Abstract
Purpose
This study was carried out to formulate poly(lactide-co-glycolide) (PLGA) nanoparticles using a quaternary ammonium salt didodecyl dimethylammonium bromide (DMAB) and checking their utility to deliver paclitaxel by oral route.
Methods
Particles were prepared by emulsion solvent diffusion evaporation method. DMAB and particles stabilized with it were evaluated by MTT and LDH cytotoxicity assays. Paclitaxel was encapsulated in these nanoparticles and evaluated in a chemical carcinogenesis model in Sprague Dawley rats.
Results
MTT and LDH assays showed the surfactant to be safe to in vitro cell cultures at concentrations <33 μM. PLGA nanoparticles prepared using this stabilizer were also found to be non-toxic to cell lines for the duration of the study. When administered orally to rats bearing chemically induced breast cancer, nanoparticles were equally effective/better than intravenous paclitaxel in cremophor EL at 50% lower dose.
Conclusions
This study proves the safety and utility of DMAB in stabilizing preformed polymers like PLGA resulting in nanoparticles. This preliminary data provides a proof of concept of enabling oral chemotherapy by efficacy enhancement for paclitaxel.
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REFERENCES
Pillai O, Dhanikula AB, Panchagnula R. Drug delivery: an odyssey of 100 years. Curr Opin Chem Biol. 2001;5:439–46.
Kante B, Couvreur P, Lenaerts V, Guiot P, Roland M, Baudhuin P, et al. Tissue distribution of [3H]actinomycin D adsorbed on polybutylcyanoacrylate nanoparticles. Int J Pharm. 1980;7:45–53.
Couvreur P, Tulkens P, Roland M. Nanocapsules: a new type of lysosomotropic carrier. FEBS Lett. 1977;84:323–6.
Moghimi SM, Kissel T. Particulate nanomedicines. Adv Drug Del Rev. 2006;58:1451–5.
Hanes J. New polymeric nanomedicines for targeted and controlled drug delivery. Nanomed Nanotech Bio Med. 2006;2:273.
Alonso MJ. Nanomedicines for overcoming biological barriers. Biomed Pharmacother. 2004;58:168–72.
Duncan R. Nanomedicine gets clinical. Materials Today. 2005;8:16–7.
Florence AT. The oral absorption of micro- and nanoparticulates: neither exceptional nor unusual. Pharm Res. 1997;14:259–66.
Sakuma S, Hayashi M, Akashi M. Design of nanoparticles composed of graft copolymers for oral peptide delivery. Adv Drug Deliv Rev. 2001;47:21–37.
Eldridge JH, Hammond CJ, Meulbroek JA, Staas JK, Gilley RM, Tice TR. Controlled vaccine release in the gut-associated lymphoid tissues. I. Orally administrated biodegradable microspheres target the Peyer’s patches. J Control Release. 1990;11:205–14.
Mathiowitz E, Jacob JS, Jong YS, Carino GP, Chickering DE, Chaturvedi P, et al. Biologically erodable microspheres as potential oral drug delivery systems. Nature 1997;386:410–4.
Desai MP, Labhasetwar V, Walter E, Levy RJ, Amidon GL. The mechanism of uptake of biodegradable microparticles in Caco-2 cells is size dependent. Pharm Res. 1997;14:1568–73.
Bhardwaj V, Hariharan S, Bala I, Lamprecht A, Kumar N, Panchagnula R, et al. Pharmaceutical aspects of polymeric nanoparticles for oral delivery. J Biomed Nanotech. 2005;1:235–58.
Bala I, Bhardwaj V, Hariharan S, Sitterberg J, Bakowsky U, Kumar MNVR. Design of biodegradable nanoparticles: a novel approach to encapsulate poorly soluble phytochemical ellagic acid. Nanotechnology 2005;16:2819–22.
Hariharan S, Bhardwaj V, Bala I, Sitterberg J, Bakowsky U, Kumar MNVR. Design of estradiol loaded PLGA nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm Res. 2006;23:184–96.
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 2009;25:2369–77.
Roy SN, Horwitz SB. A phosphoglycoprotein associated with taxol resistance in J774.2 cells. Cancer Res. 1985;45:3856–63.
Dye D, Watkins J. Suspected anaphylactic reaction to cremophor EL. Br Med J. 1980;280:1353.
Mittal G, Sahana DK, Bhardwaj V, Kumar MNVR. Estradiol loaded PLGA nanoparticles for oral administration: effect of polymer molecular weight and copolymer composition on release behavior in vitro and in vivo. J Control Release. 2007;119:77–85.
