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Toxicity Studies of Poly(Anhydride) Nanoparticles as Carriers for Oral Drug Delivery

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ABSTRACT

Purpose

To evaluate the acute and subacute toxicity of poly(anhydride) nanoparticles as carriers for oral drug/antigen delivery.

Methods

Three types of poly(anhydride) nanoparticles were assayed: conventional (NP), nanoparticles containing 2-hydroxypropyl-β-cyclodextrin (NP-HPCD) and nanoparticles coated with poly(ethylene glycol) 6000 (PEG-NP). Nanoparticles were prepared by a desolvation method and characterized in terms of size, zeta potential and morphology. For in vivo oral studies, acute and sub-acute toxicity studies were performed in rats in accordance to the OECD 425 and 407 guidelines respectively. Finally, biodistribution studies were carried out after radiolabelling nanoparticles with 99mtechnetium.

Results

Nanoparticle formulations displayed a homogeneous size of about 180 nm and a negative zeta potential. The LD50 for all the nanoparticles tested was established to be higher than 2000 mg/kg bw. In the sub-chronic oral toxicity studies at two different doses (30 and 300 mg/kg bw), no evident signs of toxicity were found. Lastly, biodistribution studies demonstrated that these carriers remained in the gut with no evidences of particle translocation or distribution to other organs.

Conclusions

Poly(anhydride) nanoparticles (either conventional or modified with HPCD or PEG6000) showed no toxic effects, indicating that these carriers might be a safe strategy for oral delivery of therapeutics.

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Abbreviations

%ID/g:

percentage of injected dose per gram

99mTc:

technetium-99m

ALT:

alanine transaminase

AST:

aspartate transaminase

Bw:

body weight

CT:

computed tomography

Hb:

hemoglobin

HCT:

hematocrit

HPCD:

2-hydroxipropyl-β-cyclodextrin

ITLC:

instant thin layer chromatography

MCH:

mean corpuscular hemoglobin

MCHC:

mean corpuscular hemoglobin concentration

MCV:

mean corpuscular volume

NP:

conventional poly(anhydride) nanoparticles

NP-HPCD:

nanoparticles containing 2-hydroxypropyl-β-cyclodextrin

NP-PEG:

pegylated poly(anhydride) nanoparticles

PEG:

poly(ethylene glycol) 6000

PLT:

platelet count

PVM/MA:

copolymer of methyl vinyl ether and maleic anhydride

RBC:

red blood corpuscles count

SPECT-CT:

single-photon emission computed tomography

WBC:

white blood corpuscles count

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the Ministry of Science and Innovation in Spain (projects SAF2008-02538) and Caja Navarra Foundation (Grant 10828). Patricia Ojer was also financially supported by a grant from the Department of Education of the Gobierno de Navarra in Spain.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmaceutical Technology, University of Navarra, C/Irunlarrea, 1, Pamplona, 31008, Spain

    Patricia Ojer & Juan M. Irache

  2. Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, 31008, Spain

    Patricia Ojer & Adela López de Cerain

  3. Radiopharmacy Unit, Department of Nuclear Medicine, University Clinic of Navarra, Pamplona, 31008, Spain

    Paloma Areses & Ivan Peñuelas

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  1. Patricia Ojer
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  2. Adela López de Cerain
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  4. Ivan Peñuelas
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Correspondence to Juan M. Irache.

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Ojer, P., de Cerain, A.L., Areses, P. et al. Toxicity Studies of Poly(Anhydride) Nanoparticles as Carriers for Oral Drug Delivery. Pharm Res 29, 2615–2627 (2012). https://doi.org/10.1007/s11095-012-0791-8

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  • DOI: https://doi.org/10.1007/s11095-012-0791-8

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