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Nano Research 2012, 5(1): 49-61 https://doi.org/10.1007/s12274-011-0184-z
Research Article | Issue | Published: 25 November 2011

Size-Tunable Nanoparticles Composed of Dextran-b-poly(D, L-lactide) for Drug Delivery Applications

Show Author's Information Mohit S. Verma1,§,  Shengyan Liu1,§,  Yih Y. Chen1,  Ameena Meerasa1,  Frank X. Gu1,2( )
Department of Chemical EngineeringUniversity of WaterlooWaterlooN2L 3G1Canada
Waterloo Institute for NanotechnologyUniversity of WaterlooWaterlooN2L 3G1Canada

§ These authors contributed equally to this work

Keywords:
nanoparticles, biodistribution, controlled drug delivery, Dextran, pharmacokinetics, in vivo
Cite this article:
Verma MS, Liu S, Chen YY, et al. Size-Tunable Nanoparticles Composed of Dextran-b-poly(D, L-lactide) for Drug Delivery Applications. Nano Research, 2012, 5(1): 49-61. https://doi.org/10.1007/s12274-011-0184-z
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Abstract Full text About this article

Nanoparticles (NPs) formulated using self-assembly of block copolymers have attracted significant attention as nano-scaled drug delivery vehicles. Here we report the development of a biodegradable NP using self-assembly of a linear amphiphilic block copolymer, Dex-b-PLA, composed of poly(D, L-lactide), and dextran. The size of the NPs can be precisely tuned between 15 and 70 nm by altering the molecular weight (MW) of the two polymer chains. Using doxorubicin as a model drug, we demonstrated that the NPs can carry up to 21% (w/w) of the drug payload. The release profile of doxorubicin from NPs showed sustained release for over 6 days. Using a rat model, we explored the pharmacokinetics profiles of Dex-b-PLA NPs, and showed proof-of-concept that long circulation lifetime of the NPs can be achieved by tuning the MW of Dex-b-PLA block copolymer. While the terminal half-life of Dex-b-PLA NPs (29.8 h) was similar to that observed in poly(ethylene glycol)-coated (PEG-coated) NPs (27.0 h), 90% of the injected Dex-b-PLA NPs were retained in the blood circulation for 38.3 h after injection, almost eight times longer than the PEG-coated NPs. The area under curve (AUC) of Dex-b-PLA NPs was almost four times higher than PEG-based NPs. The biodistribution study showed lower accumulation of Dex-b-PLA NPs in the spleen with 19.5% initial dose per gram tissue (IDGT) after 24 h compared to PEG-coated poly(lactide-co-glycolide) (PLGA) NPs (29.8% IDGT). These studies show that Dex-b-PLA block copolymer is a promising new biomaterial for making controlled nanoparticles as drug delivery vehicles.


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About this article

Size-Tunable Nanoparticles Composed of Dextran-b-poly(D, L-lactide) for Drug Delivery Applications

Show Author's information Mohit S. Verma1,§, Shengyan Liu1,§, Yih Y. Chen1, Ameena Meerasa1, Frank X. Gu1,2( )
Department of Chemical EngineeringUniversity of WaterlooWaterlooN2L 3G1Canada
Waterloo Institute for NanotechnologyUniversity of WaterlooWaterlooN2L 3G1Canada

§ These authors contributed equally to this work

Abstract

Nanoparticles (NPs) formulated using self-assembly of block copolymers have attracted significant attention as nano-scaled drug delivery vehicles. Here we report the development of a biodegradable NP using self-assembly of a linear amphiphilic block copolymer, Dex-b-PLA, composed of poly(D, L-lactide), and dextran. The size of the NPs can be precisely tuned between 15 and 70 nm by altering the molecular weight (MW) of the two polymer chains. Using doxorubicin as a model drug, we demonstrated that the NPs can carry up to 21% (w/w) of the drug payload. The release profile of doxorubicin from NPs showed sustained release for over 6 days. Using a rat model, we explored the pharmacokinetics profiles of Dex-b-PLA NPs, and showed proof-of-concept that long circulation lifetime of the NPs can be achieved by tuning the MW of Dex-b-PLA block copolymer. While the terminal half-life of Dex-b-PLA NPs (29.8 h) was similar to that observed in poly(ethylene glycol)-coated (PEG-coated) NPs (27.0 h), 90% of the injected Dex-b-PLA NPs were retained in the blood circulation for 38.3 h after injection, almost eight times longer than the PEG-coated NPs. The area under curve (AUC) of Dex-b-PLA NPs was almost four times higher than PEG-based NPs. The biodistribution study showed lower accumulation of Dex-b-PLA NPs in the spleen with 19.5% initial dose per gram tissue (IDGT) after 24 h compared to PEG-coated poly(lactide-co-glycolide) (PLGA) NPs (29.8% IDGT). These studies show that Dex-b-PLA block copolymer is a promising new biomaterial for making controlled nanoparticles as drug delivery vehicles.

