Journal of Materials Science

, Volume 54, Issue 7, pp 5695–5711 | Cite as

Phenylboronic acid-functionalized ultra-pH-sensitive micelles for enhanced tumor penetration and inhibition in vitro

  • Jiejie Qin
  • Yan Huang
  • Guoqing Yan
  • Jun Wang
  • Liefeng Hu
  • Panpan Zhang
  • Rupei TangEmail author
Materials for life sciences


In this work, the tumor-targeted ultra-pH-responsive conjugates (PBA/Dex-g-OE) and nontargeted conjugates (Dex-g-OE) were successfully prepared and could easily self-assemble into stable micelles with lower CMC values in neutral aqueous solution. Transmission electron microscopy and dynamic light scattering measurement indicated that the resulting micelles have desirable size distribution and regular spherical shape. The PBA/Dex-g-OE micelles possessed high stability in physiological condition and were pH sensitive to both extracellular and intracellular acidic conditions. Doxorubicin (DOX) was efficiently loaded to give the DOX-loaded micelles (PBA/Dex-g-OE-DOX and Dex-g-OE-DOX) with the desirable drug loading contents. In vitro cellular uptake and growth inhibition assays suggested that PBA/Dex-g-OE-DOX micelles were more efficiently internalized by monolayer tumor cells and three-dimensional multicellular tumor spheroids (MCTS) than nontargeted micelles (Dex-g-OE-DOX), leading to the fast and complete destruction of MCTS in vitro.



This work is financially supported by the National Natural Science Foundation of China (Nos. 21174054, 21004030, and 51503001), the Natural Science Foundation of Anhui Province of China (No. 1408085MB26), and the Doctor Research Foundation of Anhui University of China (No. J10113190075), and the Academic and Technology Introduction Project of Anhui University of China (AU02303203), and the Nature Science Research Programme of the Education Office of Anhui Province (Nos. KJ2016A030 and KJ2018ZD003).

Compliance with ethical standards

Conflict of interest

The authors have declared that there is no conflict of interest.

Supplementary material

10853_2018_3092_MOESM1_ESM.doc (672 kb)
Supplementary material 1 (DOC 672 kb)


