Research Article

Biodistribution and toxicity of orally administered poly (lactic-co-glycolic) acid nanoparticles to F344 rats for 21 days

149 EB Doran Bldg., Biological & Agricultural Engineering Department, LSU & LSU AgCenter, Baton Rouge, LA 70803, USA

A1218 Pathobiology & Population Medicine, College of Veterinary Medicine, PO Box 6100, Mississippi State, MS 39762-6100, USA

Search for more papers by this author

Carlos E Astete

149 EB Doran Bldg., Biological & Agricultural Engineering Department, LSU & LSU AgCenter, Baton Rouge, LA 70803, USA

Search for more papers by this author

Rhett W Stout

1527 Division of Laboratory Animal Medicine, Pathobiological Sciences, School of Veterinary Medicine, LSU, Baton Rouge, LA 70803, USA

Search for more papers by this author

Diana Coulon

149 EB Doran Bldg., Biological & Agricultural Engineering Department, LSU & LSU AgCenter, Baton Rouge, LA 70803, USA

Search for more papers by this author

Peter Mottram

1527 Division of Laboratory Animal Medicine, Pathobiological Sciences, School of Veterinary Medicine, LSU, Baton Rouge, LA 70803, USA

Search for more papers by this author

Cristina M Sabliov

*Author for correspondence:

E-mail Address: Csabliov@agcenter.lsu.edu

149 EB Doran Bldg., Biological & Agricultural Engineering Department, LSU & LSU AgCenter, Baton Rouge, LA 70803, USA

Search for more papers by this author

Published Online:27 Jun 2016https://doi.org/10.2217/nnm-2016-0022

View article

Abstract

Aim: Quantify the biodistribution and assess the toxicity of PLGA (poly-lactic-co-glycolic acid) and surface-modified PLGA chitosan (PLGA/Chi) nanoparticles (NPs) orally administered for 7, 14 and 21 days to F344 rats. Materials & methods: Fluorescent NPs were tracked in F344 rat tissues, and toxicity was evaluated by alkaline phosphatase and alanine transaminase levels, and by histologic examination of tissue samples. Results: Biodistribution of PLGA and PLGA/Chi were similar, with highest amounts found in the intestine and liver. Alkaline phosphatase increased significantly in treated rats. Mild histological differences were detected in the intestine and liver. Conclusion: PLGA and PLGA/Chi NPs behaved similarly presenting minimal toxicity in the liver and intestine, but not in kidney, lung and brain.

Keywords:

