Skip to main content

Advertisement

SpringerLink
Log in

The In vitro Sub-cellular Localization and In vivo Efficacy of Novel Chitosan/GMO Nanostructures containing Paclitaxel

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol®).

Methods

The sub-cellular localization of coumarin-6 labeled chitosan/GMO nanostructures was determined by confocal microscopy in MDA-MB-231 cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph model. Treatments consisted of intravenous Taxol® or chitosan/GMO nanostructures with or without PTX, local intra-tumor bolus of Taxol® or chitosan/GMO nanostructures with or without PTX. The tumor diameter and animal weight was monitored at various intervals. Histopathological changes were evaluated in end-point tumors.

Results

The tumor diameter increased at a constant rate for all the groups between days 7-14. After a single intratumoral bolus dose of chitosan/GMO containing PTX showed significant reduction in tumor diameter on day 15 when compared to control, placebo and intravenous PTX administration. The tumor diameter reached a maximal decrease (4-fold) by day 18, and the difference was reduced to approximately 2-fold by day 21. Qualitatively similar results were observed in a separate study containing PTX when administered intravenously.

Conclusion

Chitosan/GMO nanostructures containing PTX are safe and effective administered locally or intravenously. Partially supported by DOD Award BC045664

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

REFERENCES

  1. Singla AK, Garg A, Aggarwal GD. Paclitaxel and its formulations. Int J Pharm. 2002;235:179–92. doi:10.1016/S0378-5173(01)00986-3.

    Article  PubMed  CAS  Google Scholar 

  2. Tarr BD, Yalkowsky SH. A new parenteral vehicle for the administration of some poorly soluble anti-cancer drugs. J Parenter Sci Technol. 1987;41:31–33.

    PubMed  CAS  Google Scholar 

  3. Chao TC, Chu Z, Tseng LM, Chiou TJ, Hsieh RK, Wang WS, et al. Paclitaxel in a novel formulation containing less Cremophor EL as first-line therapy for advanced breast cancer: a phase II trial. Invest New Drugs. 2005;23:171–7. doi:10.1007/s10637-005-5863-8.

    Article  PubMed  CAS  Google Scholar 

  4. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590–8. doi:10.1016/S0959-8049(01)00171-X.

    Article  PubMed  CAS  Google Scholar 

  5. Friedland D, Gorman G, Treat J. Hypersensitivity reactions from taxol and etoposide. J Natl Cancer Inst. 1993;85:2036. doi:10.1093/jnci/85.24.2036.

    Article  PubMed  CAS  Google Scholar 

  6. Rowinsky EK, Chaudhry V, Cornblath DR, Donehower RC. Neurotoxicity of Taxol. J Natl Cancer Inst Monogr. 1993;15:107–15.

    PubMed  Google Scholar 

  7. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, et al. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8:1038–44.

    PubMed  CAS  Google Scholar 

  8. Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother. 2006;7:1041–53. doi:10.1517/14656566.7.8.1041.

    Article  PubMed  CAS  Google Scholar 

  9. Socinski M. Update on nanoparticle albumin-bound paclitaxel. Clin Adv Hematol Oncol. 2006;4:745–6.

    PubMed  Google Scholar 

  10. Lee Villano J, Mehta D, Radhakrishnan L. Abraxane induced life-threatening toxicities with metastatic breast cancer and hepatic insufficiency. Invest New Drugs. 2006;24:455–6. doi:10.1007/s10637-006-6214-0.

    Article  PubMed  CAS  Google Scholar 

  11. Moore A, Medarova Z, Potthast A, Dai G. In vivo targeting of underglycosylated MUC-1 tumor antigen using a multimodal imaging probe. Cancer Res. 2004;64:1821–7. doi:10.1158/0008-5472.CAN-03-3230.

    Article  PubMed  CAS  Google Scholar 

  12. Sandri G, Bonferoni MC, Rossi S, Ferrari F, Gibin S, Zambito Y, et al. Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. Eur J Pharm Biopharm. 2007;65:68–77. doi:doi:10.1016/j.ejpb.2006.07.016.

    Article  PubMed  CAS  Google Scholar 

  13. Bernkop-Schnurch A, Weithaler A, Albrecht K, Greimel A. Thiomers: preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system. Int J Pharm. 2006;317:76–81. doi:10.1016/j.ijpharm.2006.02.044.

    Article  PubMed  Google Scholar 

  14. Cui F, Qian F, Yin C. Preparation and characterization of mucoadhesive polymer-coated nanoparticles. Int J Pharm. 2006;316:154–61. doi:10.1016/j.ijpharm.2006.02.031.

    Article  PubMed  CAS  Google Scholar 

  15. Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MO, et al. RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther. 2006;14:476–84. doi:10.1016/j.ymthe.2006.04.010.