Ankola DD, Viswanad B, Bhardwaj V, Ramarao P, Kumar MNVR. Development of potent oral nanoparticulate formulation of coenzyme Q10 for treatment of hypertension: can the simple nutritional supplements be used as first line therapeutic agents for prophylaxis/therapy? Eur J Pharm Biopharm. 2007;67:361–9.
Kumar MNVR, Bakowsky U, Lehr CM. Preparation and characterization of cationic PLGA nanospheres as DNA carriers. Biomaterials 2004;25:1771–7.
Kumar MNVR, Vadhanam MV, Horn J, Flesher JW, Gupta RC. Formation of benzylic-DNA adducts resulting from 7, 12-dimethylbenz[a]anthracene in vivo. Chem Res Toxicol. 2005;18:686–91.
Geyer RP, Bleisch VR, Bryant JE, Robbins AN, Saslaw IM, Stare FJ. Tumor production in rats injected intravenously with oil emulsions containing 9, 10-dimethyl-1, 2-benzanthracene. Cancer Res. 1951;11:474–8.
Huggins C, Grand LC, Brillantes FP. Mammary cancer induced by a single feeding of polynuclear hydrocarbons, and its suppression. Nature 1961;189:204–7.
Song C, Labhasetwar V, Cui X, Underwood T, Levy RJ. Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model. J Control Release. 1998;54:201–11.
Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA. 2006;103:4930–4.
Champion J, Mitragotri S. Shape induced inhibition of phagocytosis of polymer particles. Pharm Res. 2009;26:244–9.
Kaufmann Y, Kornbluth J, Feng Z, Fahr M, Schaefer RF, Klimberg VS. Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development. J Parenter Enteral Nutr. 2003;27:411–8.
Rehm S. Chemically induced mammary gland adenomyoepitheliomas and myoepithelial carcinomas of mice. Immunohistochemical and ultrastructural features. Am J Pathol. 1990;136:575–84.
Azarmi S, Roa WH, Löbenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Delivery Rev. 2008;60:863–75.
Maeda H. The tumor blood vessel as an ideal target for macromolecular anticancer agents. J Control Release. 1992;19:315–24.
Duncan R. Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm Sci Tech Today. 1999;2:441–9.
Sahana D, Mittal G, Bhardwaj V, Kumar MNVR. PLGA nanoparticles for oral administration 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. 2008;97:1530–42.
Cao L, Sun D, Cruz T, Moscarello MA, Ludwin SK, Whitaker JN. Inhibition of experimental allergic encephalomyelitis in the Lewis rat by paclitaxel. J Neuroimmunol. 2000;108:103–11.
Holzgrabe U. Paclitaxel for Alzheimer treatment. Pharm Unserer Zeit. 2005;34:96.
Brahn E, Tang C, Banquerigo ML. Regression of collagen-induced arthritis with taxol, a microtubule stabilizer. Arthritis Rheum. 1994;37:839–45.
Liggins RT, Burt HM. Paclitaxel-loaded poly(-lactic acid) microspheres 3: blending low and high molecular weight polymers to control morphology and drug release. Int J Pharm. 2004;282:61–71.
Woo DDL, Jr APT, Wang CJN. Microtubule active taxanes inhibit polycystic kidney disease progression in cpk mice. Kidney Int. 1997;51:1613–8.
Ehrlich A, Booher S, Becerra Y, Borris DL, Figg WD, Turner ML, et al. Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot study. J Am Acad Dermatol. 2004;50:533–40.
Jiang Q, Yan Z, Feng J. Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons. J Bio Chem. 2006;281:29391–400.
ACKNOWLEDGMENTS
V. Bhardwaj is grateful for the financial support of a Galenos Fellowship in the Framework of the EU Project “Towards a European PhD in Advanced Drug Delivery,” Marie Curie Contract MEST-CT-2004-404992. The partial in vitro and in vivo work presented here is conducted at NIPER and authors thank Director NIPER for extending the facility. Financial support (No. IR/SO/LF-03/2006) from Department of Science and Technology (DST), Govt. of India is acknowledged.
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Bhardwaj, V., Ankola, D.D., Gupta, S.C. et al. PLGA Nanoparticles Stabilized with Cationic Surfactant: Safety Studies and Application in Oral Delivery of Paclitaxel to Treat Chemical-Induced Breast Cancer in Rat. Pharm Res 26, 2495–2503 (2009). https://doi.org/10.1007/s11095-009-9965-4
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DOI: https://doi.org/10.1007/s11095-009-9965-4