Toxicity of Polyalkylcyanoacrylate Nanoparticles I: Free Nanoparticles

Kanté, Boubacar; Couvreur, Patrick; Dubois-Krack, G.; Meester, Conrad De; Guiot, Pierre; Roland, M; Mercier, Michel; Speiseru, P.

doi:10.1002/jps.2600710716

Cited by 114 publications

(31 citation statements)

References 11 publications

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“…38 Because apparently no brain uptake was observed with control drug-polysorbate 80 solutions, the toxicity of PBCA nanoparticles was proposed as a synergistic factor for BBB permeabilization. 11 The nanoparticle doses permitting brain delivery (100 -166 mg/kg generally) were close to the lethal dose 50% of PBCA nanoparticles (230 mg/kg in mice 16 ). Polysorbate 80-coated or uncoated PBCA nanoparticles (unloaded with drug) induced a dramatic decrease in mice locomotor activity (associated with obvious signs of distress) at a nanoparticle dose of 135 mg/kg and the permeabilization of an in vitro BBB model at a concentration of 10 g/ml (to be compared to the 1.5 mg/ml theoretical concentration reached in mice blood after dosing animals with a 135 mg/kg nanoparticle dose).…”

Section: General Considerationsmentioning

confidence: 90%

“…10 Alternatively, the interaction between adsorbed drugs and the nanoparticle may lack stability, especially when a surfactant is subsequently added to the preparation 11 or, once the nanoparticles are dispersed in blood, by a combined effect of serum protein competition and polymer degradation. 12 The length of the alkyl pendant governs degradation rates 13,14 and toxicity 15,16 of poly-(alkylcyanoacrylate) nanoparticles, which decrease in the order methylϾethylϾbutyl/isobutylϾhexyl/isohexyl.…”

Section: General Considerationsmentioning

confidence: 99%

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Drug transport to brain with targeted nanoparticles

2005

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Summary: Nanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50 -300 nm generally). They cannot freely diffuse through the bloodbrain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyanoacrylate nanoparticles can deliver drugs to the brain by a still debated mechanism. Despite interesting results these nanoparticles have limitations, discussed in this review, that may preclude, or at least limit, their potential clinical applications. Long-circulating nanoparticles made of methoxypoly(ethylene glycol)-polylactide or poly(lactide-co-glycolide) (mPEG-PLA/ PLGA) have a good safety profiles and provide drug-sustained release. The availability of functionalized PEG-PLA permits to prepare target-specific nanoparticles by conjugation of cell surface ligand. Using peptidomimetic antibodies to BBB transcytosis receptor, brain-targeted pegylated immunonanoparticles can now be synthesized that should make possible the delivery of entrapped actives into the brain parenchyma without inducing BBB permeability alteration. This review presents their general properties (structure, loading capacity, pharmacokinetics) and currently available methods for immunonanoparticle preparation.

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Section: General Considerationsmentioning

confidence: 90%

Section: General Considerationsmentioning

confidence: 99%

Drug transport to brain with targeted nanoparticles

2005

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“…No mutagenicity has been shown for polyalkylcyanoacrylate nanoparticles. The 50% lethal dose for mice of polyisobutylcyanoacrylate is 196 mg/kg of body weight (10), and that of PIHCA is greater than 500 mg/kg (P. Couvreur, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of nanoparticle-bound ampicillin in the treatment of Listeria monocytogenes infection in athymic nude mice