    Article  PubMed  CAS  Google Scholar 

  16. Zheng F, Shi XW, Yang GF, Gong LL, Yuan HY, Cui YJ, et al. Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study. Life Sci. 2007;80:388–96. doi:10.1016/j.lfs.2006.09.040.

    Article  PubMed  CAS  Google Scholar 

  17. Takeuchi H, Yamamoto H, Niwa T, Hino T, Kawashima Y. Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes. Pharm Res. 1996;13:896–901. doi:10.1023/A:1016009313548.

    Article  PubMed  CAS  Google Scholar 

  18. Takeuchi H, Thongborisute J, Matsui Y, Sugihara H, Yamamoto H, Kawashima Y. Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems. Adv Drug Deliv Rev. 2005;57:1583–94. doi:10.1016/j.addr.2005.07.008.

    Article  PubMed  CAS  Google Scholar 

  19. Thongborisute J, Tsuruta A, Kawabata Y, Takeuchi H. The effect of particle structure of chitosan-coated liposomes and type of chitosan on oral delivery of calcitonin. J Drug Target. 2006;14:147–54. doi:10.1080/10611860600648346.

    Article  PubMed  CAS  Google Scholar 

  20. Trickler WJ, Nagvekar AA, Dash AK. A Novel Nanoparticle Formulation for Sustained Paclitaxel Delivery. AAPS PharmSciTech. 2008;9:486–93. doi:10.1208/s12249-008-9063-7.

    Article  PubMed  CAS  Google Scholar 

  21. Davda J, Labhasetwar V. Characterization of nanoparticle uptake by endothelial cells. Int J Pharm. 2002;233:51–9. doi:10.1016/S0378-5173(01)00923-1.

    Article  PubMed  CAS  Google Scholar 

  22. Shikata F, Tokumitsu H, Ichikawa H, Fukumori Y. In vitro cellular accumulation of gadolinium incorporated into chitosan nanoparticles designed for neutron-capture therapy of cancer. Eur J Pharm Biopharm. 2002;53:57–63. doi:10.1016/S0939-6411(01)00198-9.

    Article  PubMed  CAS  Google Scholar 

  23. Xu ZP, Niebert M, Porazik K, Walker TL, Cooper HM, Middelberg AP, et al. Subcellular compartment targeting of layered double hydroxide nanoparticles. J Control Release. 2008;130:86–94. doi:10.1016/j.jconrel.2008.05.021.

    Article  PubMed  CAS  Google Scholar 

  24. Yin M, Shen J, Gropeanu R, Pflugfelder GO, Weil T, Mullen K. Fluorescent core/shell nanoparticles for specific cell-nucleus staining. Small. 2008;4:894–8. doi:10.1002/smll.200701107.

    Article  PubMed  CAS  Google Scholar 

  25. Perumal OP, Inapagolla R, Kannan S, Kannan RM. The effect of surface functionality on cellular trafficking of dendrimers. Biomaterials. 2008;29:3469–76. doi:10.1016/j.biomaterials.2008.04.038.

    Article  PubMed  CAS  Google Scholar 

  26. Zou J, Saulnier P, Perrier T, Zhang Y, Manninen T, Toppila E, et al. Distribution of lipid nanocapsules in different cochlear cell populations after round window membrane permeation. J Biomed Mater Res B Appl Biomater. 2008;87:10–8.

    PubMed  Google Scholar 

  27. de la Fuente M, Seijoand B, Alonso MJ. Bioadhesive hyaluronan-chitosan nanoparticles can transport genes across the ocular mucosa and transfect ocular tissue. Gene Ther. 2008;15:668–76. doi:10.1038/gt.2008.16.

    Article  PubMed  Google Scholar 

  28. Lacoeuille F, Garcion E, Benoit JP, Lamprecht A. Lipid nanocapsules for intracellular drug delivery of anticancer drugs. J Nanosci Nanotechnol. 2007;7:4612–7.

    PubMed  CAS  Google Scholar 

  29. Zhang LW, Yu WW, Colvin VL, Monteiro-Riviere NA. Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes. Toxicol Appl Pharmacol. 2008;228:200–11. doi:10.1016/j.taap. 2007.12.022.

    Article  PubMed  CAS  Google Scholar 

  30. Panyam J, Labhasetwar V. Targeting intracellular targets. Curr Drug Deliv. 2004;1:235–47. doi:10.2174/1567201043334768.

    Article  PubMed  CAS  Google Scholar 

  31. Panyam J, Zhou WZ, Prabha S, Sahoo SK, Labhasetwar V. Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. Faseb J. 2002;16:1217–26. doi:10.1096/fj.02-0088com.