  1. 1.
    Kapri S, Maiti S, Bhattacharyya S (2016) Lemon grass derived porous carbon nanospheres functionalized for controlled and targeted drug delivery. Carbon 100:223–235CrossRefGoogle Scholar
  2. 2.
    Rafi AA, Mahkam M, Davaran S, Hamishehkar H (2016) A smart pH-responsive nano-carrier as a drug delivery system: a hybrid system comprised of mesoporous nanosilica MCM-41 (as a nano-container) and a pH-sensitive polymer (as smart reversible gatekeepers)—preparation, characterization and in vitro release studies of an anti-cancer drug. Eur J Pharm Sci 93:64–73CrossRefGoogle Scholar
  3. 3.
    Chen Y, Huang J, Zhang S, Gu Z (2017) Superamphiphile based cross-linked small-molecule micelles for pH-triggered release of anticancer drugs. Chem Mater 29:3083–3091CrossRefGoogle Scholar
  4. 4.
    Bae YH, Yin HQ (2008) Stability issues of polymeric micelles. J Control Release 131:2–4CrossRefGoogle Scholar
  5. 5.
    Liu M, Du H, Zhang W, Zhai G (2017) Internal stimuli-responsive nanocarriers for drug delivery: design strategies and applications. Mater Sci Eng C 71:1267–1280CrossRefGoogle Scholar
  6. 6.
    Wicki A, Witzigmann D, Balasubramanian V, Huwyler J (2015) Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. J Control Release 200:138–157CrossRefGoogle Scholar
  7. 7.
    Desai N (2012) Challenges in development of nanoparticle-based therapeutics. AAPS J 14:282–295CrossRefGoogle Scholar
  8. 8.
    Wu Y, Chen W, Meng F, Wang Z, Cheng R, Deng C, Liu H, Zhong Z (2012) Core-crosslinked pH-sensitive degradable micelles: a promising approach to resolve the extracellular stability versus intracellular drug release dilemma. J Control Release 164:338–345CrossRefGoogle Scholar
  9. 9.
    Xu X, Ho W, Zhang X, Bertrand N, Farokhzad O (2015) Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol Med 21:223–232CrossRefGoogle Scholar
  10. 10.
    Massia SP, Stark J, Letbetter DS (2000) Surface-immobilized dextran limits cell adhesion and spreading. Biomaterials 21:2253–2261CrossRefGoogle Scholar
  11. 11.
    Owen SC, Chan DPY, Shoichet MS (2012) Polymeric micelle stability. Nano Today 7:53–65CrossRefGoogle Scholar
  12. 12.
    Deng W, Li J, Yao P, He F, Huang C (2010) Green preparation process, characterization and antitumor effects of doxorubicin–BSA–dextran nanoparticles. Macromol Biosci 10:1224–1234CrossRefGoogle Scholar
  13. 13.
    Sun H, Guo B, Li X, Cheng R, Meng F, Liu H, Zhong Z (2010) Shell-sheddable micelles based on dextran–SS–poly(ε-caprolactone) diblock copolymer for efficient intracellular release of doxorubic. Biomacromolecules 11:848–854CrossRefGoogle Scholar
  14. 14.
    Lemarchand C, Gref R, Couvreur P (2004) Polysaccharide-decorated nanoparticles. Eur J Pharm Biopharm 58:327–341CrossRefGoogle Scholar
  15. 15.
    Founi ME, Soliman SMA, Vanderesse R, Acherar S, Guedon E, Chevalot I, Babin J, Six JL (2018) Light-sensitive dextran-covered PNBA nanoparticles as triggered drug delivery systems: formulation, characteristics and cytotoxicity. J Colloid Interface Sci 514:289–298CrossRefGoogle Scholar
  16. 16.
    Laville M, Babin J, Londono I, Legros M, Nouvel C, Durand A, Vanderesse R, Leonard M, Six JL (2013) Polysaccharide-covered nanoparticles with improved shell stability using click-chemistry strategies. Carbohyd Polym 93:537–546CrossRefGoogle Scholar
  17. 17.
    Deng C, Jiang Y, Cheng R, Meng F, Zhong Z (2012) Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: promises, progress and prospects. Nano Today 7:467–480CrossRefGoogle Scholar
  18. 18.
