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A Polymeric Nanoparticle Consisting of mPEG-PLA-Toco and PLMA-COONa as a Drug Carrier: Improvements in Cellular Uptake and Biodistribution

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Purpose.

To evaluate a new polymeric nanoparticulate drug delivery formulation that consists of two components: i) an amphiphilic diblock copolymer having tocopherol moiety at the end of the hydrophobic block in which the hydrophobic tocopherol moiety increases stability of hydrophobic core of the nanoparticle in aqueous medium; and ii) a biodegradable copolyester having carboxylate end group that is capable of forming ionic complex with positively charged compounds such as doxorubicin.

Methods.

A doxourubicin-loaded polymeric nanoparticle (Dox-PNP) was prepared by solvent evaporation method. The entrapment efficiency, size distribution, and in vitro release profile at various pH conditions were characterized. In vitro cellular uptake was investigated by confocal microscopy, flow cytometry, and MTT assay using drug-sensitive and drug-resistant cell lines. Pharmacokinetics and biodistribution were evaluated in rats and tumor-bearing mice.

Results.

Doxorubicin (Dox) was efficiently loaded into the PNP (higher than 95% of entrapment efficiency), and the diameter of Dox-PNP was in the range 20~25 nm with a narrow size distribution. In Vitro study showed that Dox-PNP exhibited higher cellular uptake into both human breast cancer cell (MCF-7) and human uterine cancer cell (MES-SA) than free doxorubicin solution (Free-Dox), especially into drug-resistant cells (MCF-7/ADR and MES-SA/Dx-5). In pharmacokinetics and tissue distribution study, the bioavailability of Dox-PNP calculated from the area under the blood concentration-time curve (AUC) was 69.8 times higher than that of Free-Dox in rats, and Dox-PNP exhibited 2 times higher bioavailability in tumor tissue of tumor-bearing mice.

Conclusions.

Dox-PNP exhibited enhanced cellular uptake of the drug. In the cytotoxic activity study, this improved cellular uptake was proved to be more advantageous in drug-resistant cell. Dox-PNP exhibited much higher bioavailability in blood plasma and more drug accumulation in tumor tissue than conventional doxorubicin formulation. The results of this study suggest that the PNP system is an advantageous carrier for drug delivery.

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Abbreviations

Dox-PNP:

doxorubicin-containing polymeric nanoparticle

Free-Dox:

aqueous solution of doxorubicin hydrochloride

mPEG-PLA-Toco:

methoxy poly(ethylene glycol)-b-poly(lactic acid) having a tocopherol moiety at the end of hydrophobic block

PLMA-COONa:

sodium salt of poly (lactic acid-co-mandelic acid)

PNP:

polymeric nanoparticle

References

  1. 1. V. P. Torchilin and V. S. Trubetskoy. Which polymers can make nanoparticulate drug carriers long-circulating? Adv. Drug Deliv. Rev. 16:141–155 (1995).

    Google Scholar 

  2. 2. M.-C. Jones and J.-C. Leroux. Polymeric micelles—a new generation of colloidal drug carriers. Eur. J. Pharm. Biopharm. 48:101–111 (1999).

    Google Scholar 

  3. 3. J. Panyam and V. Labhasetwar. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev. 55:329–347 (2003).

    Google Scholar 

  4. 4. K. Kataoka, T. Matsumoto, M. Yokoyama, T. Okano, Y. Sakurai, S. Fukushima, K. Okamoto, and G. S. Kwon. Doxorubicin-loaded poly(ethylene glycol)-poly(β-benzyl-L-aspartate) copolymer micelles: their pharmaceutical characteristics and biological significance. J. Control. Rel. 64:143–153 (2000).

    Google Scholar 

  5. 5. V. Alakhov, E. Klinski, S. Li, G. Pietrzynski, A. Venne, E. Batrakova, T. Bronitch, and A. Kabanov. Block-copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids Surf. B Biointerfaces 16:113–134 (1999).

    Google Scholar 

  6. 6. G. M. Barratt. Therapeutic applications of colloidal drug carriers. Pharm. Sci. Technol. Today 3:163–171 (2000).

    Google Scholar 

  7. 7. V. Torchilin. Structure and design of polymeric surfactant-based drug delivery systems. J. Control. Rel. 73:137–172 (2001).

