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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
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).
P. Couvreur, E. Fattal, and A. Andremont. Liposomes and nano-particles in the treatment of intracellular bacterial infections. Pharm. Res. 8:1079–1086 (1991).
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).
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).
P. Couvreur. Polyalkylcyanoacrylates as colloidal drug carriers. CRC Crit. Rev. Ther. Drug Car. Syst. 5:1–20 (1988).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
T. Nash. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem. J. 55:416–421 (1953).
E. Borenfreund and J.A. Puerner. Toxicity determined in vitro by morphological alterations and neutral red absorption. Toxicol. Lett. 24:119–124 (1985).
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).
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).
L. Vansnick, P. Couvreur, D. Christiaens-Leyh, and M. Roland. Molecular weights of free and drug-loaded nanoparticles. Pharm. Res. 36–41 (1985).
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).
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).
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).
B. Magenheim and S. Benita. Nanoparticle characterization: a comprehensive physicochemical approach. S.T.P. Pharma Sci. 1:221–241 (1991).
C.W.R. Wade and F. Leonard. Degradation of poly(methyl 2-cyanoacrylates). J. Biomed. Mat. Res. 6:215–220 (1972).
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).
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).
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).
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).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lescure, F., Seguin, C., Breton, P. et al. Preparation and Characterization of Novel Poly(methylidene Malonate 2.1.2.)-Made Nanoparticles. Pharm Res 11, 1270–1277 (1994). https://doi.org/10.1023/A:1018986226557
Issue Date:
DOI: https://doi.org/10.1023/A:1018986226557