Keywords: nanoparticles, biodistribution, controlled drug delivery, Dextran, pharmacokinetics, in vivo

References(52)

1

Jain, R. K.; Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 2010, 7, 653–664.
DOI Google Scholar
2

Gu, F. X.; Karnik, R.; Wang, A. Z.; Alexis, F.; Levy-Nissenbaum, E.; Hong, S.; Langer, R. S.; Farokhzad, O. C. Targeted nanoparticles for cancer therapy. Nano Today 2007, 2, 14–21.
DOI Google Scholar
3

Pridgen, E. M.; Langer, R.; Farokhzad, O. C. Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomedicine 2007, 2, 669–680.
DOI Google Scholar
4

Kim, D. K.; Dobson, J. Nanomedicine for targeted drug delivery. J. Mater. Chem. 2009, 19, 6294–6307.
DOI Google Scholar
5

Gref, R.; Minamitake, Y.; Peracchia, M. T.; Trubetskoy, V.; Torchilin, V.; Langer, R. Biodegradable long-circulating polymeric nanospheres. Science 1994, 263, 1600–1603.
DOI Google Scholar
6

Gaucher, G.; Marchessault, R. H.; Leroux, J. Polyester-based micelles and nanoparticles for the parenteral delivery of taxanes. J. Control. Release 2010, 143, 2–12.
DOI Google Scholar
7

Dong, Y.; Feng, S. In vitro and in vivo evaluation of methoxy polyethylene glycol–polylactide (MPEG–PLA) nanoparticles for small-molecule drug chemotherapy. Biomaterials 2007, 28, 4154–4160.
DOI Google Scholar
8

Gursahani, H.; Riggs-Sauthier, J.; Pfeiffer, J.; Lechuga-Ballesteros, D.; Fishburn, C. S. Absorption of polyethylene glycol (PEG) polymers: The effect of PEG size on permeability. J. Pharm. Sci. 2009, 98, 2847–2856.
DOI Google Scholar
9

Yang, J.; Cho, E.; Seo, S.; Lee, J.; Yoon, H.; Suh, J.; Huh, Y.; Haam, S. Enhancement of cellular binding efficiency and cytotoxicity using polyethylene glycol base triblock copolymeric nanoparticles for targeted drug delivery. J. Biomed. Mater. Res. A 2008, 84A, 273–280.
DOI Google Scholar
10

Wei, X.; Gong, C.; Gou, M.; Fu, S.; Guo, Q.; Shi, S.; Luo, F.; Guo, G.; Qiu, L.; Qian, Z. Biodegradable poly(ε-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system. Int. J. Pharm. 2009, 381, 1–18.
DOI Google Scholar
11

Bazile, D.; Prudhomme, C.; Bassoullet, M. T.; Marlard, M.; Spenlehauer, G.; Veillard, M. Stealth Me. PEG–PLA nano-particles avoid uptake by the mononuclear phagocytes system. J. Pharm. Sci. 1995, 84, 493–498.
DOI Google Scholar
12

Lemarchand, C.; Gref, R.; Couvreur, P. Polysaccharide-decorated nanoparticles. Eur. J. Pharm. Biopharm. 2004, 58, 327–341.
DOI Google Scholar
13

Kailasan, A.; Yuan, Q.; Yang, H. Synthesis and characterization of thermoresponsive polyamidoamine–polyethylene glycol–poly(D, L-lactide) core–shell nanoparticles. Acta Biomater. 2010, 6, 1131–1139.
DOI Google Scholar
14

Owens, D. E.; Peppas, N. A. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 2006, 307, 93–102.
DOI Google Scholar
15

Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. M. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 2008, 14, 1310–1316.
DOI Google Scholar
16

Jiang, W.; Kim, B. Y. S.; Rutka, J. T.; Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotechnol. 2008, 3, 145–150.
DOI Google Scholar
17

Karnik, R.; Gu, F.; Basto, P.; Cannizzaro, C.; Dean, L.; Kyei-Manu, W.; Langer, R.; Farokhzad, O. C. Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett. 2008, 8, 2906–2912.
DOI Google Scholar
18

Goodwin, A. P.; Tabakman, S. M.; Welsher, K.; Sherlock, S. P.; Prencipe, G.; Dai, H. Phospholipid–dextran with a single coupling point: A useful amphiphile for functionalization of nanomaterials. J. Am. Chem. Soc. 2009, 131, 289–296.
DOI Google Scholar
19

Nouvel, C.; Frochot, C.; Sadtler, V.; Dubois, P.; Dellacherie, E.; Six, J. Polylactide-grafted dextrans: Synthesis and properties at interfaces and in solution. Macromolecules 2004, 37, 4981–4988.
DOI Google Scholar
20

