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Photo-Inducible Crosslinked Nanoassemblies for pH-Controlled Drug Release

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Abstract

Purpose

To control drug release from block copolymer nanoassemblies by variation in the degree of photo-crosslinking and inclusion of acid sensitive linkers.

Methods

Poly(ethylene glycol)-poly(aspartate-hydrazide-cinnamate) (PEG-CNM) block copolymers were prepared and conjugated with a model drug, doxorubicin (DOX), through acid sensitive hydrazone linkers. The block copolymers formed photo-inducible, self-assembled nanoassemblies (piSNAs), which were used to produce photo-inducible crosslinked nanoassemblies (piCNAs) through UV crosslinking. The nanoassemblies were characterized to determine particle size, surface charge, pH- and crosslinking-dependent DOX release, in vitro cytotoxicity, and intracellular uptake as a function of photo-crosslinking degree.

Results

Nanoassemblies with varying photo-crosslinking degrees were successfully prepared while retaining particle size and surface charge. Photo-crosslinking caused no noticeable change in DOX release from the nanoassemblies at pH 7.4, but the DOX-loaded nanoassemblies modulated drug release as a function of crosslinking at pH 6.0. The nanoassemblies showed similar cytotoxicity regardless of crosslinking degrees, presumably due to the low cellular uptake and cell nucleus drug accumulation.

Conclusions

Photo-crosslinking is useful to control drug release from pH-sensitive block copolymer nanoassemblies as a function of crosslinking without altering the particle properties, and thus providing unique tools to investigate the pharmaceutical effects of drug release on cellular response.

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References

  1. Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6:714–27.

    Article  CAS  PubMed  Google Scholar 

  2. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathways for cancer drug discovery. Cancer Rev Drug Discov. 2005;4:988–1004.

    Article  CAS  Google Scholar 

  3. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7:573–84.

    Article  CAS  PubMed  Google Scholar 

  4. Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002;1:287–99.

    Article  CAS  PubMed  Google Scholar 

  5. Kawabata-Shoda E, Masuda S, Kimura H. Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan. J Clin Pharm Ther. 2012;37(5):547–52.

    Article  CAS  PubMed  Google Scholar 

  6. Atkins JH, Gershell LJ. Selective anticancer drugs. Nat Rev Drug Discov. 2002;1(7):491–2.

    Article  CAS  PubMed  Google Scholar 

  7. Wood AJJ. Side effects of adjuvant treatment of breast cancer. New Engl J Med. 2001;344:1997–2008.

    Article  Google Scholar 

  8. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108:153–64.

    Article  CAS  PubMed  Google Scholar 

  9. Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev. 2012;64:24–36.

    Article  Google Scholar 

  10. Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2012;64(Supplement):206–12.

    Article  Google Scholar 

  11. Peer D, Karp JM, Hong S, Farokhazad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol. 2007;2:751–60.

    Article  CAS  PubMed  Google Scholar 

  12. Davis ME, Chen Z, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7:771–82.

    Article  CAS  PubMed  Google Scholar 

  13. Maeda H, Matsumura Y. EPR effect based drug design and clinical outlook for enhanced cancer chemotherapy. Adv Drug Deliv Rev. 2011;63(3):129–30.

    Article  CAS  PubMed  Google Scholar 

  14. Maeda H. Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. Bioconjug Chem. 2010;21(5):797–802.

    Article  CAS  PubMed  Google Scholar 

  15. Mahon E, Salvati A, Baldelli Bombelli F, Lynch I, Dawson KA. Designing the nanoparticle-biomolecule interface for “targeting and therapeutic delivery”. J Control Release. 2012;161(2):164–74.

    Article  CAS  PubMed  Google Scholar 

  16. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov. 2010;9(8):615–27.

    Article  CAS  PubMed  Google Scholar 

  17. Bourzac K. Nanotechnology: carrying drugs. Nature. 2012;491(7425):S58–60.

    Article  PubMed  Google Scholar 

  18. Yokoyama M. Polymeric micelles as a new drug carrier system and their required considerations for clinical trials. Expert Opin Drug Del. 2010;7(2):145–58.