    Petros RA, DeSimone JM (2010) Strategies in the design of nanoparticles for therapeutic applications. Nat Rev Drug Discov 9:615–627CrossRefGoogle Scholar
  19. 19.
    Ma X, Shi X, Bai S, Gao YE, Hou M, Han MY, Xu Z (2018) Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery. J Mater Sci 53:892–907. CrossRefGoogle Scholar
  20. 20.
    Zha Q, Wang X, Cheng X, Fu S, Yang G, Yao W, Tang R (2017) Acid-degradable carboxymethyl chitosan nanogels via an ortho ester linkage mediated improved penetration and growth inhibition of 3-D tumor spheroids in vitro. Mater Sci Eng C 78:246–257CrossRefGoogle Scholar
  21. 21.
    Zhang L, Wang Y, Zhang X, Wei X, Xiong X, Zhou S (2017) Enzyme and redox dual-triggered intracellular release from actively targeted polymeric micelles. ACS Appl Mater Interfaces 9:3388–3399CrossRefGoogle Scholar
  22. 22.
    Thomas TP, Huang B, Choi SK, Silpe JE, Kotlyar A, Desai AM, Zong H, Gam J, Joice M, Baker JR (2012) Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic. Mol Pharmaceutics 9:2669–2676CrossRefGoogle Scholar
  23. 23.
    Heo DN, Yang DH, Moon HJ, Lee JB, Bae MS, Lee SC, Lee WJ, Sun IC, Kwon IK (2012) Gold nanoparticles surface-functionalized with paclitaxel drug and biotin receptor as theranostic agents for cancer therapy. Biomaterials 33:856–866CrossRefGoogle Scholar
  24. 24.
    Fan X, Zhang W, Hu Z, Li Z (2017) Facile synthesis of RGD-conjugated unimolecular micelles based on a polyester dendrimer for targeting drug delivery. J Mater Chem B 5:1062–1072CrossRefGoogle Scholar
  25. 25.
    Wang B, Chen L, Sun Y, Zhu Y, Sun Z, An T, Li Y, Lin Y, Fan D, Wang Q (2015) Development of phenylboronic acid-functionalized nanoparticles for emodin delivery. J Mater Chem B 3:3840–3847CrossRefGoogle Scholar
  26. 26.
    Deshayes S, Cabral H, Ishii T, Miura Y, Kobayashi S, Yamashita T, Matsumoto A, Miyahara Y, Nishiyama N, Kataoka K (2013) Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J Am Chem Soc 135:15501–15507CrossRefGoogle Scholar
  27. 27.
    Zhao Z, Yao X, Zhang Z, Chen L, He C, Chen X (2014) Boronic acid shell-crosslinked dextran-b-PLA micelles for acid-responsive drug delivery. Macromol Biosci 14:1609–1618CrossRefGoogle Scholar
  28. 28.
    Ellis GA, Palte MJ, Raines RT (2012) Boronate-mediated biologic delivery. J Am Chem Soc 134:3631–3634CrossRefGoogle Scholar
  29. 29.
    Ma R, Shi L (2014) Phenylboronic acid-based glucose-responsive polymeric nanoparticles: synthesis and applications in drug delivery. Polym Chem 5:1503–1518CrossRefGoogle Scholar
  30. 30.
    Wu D, Yang J, Xing Z, Han H, Wang T, Zhang A, Yang Y, Li Q (2016) Phenylboronic acid-functionalized polyamidoamine-mediated Bcl-2 siRNA delivery for inhibiting the cell proliferation. Colloid Interface Sci B 146:318–325Google Scholar
  31. 31.
    Li J, Huo M, Wang J, Zhou J, Mohammad JM, Zhang Y, Zhu Q, Waddad AY, Zhang Q (2012) Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid–deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials 33:2310–2320CrossRefGoogle Scholar
  32. 32.
    Pramod PS, Shah R, Jayakannan M (2015) Dual stimuli polysaccharide nanovesicles for conjugated and physically loaded doxorubicin delivery in breast cancer cells. Nanoscale 7:6636–6652CrossRefGoogle Scholar
  33. 33.
    Xu H, Cao W, Zhang X (2013) Selenium-containing polymers: promising biomaterials for controlled release and enzyme mimics. Acc Chem Res 46:1647–1658CrossRefGoogle Scholar
  34. 34.