Chittasupho, C.; Xie, S.; Baoum, A.; Yakovleva, T.; Siahaan, T. J.; Berkland, C. J. ICAM-1 targeting of doxorubicin-loaded PLGA nanoparticles to lung epithelial cells. Eur. J. Pharm. Sci. 2009, 37, 141–150.
DOI Google Scholar
21

Gu, F.; Zhang, L.; Teply, B. A.; Mann, N.; Wang, A.; Radovic-Moreno, A. F.; Langer, R.; Farokhzad, O. C. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 2586–2591.
DOI Google Scholar
22

Riley, T.; Govender, T.; Stolnik, S.; Xiong, C. D.; Garnett, M. C.; Illum, L.; Davis, S. S. Colloidal stability and drug incorporation aspects of micellar-like PLA–PEG nanoparticles. Colloids Surf. B-Biointerfaces. 1999, 19, 147–159.
DOI Google Scholar
23

Riley, T.; Stolnik, S.; Heald, C. R.; Xiong, C. D.; Garnett, M. C.; Illum, L.; Davis, S. S.; Purkiss, S. C.; Barlow, R. J.; Gellert, P. R. Physicochemical evaluation of nanoparticles assembled from poly(lactic acid)–poly(ethylene glycol) (PLA–PEG) block copolymers as drug delivery vehicles. Langmuir 2001, 17, 3168–3174.
DOI Google Scholar
24

Zahr, A. S.; Davis, C. A.; Pishko, M. V. Macrophage uptake of core–shell nanoparticles surface modified with poly(ethylene glycol). Langmuir 2006, 22, 8178–8185.
DOI Google Scholar
25

Dhar, S.; Gu, F. X.; Langer, R.; Farokhzad, O. C.; Lippard, S. J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(Ⅳ) prodrug–PLGA–PEG nanoparticles. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 17356–17361.
DOI Google Scholar
26

Shuai, X. T.; Ai, H.; Nasongkla, N.; Kim, S.; Gao, J. M. Micellar carriers based on block copolymers of poly(ε-caprolactone) and poly(ethylene glycol) for doxorubicin delivery. J. Control. Release 2004, 98, 415–426.
DOI Google Scholar
27

He, Y. Y.; Zhang, Y.; Gu, C. H.; Dai, W. F.; Lang, M. D. Micellar carrier based on methoxy poly(ethylene glycol)–block–poly(epsilon-caprolactone) block copolymers bearing ketone groups on the polyester block for doxorubicin delivery. J. Mater. Sci. -Mater. Med. 2010, 21, 567–574.
DOI Google Scholar
28

Missirlis, D.; Kawamura, R.; Tirelli, N.; Hubbell, J. A. Doxorubicin encapsulation and diffusional release from stable, polymeric, hydrogel nanoparticles. Eur. J. Pharm. Sci. 2006, 29, 120–129.
DOI Google Scholar
29

Kataoka, K.; Harada, A.; Nagasaki, Y. Block copolymer micelles for drug delivery: Design, characterization and biological significance. Adv. Drug Deliv. Rev. 2001, 47, 113–131.
DOI Google Scholar
30

Alpert, A. J. Hydrophilic-interaction chromatography for the separation of peptides, nucleic acids and other polar compounds. J. Chromatogr. A 1990, 499, 177–196.
DOI Google Scholar
31

Drummond, D. C.; Meyer, O.; Hong, K.; Kirpotin, D. B.; Papahadjopoulos, D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol. Rev. 1999, 51, 691–744.
Google Scholar
32

Safra, T.; Muggia, F.; Jeffers, S.; Tsao-Wei, D. D.; Groshen, S.; Lyass, O.; Henderson, R.; Berry, G.; Gabizon, A. Pegylated liposomal doxorubicin (doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann. Oncol. 2000, 11, 1029–1033.
DOI Google Scholar
33

Magenheim, B.; Levy, M. Y.; Benita, S. A new in vitro technique for the evaluation of drugrelease profile from colloidal carriers–ultrafiltration technique at lowpressure. Int. J. Pharm. 1993, 94, 115–123.
DOI Google Scholar
34

Esmaeili, F.; Ghahremani, M. H.; Ostad, S. N.; Atyabi, F.; Seyedabadi, M.; Malekshahi, M. R.; Amini, M.; Dinarvand, R. Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG–folate conjugate. J. Drug Target. 2008, 16, 415–423.
DOI Google Scholar
35

Dobrovoiskaia, M. A.; Clogston, J. D.; Neun, B. W.; Hall, J. B.; Patri, A. K.; McNeil, S. E. Method for analysis of nanoparticle hemolytic properties in vitro. Nano Lett. 2008, 8, 2180–2187.
DOI Google Scholar
36