    Google Scholar 

  8. 8. H. Maeda. The tumor blood vessel as an ideal target for macromolecular anticancer agents. J. Control. Rel. 19:315–324 (1992).

    Google Scholar 

  9. 9. T. N. Palmer, V. J. Caride, M. A. Caldecourt, J. Twickler, and V. Abdullah. The mechanism of liposome accumulation in infarction. Biochim. Biophys. Acta 797:363–368 (1984).

    Google Scholar 

  10. 10. A. A. Gabizon. Liposome circulation time and tumor targeting: implications for cancer chemotherapy. Adv. Drug Deliv. Rev. 16:285–294 (1995).

    Google Scholar 

  11. 11. H. Maeda, J. Wu, T. Sawa, Y. Matsumura, and K. Hori. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Rel. 65:271–284 (2000).

    Google Scholar 

  12. 12. K. J. Zhu, L. Xiangzhou, and Y. Shinlin. Preparation, characterization, and properties of polylactide (PLA)-poly(ethylene glycol) (PEG) copolymers: A potential drug carrier. J. Appl. Polym. Sci. 39:1–9 (1990).

    Google Scholar 

  13. 13. B. Jeong, Y. H. Bae, D. S. Lee, and S. W. Kim. Biodegradable block copolymers as injectable drug-delivery systems. Nature 388:860–862 (1997).

    Google Scholar 

  14. 14. P. R. Walker, J. Kwast-Welfeld, H. Gourdeau, J. Leblanc, W. Neugebaur, and M. Sikorska. Relationship between apoptosis and the cell cycle in lymphocytes: roles of protein kinase C, tyrosine phosphorylation, and AP1. Exp. Cell Res. 207:142–151 (1993).

    Google Scholar 

  15. 15. Y. Kakizawa and K. Kataoka. Block copolymer micelles for delivery of gene and related compounds. Adv. Drug Deliv. Rev. 54:203–222 (2002).

    Google Scholar 

  16. 16. I. Brigger, C. Dubernet, and P. Couvreur. Nanoparticles in cancer therapy and diagnosis. Adv. Drug Deliv. Rev. 54:631–651 (2002).

    Google Scholar 

  17. 17. Y. Bae, S. Fukushima, A. Harada, and K. Kataoka. Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. Angew. Chem. Int. Ed. Engl. 42:4640–4643 (2003).

    Google Scholar 

  18. 18. J. Panyam, W.-Z. Zhou, S. Prabha, S. K. Sahoo, and V. Labhasetwar. Rapid endo-lysosomal escape of poly(DL-lactide-co-glycolide) nanoparticles: implications for drug and gene delivery. FASEB J. 16:1217–1226 (2002).

    Google Scholar 

  19. 19. V. Omelyanenko, P. Kopečková, C. Gentra, and J. Kopeček. Targetable HPMA copolymer-adriamycin conjugate. Recognition, internalization, and subcellular fate. J. Control. Rel. 53:25–37 (1998).

    Google Scholar 

  20. 20. D. Nielsen, C. Maare, and T. Skovsgaard. Cellular resistance to anthracyclines. Gen. Pharmacol. 27:251–255 (1996).

    Google Scholar 

  21. 21. L. M. Leoni, E. Hamel, D. Genini, H. Shih, C. J. Carrera, H. B. Cottam, and D. A. Carson. Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells. J. Natl. Cancer Inst. 92:217–224 (2000).

    Google Scholar 

  22. 22. D. A. Scudiero, A. Monks, and E. A. Sausville. Cell line designation change: Multidrug-resistant cell line in the NCI anticancer screen. J. Natl. Cancer Inst. 90:862 (1998).

    Google Scholar 

  23. 23. H. Lage and M. Dietel. Effect of the breast-cancer resistance protein on atypical multidrug resistance. Lancet Oncol. 1:169–175 (2000).

    Google Scholar 

  24. 24. D. D. Ross, W. Yang, L. V. Abruzzo, W. S. Dalton, E. Schneider, H. Lage, M. Dietel, L. Greenberger, S. P. C. Cole, and L. A. Doyle. Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J. Natl. Cancer Inst. 91:429–433 (1999).

    Google Scholar 

  25. 25. A. J. Vander, J. H. Sherman, and D. S. Luciano. Movements of molecules across cell membranes. In A. J. Vander, J. H. Sherman, and D.S. Luciano (eds.), Human Physiology, 6th Ed., McGraw-Hill, New York, 1994, pp. 115–145.