References

1 Leray AM, Vert M, Gautier JC, Benoit JP. Fate of [C-14] poly(dl-lactide-co-glycolide) nanoparticles after intravenous and oral-administration to mice. Int. J. Pharm. 106(3), 201–211 (1994).Crossref, CAS, Google Scholar
2 Yin YS, Chen DW, Qiao MX, Wei XY, Hu HY. Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution. J. Control. Release 123(1), 27–38 (2007).Crossref, Medline, CAS, Google Scholar
3 Semete B, Booysen L, Lemmer Y et al. In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. Nanomedicine 6(5), 662–671 (2010).Crossref, Medline, CAS, Google Scholar
4 Esmaeili F, Ghahremani MH, Esmaeili B, Khoshayand MR, Atyabi F, Dinarvand R. PLGA nanoparticles of different surface properties: preparation and evaluation of their body distribution. Int. J. Pharm. 349(1–2), 249–255 (2008).Crossref, Medline, CAS, Google Scholar
5 Loeschner K, Hadrup N, Qvortrup K et al. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate. Part. Fiber Toxicol. 8(18), 1–14 (2011).Medline, Google Scholar
6 Lasagna-Reeves C, Gonzalez-Romero D, Barria MA et al. Bioaccumulation and toxicity of gold nanoparticles after repeated administration in mice. Biochem. Biophys. Res. Commun. 393(4), 649–655 (2010).Crossref, Medline, CAS, Google Scholar
7 Sarlo K, Blackburn KL, Clark ED et al. Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat. Toxicology 263(2–3), 117–126 (2009).Crossref, Medline, CAS, Google Scholar
8 Saadati R, Dadashzadeh S, Abbasian Z, Soleimanjahi H. Accelerated blood clearance of PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, peg coating, and encapsulated anticancer drug. Pharm. Res. 30(4), 985–995 (2013).Crossref, Medline, CAS, Google Scholar
9 Simon L, Sabliov C. Time analysis of poly(lactic-co-glycolic) acid nanoparticle uptake by major organs following acute intravenous and oral administration in mice and rats. Industrial Biotechnology 9(1), 19–23 (2013).Crossref, CAS, Google Scholar
10 Jani P, Halbert GW, Langridge J, Florence AT. Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J. Pharm. Pharmacol. 42(12), 821–826 (1990).Crossref, Medline, CAS, Google Scholar
11 Alqahtani S, Simon L, Astete CE et al. Cellular uptake, antioxidant and antiproliferative activity of entrapped alpha-tocopherol and gamma-tocotrienol in poly (lactic-co-glycolic) acid (PLGA) and chitosan covered PLGA nanoparticles (PLGA-Chi). J. Colloid Interf. Sci 445, 243–251 (2015).Crossref, Medline, CAS, Google Scholar
12 Trif M, Florian PE, Roseanu A et al. Cytotoxicity and intracellular fate of PLGA and chitosan-coated PLGA nanoparticles in Madin-Darby bovine kidney (MDBK) and human colorectal adenocarcinoma (Colo 205) cells. J. Biomed. Mater. Res. A 103(11), 3599–3611 (2015).Crossref, Medline, CAS, Google Scholar
13 Marslin G, Sheeba CJ, Kalaichelvan VK, Manavalan R, Reddy PN, Franklin G. Poly(D,L-lactic-co-glycolic acid) nanoencapsulation reduces erlotinib-induced subacute toxicity in rat. J. Biomed. Nanotechnol. 5(5), 464–471 (2009).Crossref, Medline, CAS, Google Scholar
14 Peetla C, Labhasetwar V. Effect of molecular structure of cationic surfactants on biophysical interactions of surfactant-modified nanoparticles with a model membrane and cellular uptake. Langmuir 25(4), 2369–2377 (2009).Crossref, Medline, CAS, Google Scholar
15 Sahoo SK, Panyam J, Prabha S, Labhasetwar V. Residual polyvinyl alcohol associated with poly (D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J. Control. Release 82(1), 105–114 (2002).Crossref, Medline, CAS, Google Scholar
16 Sharma G, Van Der Walle CF, Kumar MNVR. Antacid co-encapsulated polyester nanoparticles for peroral delivery of insulin: Development, pharmacokinetics, biodistribution and pharmacodynamics. Int. J. Pharm. 440(1), 99–110 (2013).Crossref, Medline, CAS, Google Scholar
17 Xu F, Yuan Y, Shan X et al. Long-circulation of hemoglobin-loaded polymeric nanoparticles as oxygen carriers with modulated surface charges. Int. J. Pharm. 377(1–2), 199–206 (2009).Crossref, Medline, CAS, Google Scholar