    Huang S, Shao K, Liu Y, Kuang Y, Li J, An S, Guo Y, Ma H, Jiang C (2013) Tumor-targeting and microenvironment-responsive smart nanoparticles for combination therapy of antiangiogenesis and apoptosis. ACS Nano 7:2860–2871CrossRefGoogle Scholar
  35. 35.
    Loh XJ (2013) Poly(DMAEMA-co-PPGMA): dual-responsive ‘‘reversible’’ micelles. J Appl Polym Sci 127:992–1000CrossRefGoogle Scholar
  36. 36.
    Zhang M, Liu J, Kuang Y, Li Q, Zheng DW, Song Q, Chen H, Chen X, Xu Y, Li C, Jiang B (2017) Ingenious pH-sensitive dextran/mesoporous silica nanoparticles based drug delivery systems for controlled intracellular drug release. Int J Biol Macromol 98:691–700CrossRefGoogle Scholar
  37. 37.
    Chen W, Hou Y, Tu Z, Gao L, Haag R (2017) pH-degradable PVA-based nanogels via photo-crosslinking of thermo-preinduced nanoaggregates for controlled drug delivery. J Control Release 259:160–167CrossRefGoogle Scholar
  38. 38.
    Kanamala M, Wilson WR, Yang M, Palmer BD, Wu Z (2016) Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review. Biomaterials 85:152–167CrossRefGoogle Scholar
  39. 39.
    Murthy N, Campbell J, Fausto N, Hoffman AS, Stayton PS (2003) Design and synthesis of pH-responsive polymeric carriers that target uptake and enhance the intracellular delivery of oligonucleotides. J Control Release 89:365–374CrossRefGoogle Scholar
  40. 40.
    Du JZ, Du XJ, Mao CQ, Wang J (2011) Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. J Am Chem Soc 133:17560–17563CrossRefGoogle Scholar
  41. 41.
    Qiao ZY, Qiao SL, Fan G, Fan YS, Chen Y, Wang H (2014) One-pot synthesis of pH-sensitive poly(RGD-co-bamino ester)s for targeted intracellular drug delivery. Polym Chem 5:844–853CrossRefGoogle Scholar
  42. 42.
    Mukhopadhyay P, Chakraborty S, Bhattacharya S, Mishra R, Kundu PP (2015) pH-sensitive chitosan/alginate core-shell nanoparticles for efficient and safe oral insulin delivery. Int J Biol Macromol 72:640–648CrossRefGoogle Scholar
  43. 43.
    Liu J, Huang Y, Kumar A, Tan A, Jin S, Mozhi A, Liang XJ (2014) pH-Sensitive nano-systems for drug delivery in cancer therapy. Biotechnol Adv 32:693–710CrossRefGoogle Scholar
  44. 44.
    Li L, Knickelbein K, Zhang L, Wang J, Obrinske M, Ma GZ, Zhang L, Bitterman L, Du W (2015) Amphiphilic sugar poly(orthoesters) as pH-responsive nanoscopic assemblies for acidity-enhanced drug delivery and cell killing. Chem Commun 51:13078–13081CrossRefGoogle Scholar
  45. 45.
    Gillies ER, Frechet JMJ (2005) pH-responsive copolymer assemblies for controlled release of doxorubicin. Bioconjugate Chem 16:361–368CrossRefGoogle Scholar
  46. 46.
    Lee S, Saito K, Lee HR, Lee MJ, Shibasaki Y, Oishi Y, Kim BS (2012) Hyperbranched double hydrophilic block copolymer micelles of poly(ethylene oxide) and polyglycerol for pH-responsive drug delivery. Biomacromolecules 13:1190–1196CrossRefGoogle Scholar
  47. 47.
    Li L, Xu Y, Milligan I, Fu L, Franckowiak EA, Du W (2013) Synthesis of highly pH-responsive glucose poly(orthoester). Angew Chem Int Ed 52:13699–13702CrossRefGoogle Scholar
  48. 48.
    Yan G, Wang J, Qin J, Hu L, Zhang P, Wang X, Tang R (2017) Well-defined poly(ortho ester amides) for potential drug carriers: probing the effect of extra- and intracellular drug release on chemotherapeutic efficacy. Macromol Biosci 17:1600503CrossRefGoogle Scholar
  49. 49.
    Yan G, Zha Q, Wang J, Wang X, Cheng X, Yao W, Tang R (2017) Dynamic, ultra-pH-sensitive graft copolymer micelles mediated rapid, complete destruction of 3-D tumor spheroids in vitro. Polymer 111:192–203CrossRefGoogle Scholar
  50. 50.