    Article  PubMed  CAS  Google Scholar 

  32. Erni C, Suard C, Freitas S, Dreher D, Merkle HP, Walter E. Evaluation of cationic solid lipid microparticles as synthetic carriers for the targeted delivery of macromolecules to phagocytic antigen-presenting cells. Biomaterials. 2002;23:4667–76. doi:10.1016/S0142-9612(02)00216-8.

    Article  PubMed  CAS  Google Scholar 

  33. Koval M, Preiter K, Adles C, Stahl PD, Steinberg TH. Size of IgG-opsonized particles determines macrophage response during internalization. Exp Cell Res. 1998;242:265–73. doi:10.1006/excr.1998.4110.

    Article  PubMed  CAS  Google Scholar 

  34. Costanzo PJ, Patten TE, Seery TA. Nanoparticle agglutination: acceleration of aggregation rates and broadening of the analyte concentration range using mixtures of various-sized nanoparticles. Langmuir. 2006;22:2788–94. doi:10.1021/la0522909.

    Article  PubMed  CAS  Google Scholar 

  35. Chavanpatil MD, Khdair A, Panyam J. Nanoparticles for cellular drug delivery: mechanisms and factors influencing delivery. J Nanosci Nanotechnol. 2006;6:2651–63. doi:10.1166/jnn.2006.443.

    Article  PubMed  CAS  Google Scholar 

  36. Panyam J, Labhasetwar V. Dynamics of endocytosis and exocytosis of poly(D, L-lactide-co-glycolide) nanoparticles in vascular smooth muscle cells. Pharm Res. 2003;20:212–20. doi:10.1023/A:1022219003551.

    Article  PubMed  CAS  Google Scholar 

  37. Harush-Frenkel O, Rozentur E, Benita S, Altschuler Y. Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells. Biomacromolecules. 2008;9:435–43. doi:10.1021/bm700535p.

    Article  PubMed  CAS  Google Scholar 

  38. Harush-Frenkel O, Debotton N, Benita S, Altschuler Y. Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochem Biophys Res Commun. 2007;353:26–32. doi:10.1016/j.bbrc.2006.11.135.

    Article  PubMed  CAS  Google Scholar 

  39. Xu P, Van Kirk EA, Zhan Y, Murdoch WJ, Radosz M, Shen Y. Targeted charge-reversal nanoparticles for nuclear drug delivery. Angew Chem Int Ed Engl. 2007;46:4999–5002. doi:10.1002/anie.200605254.

    Article  PubMed  CAS  Google Scholar 

  40. Berry CC, de la Fuente JM, Mullin M, Chu SW, Curtis AS. Nuclear localization of HIV-1 tat functionalized gold nanoparticles. IEEE Trans Nanobioscience. 2007;6:262–9. doi:10.1109/TNB.2007.908973.

    Article  PubMed  CAS  Google Scholar 

  41. Ryan JA, Overton KW, Speight ME, Oldenburg CN, Loo L, Robarge W, et al. Cellular uptake of gold nanoparticles passivated with BSA-SV40 large T antigen conjugates. Anal Chem. 2007;79:9150–9. doi:10.1021/ac0715524.

    Article  PubMed  CAS  Google Scholar 

  42. Tkachenko AG, Xie H, Liu Y, Coleman D, Ryan J, Glomm WR, et al. Cellular trajectories of peptide-modified gold particle complexes: comparison of nuclear localization signals and peptide transduction domains. Bioconjug Chem. 2004;15:482–90. doi:10.1021/bc034189q.

    Article  PubMed  CAS  Google Scholar 

  43. Tkachenko AG, Xie H, Coleman D, Glomm W, Ryan J, Anderson MF, et al. Multifunctional gold nanoparticle-peptide complexes for nuclear targeting. J Am Chem Soc. 2003;125:4700–1. doi:10.1021/ja0296935.

    Article  PubMed  CAS  Google Scholar 

  44. Mugabe C, Hadaschik BA, Kainthan RK, Brooks DE, So AI, Gleave ME, Burt HM. Paclitaxel incorporated in hydrophobically derivatized hyperbranched polyglycerols for intravesical bladder cancer therapy. BJU Int (2008)

  45. Danhier F, Lecouturier N, Vroman B, Jerome C, Marchand-Brynaert J, Feron O, et al. Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation. J Control Release. 2009;133:11–7. doi:10.1016/j.jconrel.2008.09.086.

    Article  PubMed  CAS  Google Scholar 

  46. Zhang Z, Lee SH, Gan CW, Feng SS. In vitro and in vivo investigation on PLA-TPGS nanoparticles for controlled and sustained small molecule chemotherapy. Pharm Res. 2008;25:1925–35. doi:10.1007/s11095-008-9611-6.

    Article  PubMed  Google Scholar 

  47. Nornoo AO, Chow DS. Cremophor-free intravenous microemulsions for paclitaxel II. Stability, in vitro release and pharmacokinetics. Int J Pharm. 2008;349:117–23. doi:10.1016/j.ijpharm.2007.07.043.

