Pharmaceutical Research

, Volume 11, Issue 9, pp 1270–1277

Preparation and Characterization of Novel Poly(methylidene Malonate 2.1.2.)-Made Nanoparticles

  • François Lescure
  • Christine Seguin
  • Pascal Breton
  • Philippe Bourrinet
  • Didier Roy
  • Patrick Couvreur
Article

Abstract

Poly(methylidene malonate 2.1.2.) (PMM 2.1.2.) nanoparticles were prepared in phosphate buffer through emulsion polymerization of monomeric units; the kinetics of the reaction was monitored by spectrophotometry at 400 nm. Average nanoparticle sizes, molecular weights, and biodegradability of this potential drug carrier were determined under various conditions. As previously demonstrated for other similar monomers, i.e. IHCA or IBCA, pH influenced the physico-chemical characteristics of the nanoparticles obtained. Ethanol release from the ester-bearing side chains indicated that the polymers were susceptible to hydrolysis when incubated in basic pH or in rat plasma. A secondary degradation pathway, yielding formaldehyde through a reverse Knoevenagel’s reaction, was minimal. Cytotoxicity studies of this new vector, in vitro, against L929 fibroblast cells demonstrated that PMM 2.1.2. nanoparticles were better tolerated than other poly(alkylcyanoacrylate) (PACA) carriers. Pharmacokinetic studies were also carried out to observe the fate of 14C-labelled PMM 2.1.2. nanoparticles after intravenous administration to rats. Forty eight hour post-injection, more than 80% of the radioactivity was recovered in urine and faeces. The body distribution of the polymer was estimated by measuring the radioactivity associated with liver, spleen, lung and kidneys. Five minutes after injection, a maximum of 24 ± 2% of the total radioactivity was detected in the liver and less than 0.4% in the spleen. The liver-associated radioactivity decreased according to a biphasic profile and less than 8% of the total radioactivity remained after 6 days.

drug targeting polymeric drug carrier nanoparticle polymerization biodegradation pharmacokinetics 