18 Sahana DK, Mittal G, Bhardwaj V, Kumar MNVR. PLGA nanoparticles for oral delivery of hydrophobic drugs: Influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug. J. Pharm. Sci. 97(4), 1530–1542 (2008).Crossref, Medline, CAS, Google Scholar
19 Astete CE, Dolliver D, Whaley M, Khachatryan L, Sabliov CM. Antioxidant poly(lactic-co-glycolic) acid nanoparticles made with alpha-tocopherol-ascorbic acid surfactant. ACS Nano 5(12), 9313–9325 (2011).Crossref, Medline, CAS, Google Scholar
20 Murugeshu A, Astete C, Leonardi C, Morgan T, Sabliov CM. Chitosan/PLGA particles for controlled release of alpha-tocopherol in the GI tract via oral administration. Nanomedicine 6(9), 1513–1528 (2011).Link, CAS, Google Scholar
21 Llabot JM, Salman H, Millotti G, Bernkop-Schnurch A, Allemandi D, Manuel Irache J. Bioadhesive properties of poly(anhydride) nanoparticles coated with different molecular weights chitosan. J. Microencapsul. 28(5), 455–463 (2011).Crossref, Medline, CAS, Google Scholar
22 Smith J, Wood E, Dornish M. Effect of chitosan on epithelial cell tight junctions. Pharm. Res. 21(1), 43–49 (2004).Crossref, Medline, CAS, Google Scholar
23 Nagpal K, Singh SK, Mishra DN. Chitosan nanoparticles: a promising system in novel drug delivery. Chem. Pharm. Bull. (Tokyo) 58(11), 1423–1430 (2010).Crossref, Medline, CAS, Google Scholar
24 Basu S, Harfouche R, Soni S, Chimote G, Mashelkar RA, Sengupta S. Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy. Proc. Natl Acad. Sci. USA 106(19), 7957–7961 (2009).Crossref, Medline, CAS, Google Scholar
25 Carpino LA, Elfaham A, Albericio F. Efficiency in peptide coupling – 1-hydroxy-7-azabenzotriazole vs 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine. J. Org. Chem. 60(11), 3561–3564 (1995).Crossref, CAS, Google Scholar
26 Astete CE, Sabliov CM. Synthesis and characterization of PLGA nanoparticles. J. Biomat. Sci-Polym. E 17(3), 247–289 (2006).Crossref, Medline, CAS, Google Scholar
27 Zigoneanu IG, Astete CE, Sabliov CM. Nanoparticles with entrapped alpha-tocopherol: synthesis, characterization, and controlled release. Nanotechnology 19(10), (2008).Crossref, Medline, Google Scholar
28 Navarro SM, Darensbourg C, Cross L et al. Biodistribution of PLGA and PLGA/chitosan nanoparticles after repeat-dose oral delivery in F344 rats for 7 days. Ther. Deliv. 5(11), 1191–1201 (2014).Crossref, Medline, CAS, Google Scholar
29 Bowers GN Jr., Mccomb RB. Measurement of total alkaline phosphatase activity in human serum. Clin. Chem. 21(13), 1988–1995 (1975).Crossref, Medline, CAS, Google Scholar
30 Wroblewski F, Ladue JS. Serum glutamic pyruvic transaminase in cardiac with hepatic disease. Proc. Soc. Exp. Biol. Med. 91(4), 569–571 (1956).Crossref, Medline, CAS, Google Scholar
31 Bergmeyer HU, Horder M. International federation of clinical chemistry. Scientific committee. Expert panel on enzymes. IFCC document stage 2, draft 1; 1979–11–19 with a view to an IFCC recommendation. IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase. J. Clin. Chem. Clin. Biochem. 18(8), 521–534 (1980).Medline, CAS, Google Scholar
32 Rogers AB, Theve EJ, Feng Y et al. Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res. 67(24), 11536–11546 (2007).Crossref, Medline, CAS, Google Scholar
33 Gilat T, Leikin-Frenkel A, Goldiner I et al. Prevention of diet-induced fatty liver in experimental animals by the oral administration of a fatty acid bile acid conjugate (FABAC). Hepatology 38(2), 436–442 (2003).Crossref, Medline, CAS, Google Scholar
34 Mahler M, Bristol IJ, Leiter EH et al. Differential susceptibility of inbred mouse strains to dextran sulfate sodium-induced colitis. Am. J. Physiol. 274(3), G544–G551 (1998).Medline, CAS, Google Scholar
35 Jain AK, Swarnakar NK, Godugu C, Singh RP, Jain S. The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. Biomaterials 32(2), 503–515 (2011).Crossref, Medline, CAS, Google Scholar
36 Malathi S, Nandhakumar P, Pandiyan V, Webster TJ, Balasubramanian S. Novel PLGA-based nanoparticles for the oral delivery of insulin. Int. J. Nanomedicine 10, 2207–2218 (2015).Medline, CAS, Google Scholar