Kim, D.; El-Shall, H.; Dennis, D.; Morey, T. Interaction of PLGA nanoparticles with human blood constituents. Colloid Surf. B-Biointerfaces 2005, 40, 83–91.
DOI Google Scholar
37

Fischer, D.; Li, Y. X.; Ahlemeyer, B.; Krieglstein, J.; Kissel, T. In vitro cytotoxicity testing of polycations: Influence of polymer structure on cell viability and hemolysis. Biomaterials 2003, 24, 1121–1131.
DOI Google Scholar
38

Sacco, J. J.; Botten, J.; Macbeth, F.; Bagust, A.; Clark, P. The average body surface area of adult cancer patients in the UK: A multicentre retrospective study. PLoS One 2010, 5, e8933–e8933.
DOI Google Scholar
39

Kusnierz-Glaz, C. R.; Still, B. J.; Amano, M.; Zukor, J. D.; Negrin, R. S.; Blume, K. G.; Strober, S. Granulocyte colony-stimulating factor-induced comobilization of CD4−CD8−T cells and hematopoietic progenitor cells (CD34+) in the blood of normal donors. Blood 1997, 89, 2586–2595.
DOI Google Scholar
40

Yang, Z.; Leon, J.; Martin, M.; Harder, J. W.; Zhang, R.; Liang, D.; Lu, W.; Tian, M.; Gelovani, J. G.; Qiao, A. et al. Pharmacokinetics and biodistribution of near-infrared fluorescence polymeric nanoparticles. Nanotechnology 2009, 20, 165101.
DOI Google Scholar
41

Gaucher, G.; Asahina, K.; Wang, J.; Leroux, J. Effect of poly(N-vinyl-pyrrolidone)-block-poly(D, L-lactide) as coating agent on the opsonization, phagocytosis, and pharmacokinetics of biodegradable nanoparticles. Biomacromolecules 2009, 10, 408–416.
DOI Google Scholar
42

Gaur, U.; Sahoo, S. K.; De, T. K.; Ghosh, P. C.; Maitra, A.; Ghosh, P. K. Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system. Int. J. Pharm. 2000, 202, 1–10.
DOI Google Scholar
43

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, 3657–3666.
DOI Google Scholar
44

Lee, H.; Fonge, H.; Hoang, B.; Reilly, R. M.; Allen, C. The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nano-particles. Mol. Pharm. 2010, 7, 1195–1208.
DOI Google Scholar
45

Allen, T. M.; Hansen, C. Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim. Biophys. Acta-Biomembr. 1991, 1068, 133–141.
DOI Google Scholar
46

Rehor, A.; Schmoekel, H.; Tirelli, N.; Hubbell, J. A. Functionalization of polysulfide nanoparticles and their performance as circulating carriers. Biomaterials 2008, 29, 1958–1966.
DOI Google Scholar
47

Portet, D.; Denizot, B.; Rump, E.; Hindre, F.; Le Jeune, J.; Jallet, P. Comparative biodistribution of thin-coated iron oxide nanoparticles TCION: Effect of different bisphosphonate coatings. Drug Dev. Res. 2001, 54, 173–181.
DOI Google Scholar
48

Li, S.; Huang, L. Pharmacokinetics and biodistribution of nanoparticles. Mol. Pharm. 2008, 5, 496–504.
DOI Google Scholar
49

Peracchia, M. T.; Fattal, E.; Desmaele, D.; Besnard, M.; Noel, J. P.; Gomis, J. M.; Appel, M.; d'Angelo, J.; Couvreur, P. Stealth® PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J. Control. Release 1999, 60, 121–128.
DOI Google Scholar
50

Chouly, C.; Pouliquen, D.; Lucet, I.; Jeune, J. J.; Jallet, P. Development of superparamagnetic nanoparticles for MRI: Effect of particle size, charge and surface nature on biodistribution. J. Microencapsul. 1996, 13, 245–255.
DOI Google Scholar
51

Passirani, C.; Barratt, G.; Devissaguet, J.; Labarre, D. Long-circulating nanoparticles bearing heparin or dextran covalently bound to poly(methyl methacrylate). Pharm. Res. 1998, 15, 1046–1050.
DOI Google Scholar
52

Meerasa, A.; Huang, J. G.; Gu, F. X. CH(50): A revisited hemolytic complement consumption assay for evaluation of nanoparticles and blood plasma protein interaction. Curr. Drug Deliv. 2011, 8, 290–298.
DOI Google Scholar
Publication history
Copyright
Acknowledgements

Publication history

Received: 05 September 2011
Revised: 19 October 2011
Accepted: 28 October 2011
Published: 25 November 2011
Issue date: January 2012

Copyright

© Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2011

Acknowledgements

Acknowledgements

This work was financially supported by Natural Sciences and Engineering Research Council of Canada.

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