10.1021/bm401312j.

    Article  Google Scholar 

  43. Pulkkinen M, Pikkarainen J, Wirth T, Tarvainen T, Haapa-aho V, Korhonen H, et al. Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology: formulation development and in vitro anticancer activity. Eur J Pharm Biopharm. 2008;70:66–74. doi:10.1016/j.ejpb.2008.04.018.

    Article  Google Scholar 

  44. Liu X, Ma R, Shen J, Xu Y, An Y, Shi L. Controlled release of ionic drugs from complex micelles with charged channels. Biomacromolecules. 2012;13:1307–14. doi:10.1021/bm2018382.

    Article  Google Scholar 

  45. Copolymers D, Li G, Shi L, Ma R, An Y, Huang N. Formation of complex micelles with double-responsive channels from self-assembly of two diblock copolymers. Angew Chemie. 2006;118:5081–4. doi:10.1002/ange.200600172.

    Article  Google Scholar 

  46. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001;47:113–31. doi:10.1016/s0169-409x(00)00124-1.

    Article  Google Scholar 

  47. Simnick AJ, Amiram M, Liu W, Hanna G, Dewhirst MW, Kontos CD, et al. In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide. J Control Release. 2011;155:144–51. doi:10.1016/j.jconrel.2011.06.044.

    Article  Google Scholar 

  48. Li G, Guo L, Ma S, Liu J. Complex micelles formed from two diblock copolymers for applications in controlled drug release. J Polym Sci A. 2009;47:1804–10. doi:10.1002/pola.23274.

    Article  Google Scholar 

  49. Gao H, Xiong J, Cheng T, Liu JJ, Chu L, Ma R, et al. In vivo biodistribution of mixed shell micelles with tunable hydrophilic/hydrophobic surface. Biomacromolecules. 2013;14:460–7. doi:10.1021/bm301694t.

    Article  Google Scholar 

  50. Huang Y, Jiang Y, Wang H, Wang J, Shin MC, Byun Y, et al. Curb challenges of the “Trojan Horse” approach: smart strategies in achieving effective yet safe cell-penetrating peptide-based drug delivery. Adv Drug Deliv Rev. 2013;65:1299–315. doi:10.1016/j.addr.2012.11.007.

    Article  Google Scholar 

  51. Taghdisi SM, Lavaee P, Ramezani M, Abnous K. Reversible Targeting and controlled release delivery of daunorubicin to cancer cells by aptamer-wrapped carbon nanotubes. Eur J Pharm Biopharm. 2011;77:200–6. doi:10.1016/j.ejpb.2010.12.005.

    Article  Google Scholar 

  52. Yellepeddi VK, Kumar A, Palakurthi S. Biotinylated poly(amido)amine (PAMAM) dendrimers as carriers for drug delivery to ovarian cancer cells in vitro. Anticancer Res 2009;29:2933–2943. http://www.ncbi.nlm.nih.gov/pubmed/19661298. Accessed 18 Apr 2014.

  53. Yang W, Cheng Y, Xu T, Wang X, Wen L-P. Targeting cancer cells with biotin-dendrimer conjugates. Eur J Med Chem. 2009;44:862–8. doi:10.1016/j.ejmech.2008.04.021.

    Article  Google Scholar 

  54. Quan C-Y, Wu D-Q, Chang C, Zhang G, Cheng S, Zhang X, et al. Synthesis of thermo-sensitive micellar aggregates self-assembled from biotinylated PNAS- b -PNIPAAm- b -PCL triblock copolymers for tumor targeting. J Phys Chem C. 2009;113:11262–7. doi:10.1021/jp902637n.

    Article  Google Scholar 

  55. Cheng C, Wei H, Shi B-X, Cheng H, Li C, Gu Z-W, et al. Biotinylated thermoresponsive micelle self-assembled from double-hydrophilic block copolymer for drug delivery and tumor target. Biomaterials. 2008;29:497–505. doi:10.1016/j.biomaterials.2007.10.004.

    Article  Google Scholar 

  56. Cheng C, Wei H, Zhang X-Z, Cheng S-X, Zhuo R-X. Thermo-triggered and biotinylated biotin-P(NIPAAm-co-HMAAm)-b-PMMA micelles for controlled drug release. J Biomed Mater Res A. 2009;88:814–22. doi:10.1002/jbm.a.31770.

    Article  Google Scholar 

  57. Salmaso S, Caliceti P, Amendola V, Meneghetti M, Magnusson JP, Pasparakis G, et al. Cell up-take control of gold nanoparticles functionalized with a thermoresponsive polymer. J Mater Chem. 2009;19:1608. doi:10.1039/b816603j.

    Article  Google Scholar 

  58. Abulateefeh SR, Spain SG, Thurecht KJ, Aylott JW, Chan WC, Garnett MC, et al. Enhanced uptake of nanoparticle drug carriers via a thermoresponsive shell enhances cytotoxicity in a cancer cell line. Biomater Sci. 2013;1:434. doi:10.1039/c2bm00184e.

    Article  Google Scholar 

  59. Meyer DE, Shin BC, Kong GA, Dewhirst MW, Chilkoti A. Drug targeting using thermally responsive polymers and local hyperthermia. J Control Release. 2001;74:213–24. doi:10.1016/S0168-3659(01)00319-4.

    Article  Google Scholar 

  60. Wu C, Han D, Chen T, Peng L, Zhu G, You M, et al. Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy. J Am Chem Soc. 2013;. doi:10.1021/ja4094617.

    Google Scholar 

  61. Tian Q, Zhang C-N, Wang X-H, Wang W, Huang W, Cha R-T, et al. chitosan/poly(ethylene glycol) nanoparticles for liver-targeted delivery. Biomaterials. 2010;31:4748–56. doi:10.1016/j.biomaterials.2010.02.042.

    Article  Google Scholar 

  62. Zhang C, Wang W, Liu T, Wu Y, Guo H, Wang P, et al. Doxorubicin-loaded glycyrrhetinic acid-modified alginate nanoparticles for liver tumor chemotherapy. Biomaterials. 2012;33:2187–96. doi:10.1016/j.biomaterials.2011.11.045.

    Article  Google Scholar 

  63. Macewan SR, Chilkoti A. Controlled apoptosis by a thermally toggled nanoscale amplifier of cellular uptake. Nano Lett. 2014;14:2058–64. doi:10.1021/nl5002313.

    Article  Google Scholar 

  64. McDaniel JR, MacEwan SR, Li X, Radford DC, Landon CD, Dewhirst M, et al. Rational design of “heat seeking” drug loaded polypeptide nanoparticles that thermally target solid tumors. Nano Lett. 2014;14:2890–5. doi:10.1021/nl5009376.

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (51433004), Natural Science Foundation of Tianjin (13JCYBJC25100), and PCSIRT (IRT1257). We thank Prof. Deling Kong, Nankai University, for his help with the whole cell experiments.

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Correspondence to Zhi Yuan.

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Wu, Y., Yang, C., Lai, Q. et al. Fabrication of thermo-sensitive complex micelles for reversible cell targeting. J Mater Sci: Mater Med 26, 255 (2015). https://doi.org/10.1007/s10856-015-5584-2

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