    Article  CAS  Google Scholar 

  19. Oerlemans C, Bult W, Bos M, Storm G, Nijsen JF, Hennink WE. Polymeric micelles in anticancer therapy: targeting, imaging and triggered release. Pharm Res. 2010;27(12):2569–89.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Vicent MJ, Ringsdorf H, Duncan R. Polymer therapeutics: clinical applications and challenges for development. Adv Drug Deliv Rev. 2009;61(13):1117–20.

    Article  CAS  PubMed  Google Scholar 

  21. Matsumura Y, Kataoka K. Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer Sci. 2009;100(4):572–9.

    Article  CAS  PubMed  Google Scholar 

  22. Perrault SD, Walkey C, Jennings T, Fischer HC, Chan WCW. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 2009;9:1909–15.

    Article  CAS  PubMed  Google Scholar 

  23. Albanese A, Tang PS, Chan WCW. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng. 2012;14:1–16.

    Article  CAS  PubMed  Google Scholar 

  24. He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657–66.

    Article  CAS  PubMed  Google Scholar 

  25. Ruenraroengsak P, Cook JM, Florence AT. Nanosystem drug targeting: facing up to complex realities. J Control Release. 2010;141(3):265–76.

    Article  CAS  PubMed  Google Scholar 

  26. Kell DB, Dobson PD, Oliver SG. Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Discov Today. 2011;16(15–16):704–14.

    Article  CAS  PubMed  Google Scholar 

  27. Anraku Y, Kishimura A, Kobayashi A, Oba M, Kataoka K. Size-controlled long-circulating PICsome as a ruler to measure critical cut-off disposition size into normal and tumor tissues. Chem Commun. 2011;47(21):6054–6.

    Article  CAS  Google Scholar 

  28. Stella VJ. Prodrugs: some thoughts and current issues. J Pharm Sci. 2010;99(12):4755–65.

    Article  CAS  PubMed  Google Scholar 

  29. Lee HJ, Bae Y. Pharmaceutical differences between block copolymer self-assembled and cross-linked nanoassemblies as carriers for tunable drug release. Pharm Res. 2013;30(2):478–88.

    Article  CAS  PubMed  Google Scholar 

  30. Lee HJ, Ponta A, Bae Y. Polymer nanoassemblies for cancer treatment and imaging. Ther Deliv. 2010;1(6):803–17.

    Article  CAS  PubMed  Google Scholar 

  31. Yallapu MM, Jaggi M, Chauhan S. Design and engineering of nanogels for cancer treatment. Drug Discov Today. 2011;16:457–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Shuai X, Merdan T, Schaper AK, Xi F, Kissel T. Core-cross-linked polymeric micelles as paclitaxel carriers. Bioconjug Chem. 2004;15:441–8.

    Article  CAS  PubMed  Google Scholar 

  33. Sun G, Hagooly A, Xu J, Nystrom AM, Li Z, Rossin R, et al. Facile, efficient approach to accomplish tunable chemistries and variable biodistributions for shell cross-linked nanoparticles. Biomacromolecules. 2008;9:1997–2006.

    Article  CAS  PubMed  Google Scholar 

  34. Lee HJ, Bae Y. Cross-linked nanoassemblies from poly(ethylene glycol)-poly(aspartate) block copolymers as stable supramolecular templates for particulate drug delivery. Biomacromolecules. 2011;12:2686–96.

    Article  CAS  PubMed  Google Scholar 

  35. Oberoi HS, Laquer FC, Marky LA, Kabanov AV, Bronich TK. Core cross-linked block ionomer micelles as pH-responsive carriers for cis-diamminedichloroplatinum(II). J Control Release. 2011;153(1):64–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Sahay G, Kim JO, Kabanov AV, Bronich TK. The exploitation of differential endocytic pathways in normal and tumor cells in the selective targeting of nanoparticulate chemotherapeutic agents. Biomaterials. 2010;31(5):923–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Kim JO, Sahay G, Kabanov AV, Bronich TK. Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents. Biomacromolecules. 2010;11(4):919–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bontha S, Kabanov AV, Bronich TK. Polymer micelles with cross-linked ionic cores for delivery of anticancer drugs. J Control Release. 2006;114(2):163–74.