37 Plapied L, Duhem N, Des Rieux A, Preat V. Fate of polymeric nanocarriers for oral drug delivery. Curr. Opin. Colloid Interface Sci. 16(3), 228–237 (2011).Crossref, CAS, Google Scholar
38 Cho WS, Kang BC, Lee JK, Jeong J, Che JH, Seok SH. Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part. Fiber Toxicol. 10(9), 1–9 (2013).Medline, Google Scholar
39 Kim YS, Kim JS, Cho HS et al. Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. Inhal. Toxicol. 20(6), 575–583 (2008).Crossref, Medline, CAS, Google Scholar
40 Hadrup N, Loeschner K, Bergstrom A et al. Subacute oral toxicity investigation of nanoparticulate and ionic silver in rats. Arch. Toxicol. 86(4), 543–551 (2012).Crossref, Medline, CAS, Google Scholar
41 Semete B, Booysen LIJ, Kalombo L et al. In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles. Toxicol. Appl. Pharmacol. 249(2), 158–165 (2010).Crossref, Medline, CAS, Google Scholar
42 Bazile DV, Ropert C, Huve P et al. Body distribution of fully biodegradable [¹⁴C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats. Biomaterials 13(15), 1093–1102 (1992).Crossref, Medline, CAS, Google Scholar
43 Baati T, Bourasset F, Gharbi N et al. The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. Biomaterials 33(19), 4936–4946 (2012).Crossref, Medline, CAS, Google Scholar
44 Steiniger B. Spleen. In: Encyclopedia of Life Science. Wiley (2006).Crossref, Google Scholar
45 Dinarvand R, Sepehri N, Manoochehri S, Rouhani H, Atyabi F. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents. Int. J. Nanomedicine 6, 877–895 (2011).Crossref, Medline, CAS, Google Scholar
46 Stockham SL, Scott M. Fundamentals of Veterinary Clinical Pathology (First Edition). Blackwell Publishing Company, IA, USA, 1, 435–450 (2002).Google Scholar
47 Crl I. Baseline Hematology and Clinical Chemistry Values for Charles River Fischer344 Rats-CDF® (F-344)CrlBR as a Function of Sex and Age (1984). www.qda.med.kyushu-u.ac.jp:8080/koukai/data/Clinical%20Biochemistry%20Reference%20Valuese.pdf.Google Scholar
48 Suber RL. the effect of three Phlebotomy techniques on hematological ans clinical chemical evaluation in Sprague-Dawley rats. Vet. Clin. Pathol. XIV(1), 23–30 (1985).Crossref, Google Scholar
49 Sonntag O. Haemolysis as an interference factor in clinical chemistry. J. Clin. Chem. Clin. Biochem. 24(2), 127–139 (1986).Medline, CAS, Google Scholar
50 Dziedziejko V, Safranow K, Slowik-Zylka D et al. Comparison of rat and human alkaline phosphatase isoenzymes and isoforms using HPLC and electrophoresis. Biochim. Biophys. Acta 1752(1), 26–33 (2005).Crossref, Medline, CAS, Google Scholar
51 Kominami T, Oda K, Ikehara Y. Induction of rat hepatic alkaline phosphatase and its appearance in serum: electrophoretic characterization of liver-membranous and serum-soluble forms. J. Biochem. 96(3), 901–911 (1984).Crossref, Medline, CAS, Google Scholar
52 Das A, Fishero BA, Christophel JJ et al. Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair. Cell. Tissue Res. 364(1), 125–135 (2015).Crossref, Medline, Google Scholar
53 Qiao C, Zhang K, Sun B et al. Sustained release poly (lactic-co-glycolic acid) microspheres of bone morphogenetic protein 2 plasmid/calcium phosphate to promote in vitro bone formation and in vivo ectopic osteogenesis. Am. J. Transl. Res. 7(12), 2561–2572 (2015).Medline, CAS, Google Scholar

Vol. 11, No. 13

Metrics

Downloaded 189 times

History

Published online 27 June 2016

Published in print July 2016

Information

Keywords

Financial & competing interests disclosure

This work was supported by the Increasing Scientific Data on the Fate, Transport and Behavior of Engineered Nanomaterials in Selected Environmental and Biological Matrices funding program administered jointly by the Environmental Protection Agency (EPA), National Science Foundation (NSF) and US Department of Agriculture (USDA). EPA-G2010-STAR-N2 Food Matrices Award # 2010–05269. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Open access

This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

PDF download