    Google Scholar 

  26. 26. C. Allen, Y. Yu, A. Eisenberg, and D. Maysinger. Cellular internalization of PCL20-b-PEO44 block copolymer micelles. Biochim. Biophys. Acta 1421:32–38 (1999).

    Google Scholar 

  27. 27. R. Savic, L. Luo, A. Eisenberg, and D. Maysinger. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science 300:615–618 (2003).

    Google Scholar 

  28. 28. C. Vauthier, C. Dubernet, C. Chauvierre, I. Brigger, and P. Couvreur. Drug delivery to resistant tumors: the potential of poly(alkyl cyanoacrylate) nanoparticles. J. Control. Rel. 93:151–160 (2003).

    Google Scholar 

  29. 29. C. Vauthier, C. Dubernet, E. Fattal, H. Pinto-Alphandary, and P. Couvreur. Poly(alkylcyanoacrylates) as biodegradable materials for biomedical applications. Adv. Drug Deliv. Rev. 55:519–548 (2003).

    Google Scholar 

  30. 30. C. Cuvier, L. Roblot-Treupel, J. M. Millot, G. Lizard, S. Chevillard, M. Manfait, P. Couvreur, and M. F. Poupon. Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance. Biochem. Pharmacol. 44:509–517 (1992).

    Google Scholar 

  31. 31. S. Bennis, C. Chapey, P. Couvreur, and J. Robert. Enhanced cytotoxicity of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres against multidrug-resistant tumour cells in culture. Eur. J. Cancer 30A:89–93 (1994).

    Google Scholar 

  32. 32. F. Nemati, C. Dubernet, A. Colin de Verdière, M. F. Poupon, L. Treupel Acar, F. Puisieux, and P. Couvreur. Some parameters influencing cytotoxicity of free doxorubicin loaded nanoparticles in sensitive and multidrug resistant leucemic murine cells: incubation time, number of particles per cell. Int. J. Pharm. 102:55–62 (1994).

    Google Scholar 

  33. 33. A. Colin de Verdiere, C. Dubernet, F. Nemati, M. F. Poupon, F. Puisieux, and P. Couvreur. Uptake of doxorubicin from loaded nanoparticles in multidrug-resistant leukemic murine cells. Cancer Chemother. Pharmacol. 33:504–508 (1994).

    Google Scholar 

  34. 34. A. Colin de Verdiere, C. Dubernet, F. Nemati, E. Soma, M. Appel, J. Ferte, S. Bernard, F. Puisieux, and P. Couvreur. Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action. Br. J. Cancer 76:198–205 (1997).

    Google Scholar 

  35. 35. X. Pepin, L. Attali, C. Domrault, S. Gallet, J. M. Metreau, Y. Reault, P. J. Cardot, M. Imalalen, C. Dubernet, E. Soma, and P. Couvreur. On the use of ion-pair chromatography to elucidate doxorubicin release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level. J. Chromatogr. B 702:181–191 (1997).

    Google Scholar 

  36. 36. R. Mehta and T. G. Burke. Membrane biophysical parameters influencing anthracycline action. In W. Priebe (ed.), Anthracycline Antibiotics, ACS Symposium Series 574, American Chemical Society, Washington DC, 1995, pp. 222–240.

    Google Scholar 

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Authors and Affiliations

  1. Parenteral Delivery Research, Samyang R&D Center, Yuseong-Gu, 305-717, Daejeon, South Korea

    Yilwoong Yi, Jae Hong Kim, Hye-Won Kang, Hun Seung Oh & Min Hyo Seo

  2. National Research Laboratory of Pharmaceutical Technology College of Pharmacy, Chungnam National University, Yuseong-Gu, 305-764, Daejeon, South Korea

    Yilwoong Yi

  3. Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, 84112-9452, Salt Lake City, Utah, USA

    Sung Wan Kim

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  1. Yilwoong Yi
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  2. Jae Hong Kim
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Correspondence to Min Hyo Seo.

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Yi, Y., Kim, J., Kang, HW. et al. A Polymeric Nanoparticle Consisting of mPEG-PLA-Toco and PLMA-COONa as a Drug Carrier: Improvements in Cellular Uptake and Biodistribution. Pharm Res 22, 200–208 (2005). https://doi.org/10.1007/s11095-004-1187-1

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