    Article  PubMed  CAS  Google Scholar 

  48. Dong Y, Feng SS. In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy. Biomaterials. 2007;28:4154–60. doi:10.1016/j.biomaterials.2007.05.026.

    Article  PubMed  CAS  Google Scholar 

  49. Lee SW, Chang DH, Shim MS, Kim BO, Kim SO, Seo MH. Ionically fixed polymeric nanoparticles as a novel drug carrier. Pharm Res. 2007;24:1508–16. doi:10.1007/s11095-007-9269-5.

    Article  PubMed  CAS  Google Scholar 

  50. Koziara JM, Whisman TR, Tseng MT, Mumper RJ. In-vivo efficacy of novel paclitaxel nanoparticles in paclitaxel-resistant human colorectal tumors. J Control Release. 2006;112:312–9. doi:10.1016/j.jconrel.2006.03.001.

    Article  PubMed  CAS  Google Scholar 

  51. Win KY, Feng SS. In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D, L-lactic-co-glycolic acid) nanoparticles for paclitaxel formulation. Biomaterials. 2006;27:2285–91. doi:10.1016/j.biomaterials.2005.11.008.

    Article  PubMed  CAS  Google Scholar 

  52. Chen DB, Yang TZ, Lu WL, Zhang Q. In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. Chem Pharm Bull (Tokyo). 2001;49:1444–7. doi:10.1248/cpb.49.1444.

    Article  CAS  Google Scholar 

  53. Sharma D, Chelvi TP, Kaur J, Chakravorty K, De TK, Maitra A, et al. Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res. 1996;8:281–6.

    PubMed  CAS  Google Scholar 

  54. Wang Y, Li Y, Zhang L, Fang X. Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles. Arch Pharm Res. 2008;31:530–8. doi:10.1007/s12272-001-1189-2.

    Article  PubMed  CAS  Google Scholar 

  55. Han LM, Guo J, Zhang LJ, Wang QS, Fang XL. Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with Pluronic P123. Acta Pharmacol Sin. 2006;27:747–53. doi:10.1111/j.1745-7254.2006.00340.x.

    Article  PubMed  CAS  Google Scholar 

  56. Kim SC, Kim DW, Shim YH, Bang JS, Oh HS, Wan Kim S, et al. In vivo evaluation of polymeric micellar paclitaxel formulation: toxicity and efficacy. J Control Release. 2001;72:191–202. doi:10.1016/S0168-3659(01)00275-9.

    Article  PubMed  CAS  Google Scholar 

  57. Hamaguchi T, Matsumura Y, Suzuki M, Shimizu K, Goda R, Nakamura I, et al. NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel. Br J Cancer. 2005;92:1240–6. doi:10.1038/sj.bjc.6602479.

    Article  PubMed  CAS  Google Scholar 

  58. Yang T, Choi MK, Cui FD, Lee SJ, Chung SJ, Shim CK, et al. Antitumor effect of paclitaxel-loaded PEGylated immunoliposomes against human breast cancer cells. Pharm Res. 2007;24:2402–11. doi:10.1007/s11095-007-9425-y.

    Article  PubMed  CAS  Google Scholar 

  59. Turturro F, Von Burton G, Friday E. Hyperglycemia-induced thioredoxin-interacting protein expression differs in breast cancer-derived cells and regulates paclitaxel IC50. Clin Cancer Res. 2007;13:3724–30. doi:10.1158/1078-0432.CCR-07-0244.

    Article  PubMed  CAS  Google Scholar 

  60. Han GZ, Liu ZJ, Shimoi K, Zhu BT. Synergism between the anticancer actions of 2-methoxyestradiol and microtubule-disrupting agents in human breast cancer. Cancer Res. 2005;65:387–93.

    PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS

This work was partially supported by a Department of Defense Concept Award BC045664 and Health Future Foundations, Omaha, NE. This research was also partially conducted at the Integrative Biological Imaging Facility at Creighton University, Omaha, NE. This facility, supported by the C.U. Medical School, was constructed with support from C06 Grant RR17417-01 from the NCRR, NIH.

Author information

Authors and Affiliations

  1. Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University Medical Center, 2500 California Plaza, Omaha, Nebraska, 68178, USA

    W.J. Trickler, A.A. Nagvekar & A.K. Dash

Authors
  1. W.J. Trickler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A.A. Nagvekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A.K. Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A.K. Dash.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trickler, W., Nagvekar, A. & Dash, A. The In vitro Sub-cellular Localization and In vivo Efficacy of Novel Chitosan/GMO Nanostructures containing Paclitaxel. Pharm Res 26, 1963–1973 (2009). https://doi.org/10.1007/s11095-009-9911-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-9911-5

KEY WORDS

Search

Navigation