    Article  CAS  PubMed  Google Scholar 

  39. Li Y, Hindi K, Watts Kristin M, Taylor Jane B, Zhang K, Li Z, et al. Shell crosslinked nanoparticles carrying silver antimicrobials as therapeutics. Chem Commun. 2010;46(1):121–3.

    Article  CAS  Google Scholar 

  40. Van Horn BA, Wooley KL. Toward cross-linked degradable polyester materials: investigations into the compatibility and use of reductive amination chemistry for cross-linking. Macromolecules. 2007;40(5):1480–8.

    Article  Google Scholar 

  41. O’Reilly RK, Joralemon MJ, Hawker CJ, Wooley KL. Facile syntheses of surface-functionalized micelles and shell cross-linked nanoparticles. J Polym Sci Part A Polym Chem. 2006;44(17):5203–17.

    Article  Google Scholar 

  42. Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science. 2012;338(6109):903–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Ali AH, Srinivasan KSV. Synthesis, characterization, and studies on the solid-state cross-linking of functionalized vinyl cinnamate polymers. J App Polym Sci. 1997;67:441–8.

    Article  Google Scholar 

  44. Sung S-J, Cho K-Y, Hah H, Lee J, Shim H-K, Park J-K. Two different reaction mechanisms of cinnamate side groups attached to the various polymer backbones. Polymer. 2006;47:2314–21.

    Article  CAS  Google Scholar 

  45. Bae Y, Fukushima S, Harada A, Kataoka K. Design of environment-sensitive supramulecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew Chem Int Ed. 2003;42:4640–3.

    Article  CAS  Google Scholar 

  46. Bae Y, Jang W-D, Nishiyama N, Fukushima S, Kataoka K. Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery. Mol BioSyst. 2005;1(3):242–50.

    Article  CAS  PubMed  Google Scholar 

  47. Scott D, Rohr J, Bae Y. Nanoparticulate formulations of mithramycin analogs for enhanced cytotoxicity. Int J Nanomed. 2011;6:2757–67.

    Article  CAS  Google Scholar 

  48. West KR, Otto S. Reversible covalent chemistry in drug delivery. Curr Drug Discov Technol. 2005;2(3):123–60.

    Article  CAS  PubMed  Google Scholar 

  49. Jones AT, Gumbleton M, Duncan R. Understanding endocytic pathways and intracellular trafficking: a prerequisite for effective design of advanced drug delivery systems. Adv Drug Deliv Rev. 2003;55(11):1353–7.

    Article  CAS  PubMed  Google Scholar 

  50. Bandak S, Ramu A, Barenholz Y, Gabizon A. Reduced UV-induced degradation of doxorubicin encapsulated in polyethyleneglycol-coated liposomes. Pharm Res. 1999;6:841–6.

    Article  Google Scholar 

  51. Mizutani H, Tada-Oikawa S, Hiraku Y, Kojima M, Kawanishi S. Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci. 2005;76:1439–53.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments and Disclosures

MD acknowledges the University of Kentucky Cancer Nanotechnology Training Center (UK-CNTC) postdoctoral traineeship, supported by the NCI/NIH and part of the National Cancer Institute Alliance for Nanotechnology in Cancer (5R25CA153954).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky, 40536-0596, USA

    Matthew Dickerson, Nickolas Winquist & Younsoo Bae

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  1. Matthew Dickerson
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  2. Nickolas Winquist
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  3. Younsoo Bae
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Correspondence to Younsoo Bae.

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Dickerson, M., Winquist, N. & Bae, Y. Photo-Inducible Crosslinked Nanoassemblies for pH-Controlled Drug Release. Pharm Res 31, 1254–1263 (2014). https://doi.org/10.1007/s11095-013-1246-6

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  • DOI: https://doi.org/10.1007/s11095-013-1246-6

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