Youssef

Fattal

Alonso

et al. 1988

Antimicrob Agents Chemother

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The effectiveness of nanoparticle-bound ampicillin was tested in the treatment of experimental Listeria monocytogenes infection in congenitally athymic nude mice. Nanoparticles of polyisohexylcyanoacrylate (PIHCA) 187 13 nm in diameter were bound to ampicillin at an ampicillin/PIHCA ratio of 0.2:1. The proportion of ampicillin bound was 90% + 3%. After adsorption onto nanoparticles, the therapeutic activity of ampicillin increased dramatically over that in the free state. Thus, 2.4 mg of nanoparticle-bound ampicillin (three doses of 0.8 mg each) had a greater therapeutic effect than 48 mg of free ampicillin (three doses of 16 mg each). These results might provide an incentive for further development of intracellular targeting of antibiotics on biodegradable polymeric carriers.Infections caused by obligate or facultative intracellular microorganisms such as Listeria monocytogenes are difficult to treat, especially in immunocompromised patients (15). The need for intracellular chemotherapy of these infections has been recognized for many years (19). It was recently observed that the use of particulate carriers able to undergo endocytosis increased intracellular delivery of antibiotics (18,20). For instance, when ampicillin was entrapped in liposomes it had an enhanced therapeutic effect on listeriosis in normal mice (1). This was probably because the liposomal encapsulation of ampicillin made it more readily available to intracellular bacteria and allowed lysosomal uptake of the drug (2).Although these results are interesting, large-scale manufacture of liposomes is still difficult. The disruptive effects of human serum on liposomes may lead to some extrusion of trapped drugs (11), and the limited stability of liposomes in circulating blood has been stressed (17). For these reasons, we investigated the possibility of using biodegradable polymeric nanoparticles as an alternative carrier to enhance intracellular drug delivery (4). Owing to their polymeric nature, polyalkylcyanoacrylate nanoparticles may be more stable than liposomes in biological fluids and during storage, and they can generally entrap molecules in a stable and reproducible way (5). This is why we recently described the conditions required for the binding of ampicillin to nanoparticles of polyisohexylcyanoacrylate (PIHCA) and showed that the antimicrobial activity of the drug remained unaltered after linkage to this carrier (8). Desorption of ampicillin from PIHCA nanoparticles is only 10% of the loaded dose after 2 h of incubation in phosphate buffer at 37°C (8).In the present study of experimental murine listeriosis, we found that such nanoparticle-bound ampicillin was significantly more effective than free ampicillin. MATERIALS AND METHODSIsohexylcyanoacrylate monomer (Sopar, Saint-DarmesAvelines, Belgium) (100 ,u) was mechanically stirred at room temperature into 10 ml of an aqueous polymerization medium (1% dextran 70 [Sigma], 5% glucose, 0.001 N HCI) containing 2 mg of ampicillin trihydrate (Negma, Buc, France) per ml. After a 6-h polymerizat...

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“…PACA nanoparticles have first been tested for their toxicity by Kante et al [97] and the authors observed a correlation of toxicity and degradation rate of the homologues. Initially, degradation was believed to occur via a formaldehydeproducing pathway [98], which, however, was later found to be of minor relevance.…”

Section: Toxicitymentioning

confidence: 99%

Poly(alkycyanoacrylate) nanoparticles for enhanced delivery of therapeutics – is there real potential?

Graf

McDowell

Rades

2009

Expert Opinion on Drug Delivery

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The properties inherent in poly(alkylcyanoacrylate) (PACA) nanoparticles, such as biocompatibility and biodegradability of the polymer, a simple preparation process and particularly the entrapment of bioactives, specifically proteins and peptides, have sparked extensive interest in these nanoparticles as drug delivery systems. Research has focused on the oral route of administration, however ocular, transdermal and delivery across the blood-brain barrier have also been investigated. Despite numerous promising studies, no formulation with this colloidal carrier has been marketed to date. A number of factors have been identified as interfering with the reproducibility of in vitro and in vivo results, which impedes the comparison of the plethora of experiments done with PACA nanoparticles. This review will highlight the challenges and opportunities of using PACA nanoparticles as drug delivery systems, including polymerisation mechanisms and templates, entrapment, release, nanoparticle uptake and toxicity. In vitro and in vivo studies, as well as possible surface modifications for targeted delivery in the human field and veterinary applications of PACA nanoparticles are reviewed. Emphasis will be placed on microemulsions as templates for the preparation of PACA nanoparticles and oral delivery of proteins and peptides.

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Toxicity of Polyalkylcyanoacrylate Nanoparticles I: Free Nanoparticles

Cited by 114 publications

References 11 publications

Drug transport to brain with targeted nanoparticles

Drug transport to brain with targeted nanoparticles

Effectiveness of nanoparticle-bound ampicillin in the treatment of Listeria monocytogenes infection in athymic nude mice

Poly(alkycyanoacrylate) nanoparticles for enhanced delivery of therapeutics – is there real potential?

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