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REFERENCES

  1. 1.
    N. Chiannilkulchai, Z. Driouich, J.P. Benoit, A.L. Parodi, and P. Couvreur. Doxorubicin-loaded nanoparticles: increased efficiency in murine hepatic metastases. Sel. Cancer Ther. 5:1–11 (1989).Google Scholar
  2. 2.
    P. Couvreur, E. Fattal, and A. Andremont. Liposomes and nano-particles in the treatment of intracellular bacterial infections. Pharm. Res. 8:1079–1086 (1991).Google Scholar
  3. 3.
    C. Damgé, C. Michel, M. Aprahamian, and P. Couvreur. New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier. Diabetes 37:246–251 (1988).Google Scholar
  4. 4.
    J.C. Gautier, J.L. Grangier, A. Barbier, P. Dupont, D. Dussossoy, G. Pastor, and P. Couvreur. Biodegradable nanoparticles for subcutaneous administration of growth hormone releasing factor (hGRF). J. Controlled Rel. 20:67–78 (1992).Google Scholar
  5. 5.
    P. Couvreur. Polyalkylcyanoacrylates as colloidal drug carriers. CRC Crit. Rev. Ther. Drug Car. Syst. 5:1–20 (1988).Google Scholar
  6. 6.
    J. Kattan, J.P. Droz, P. Couvreur, J.P. Marino, A. Boutan-Laroze, P. Rougier, P. Brault, H. Vranckx, J.M. Grognet, X. Morge, and H. Sancho-Garnier. Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexyl-cyanoacrylate nanoparticles. Invest. New Drugs 10:191–199 (1992).Google Scholar
  7. 7.
    P. Couvreur, B. Kante, M. Roland, P. Guiot, P. Bauduin, and P. Speiser. Polycyanoacrylate nanocapsules as potential lysosomotropic carriers: preparation, morphological and sorptive properties. J. Pharm. Pharmacol. 31:331–332 (1979).Google Scholar
  8. 8.
    V. Lenaerts, P. Couvreur, D. Christiaens-Leyh, E. Joiris, M. Roland, B. Rollman, and P. Speiser. Degradation of poly(isobutylcyanoacrylate) nanoparticles. Biomaterials 5:65–68 (1984).Google Scholar
  9. 9.
    C. Lherm, R.H. Müller, F. Puisieux, and P. Couvreur. Alkylcyanoacrylate drug carriers: II. Cytotoxicity of cyanoacrylate nanoparticles with different alkyl chain length. Int. J. Pharm. 84:13–22 (1992).Google Scholar
  10. 10.
    J.-L. De Keyser, C.J.C. De Cock, J.H. Poupaert, and P. Dumont. Synthesis of 14C labelled acrylic derivatives: diethyl [3-14C] methylidenemalonate and isobutyl [3-14C] cyanoacrylate. J. Label. Comp. Radiopharm. 27:909–916 (1989).Google Scholar
  11. 11.
    J.-L. De Keyser, J.H. Poupaert, and P. Dumont. Poly(diethyl methylidenemalonate) nanoparticules as a potential drug carrier: preparation, distribution and elimination after intravenous and peroral administration to mice. J. Pharm. Sci. 80:67–70 (1991).Google Scholar
  12. 12.
    N. Bru-Magniez, C. De Cock, J. Poupaert, J.-L. De Keyser, and P. Dumont. Procédés de préparation de monoesters ou diesters de l'acide endoéthano-9,10 dihydro-9,10 anthracène dicarboxylique-11,11, nouveaux monoesters ou diesters ainsi préparés et utilisation de ceux-ci pour la préparation de methylidènemalonate symétriques ou asymétriques. Eur. Pat. 0 283 364 A2:(1988).Google Scholar
  13. 13.
    P. Bourrinet. Etude de la cinétique sanguine et plasmatique, de la distribution tissulaire et de l'élimination des nanoparticules de méthylidène malonate 2.1.2. administrées par voie intraveineuse chez le rat. Thesis, University of Paris V (1992).Google Scholar
  14. 14.
    F. Lescure, C. Zimmer, D. Roy, J.M. Teulon, and P. Couvreur. Synthesis and evaluation of a new biodegradable monomer. Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 18:325–326 (1991).Google Scholar
  15. 15.
    F. Lescure, C. Zimmer, D. Roy, and P. Couvreur. Optimization of polyalkylcyanoacrylate nanoparticle preparation: Influence of sulfur dioxide and pH on nanoparticle characteristics. J. Colloid Interface Sci. 154:77–86 (1992).Google Scholar
  16. 16.
    T. Nash. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem. J. 55:416–421 (1953).Google Scholar
  17. 17.
    E. Borenfreund and J.A. Puerner. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol. Lett. 24:119–124 (1985).Google Scholar
  18. 18.
    S.J. Douglas, L. Illum, S.S. Davis, and J. Kreuter. Particle size and size distribution of poly(butyl-2-cyanoacrylate) nanoparticles. I. Influence of physicochemical factors. J. Colloid Interface Sci. 101:149–158 (1984).Google Scholar
  19. 19.
    D. Leyh, P. Couvreur, V. Lenaerts, M. Roland, and P. Speiser. Etude du mécanisme de dégradation des nanoparticules de polycyanoacrylate d'alkyle. Labo-Pharma-Probl. Tech. 32:100–104 (1984).Google Scholar
  20. 20.
    L. Vansnick, P. Couvreur, D. Christiaens-Leyh, and M. Roland. Molecular weights of free and drug-loaded nanoparticles. Pharm. Res. 36–41 (1985).Google Scholar
  21. 21.
    S.J. Douglas, S.S. Davis, and S.R. Holding. Molecular weights of poly(butyl 2-cyanoacrylate) produced during nanoparticle formation. Br. Polym. J. 17:339–342 (1985).Google Scholar
  22. 22.
    W.R. Vezin and A.T. Florence. In vitro heterogeneous degradation of poly(n-alkyl α-cyanoacrylates). J. Biomed. Mat. Res. 14:93–106 (1980).Google Scholar
  23. 23.
    F. Leonard, R.K. Kulkarni, G. Brandes, J. Nelson, and J.J. Cameron. Synthesis and degradation of poly(alkyl α-cyanoacrylates). J. Appl. Polym. Sci. 10:259–272 (1966).Google Scholar
  24. 24.
    B. Magenheim and S. Benita. Nanoparticle characterization: a comprehensive physicochemical approach. S.T.P. Pharma Sci. 1:221–241 (1991).Google Scholar
  25. 25.
    C.W.R. Wade and F. Leonard. Degradation of poly(methyl 2-cyanoacrylates). J. Biomed. Mat. Res. 6:215–220 (1972).Google Scholar
  26. 26.
    L. Illum and S.S. Davis. The organ uptake of intravenously administered colloidal particles can be altered using a non-ionic surfactant (Poloxamer 338). FEBS. Lett. 167:79–82 (1984).Google Scholar
  27. 27.
    J. Kreuter. Evaluation of nanoparticles as drug-delivery systems II: comparison of the body distribution of nanoparticles with the body distribution of microspheres (diameter <1 μm) liposomes, and emulsions. Pharm. Acta Helv. 58:217–226 (1989).Google Scholar
  28. 28.
    L. Grislain, P. Couvreur, V. Lenaerts, M. Roland, D. Deprez-Decampeneere, and P. Speiser. Pharmacokinetics and distribution of a biodegradable drug-carrier. Int. J. Pharm. 15:335–345 (1983).Google Scholar
  29. 29.
    E.M. Gipps, P. Groscurth, J. Kreuter, and P.P. Speiser. Distribution of polyhexylcyanoacrylate nanoparticles in nude mice over extended times and after repeated injection. J. Pharm. Sci. 77:208–209 (1988).Google Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • François Lescure
    • 1
  • Christine Seguin
    • 1
  • Pascal Breton
    • 1
  • Philippe Bourrinet
    • 1
  • Didier Roy
    • 1
  • Patrick Couvreur
    • 3
  1. 1.Laboratoires UPSALaboratoire de Recherche GaléniqueFrance
  2. 2.Dr F. Lescure, Laboratoires UPS ALaboratoire de Recherche GaléniqueFrance
  3. 3.Laboratoire de Pharmacie Galénique et de BiopharmacieUniversitéParis XIFrance

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