    Yu M, Huang S, Yu KJ, Clyne AM (2012) Dextran and polymer polyethylene glycol (PEG) coating reduce both 5 and 30 nm iron oxide nanoparticle cytotoxicity in 2D and 3D cell culture. Int J Mol Sci 13:5554–5570CrossRefGoogle Scholar
  51. 51.
    Zhang S, Yang K, Feng L, Liu Z (2011) In vitro and in vivo behaviors of dextran functionalized grapheme. Carbon 49:4040–4049CrossRefGoogle Scholar
  52. 52.
    Hu Y, He L, Ding J, Sun D, Chen L, Chen X (2016) One-pot synthesis of dextran decorated reduced graphene oxide nanoparticles for targeted photo-chemotherapy. Carbohyd Polym 144:223–229CrossRefGoogle Scholar
  53. 53.
    Shaterabadi Z, Nabiyouni G, Soleymani M (2017) High impact of in situ dextran coating on biocompatibility, stability and magnetic properties of iron oxide nanoparticles. Mater Sci Eng C 75:947–956CrossRefGoogle Scholar
  54. 54.
    Balakrishnan B, Soman D, Payanam U, Laurent A, Labarre D, Jayakrishnan A (2017) A novel injectable tissue adhesive based on oxidized dextran and chitosan. Acta Biomater 53:343–354CrossRefGoogle Scholar
  55. 55.
    Chen X, Yao X, Chen L (2015) Intracellular pH-sensitive dextran-based micelles as efficient drug delivery platforms. Polym Int 64:430–436CrossRefGoogle Scholar
  56. 56.
    Tang R, Ji W, Wang C (2010) Amphiphilic block copolymers bearing ortho ester side-chains: pH-dependent hydrolysis and self-assembly in water. Macromol Biosci 10:192–201CrossRefGoogle Scholar
  57. 57.
    Zhou X, Luo S, Tang R, Wang R, Wang J (2015) Diblock copolymers of polyethylene glycol and a polymethacrylamide with side-chains containing twin ortho ester rings: synthesis, characterization, and evaluation as potential pH-responsive micelles. Macromol Biosci 15:385–394CrossRefGoogle Scholar
  58. 58.
    Wang X, Tang H, Wang C, Zhang J, Wu W, Jiang X (2016) Phenylboronic acid-mediated tumor targeting of chitosan nanoparticles. Theranostics 6:1378–1392CrossRefGoogle Scholar
  59. 59.
    Wang X, Yang C, Zhang Y, Zhen X, Wu W, Jiang X (2014) Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles. Biomaterials 35:6439–6453CrossRefGoogle Scholar
  60. 60.
    Yu M, Zhang L, Wang J, Tang R, Yan G, Cao Z, Wang X (2016) Acid-labile poly(ortho ester amino alcohols) by ring-opening polymerization for controlled DNA release and improved serum tolerance. Polymer 96:146–155CrossRefGoogle Scholar
  61. 61.
    Tang R, Ji W, Wang C (2011) Synthesis and characterization of new poly(ortho ester amidine) copolymers for non-viral gene delivery. Polymer 52:921–932CrossRefGoogle Scholar
  62. 62.
    Lai J, Xu Z, Tang R, Ji W, Wang R, Wang J (2014) PEGylated block copolymers containing tertiary amine side-chains cleavable via acid-labile ortho ester linkages for pH-triggered release of DNA. Polymer 55:2761–2771CrossRefGoogle Scholar
  63. 63.
    Gaio E, Scheglmann D, Reddi E, Moret F (2016) Uptake and photo-toxicity of Foscan®, Foslip® and Fospeg® in multicellular tumor spheroids. J Photochem Photobiol B 161:244–252CrossRefGoogle Scholar
  64. 64.
    Fu S, Yang G, Wang J, Wang X, Cheng X, Zha Q, Tang R (2017) pH-sensitive poly(ortho ester urethanes) copolymers with controlled degradation kinetic: synthesis, characterization, and in vitro evaluation as drug carriers. Eur Polym J 95:275–288CrossRefGoogle Scholar
  65. 65.
    Yang G, Wang X, Fu S, Tang R, Wang J (2017) pH-triggered chitosan nanogels via an ortho ester-based linkage for efficient chemotherapy. Acta Biomater 60:232–243CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life SciencesAnhui UniversityHefeiPeople’s Republic of China

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