Gülseren ÇAĞLAR, Serap YALÇIN, Güngör GÜNDÜZ, Ufuk GÜNDÜZ

Anti-kanser İlaç Taşınması için Doksorubisin-Poli (DL-Laktik- Ko-Glikolik Asit) Mikroparçacıklarının Formülasyonları

Kanser, hücrelerin kontrolsuz çoğalma ve yayılma özelliği kazandığı bir hastalıktır. Kanserin kemoterapi ile tedavisinde ilaçlar genelde sistemik olarak verilir ve kanser hücrelerinde toksik etkiye ulaşır. Ancak kanserli hücrelerin yanı sıra sağlıklı hücrelerde de ilaç seviyesi toksik düzeylere ulaştığında ciddi yan etkilere neden olmaktadır. Kemoterapi ile ilgili bir başka önemli problemde anti-kanser ilaçlara karşı gelişen dirençliliktir (çoklu ilaç dirençliliği). Bu problemleri çözmek için, çalışmada iki farklı mikroparçacık üretim metodu karşılaştırılmıştır; PLGA mikroparçacıklarının içine, Doksorubisin tekli emulsiyon çözücü buharlaştırma (SE) yöntemi ile tutuklanmıştır. En yüksek ilaç tutuklanma yüzdesi SE tekniği ile elde edilmiştir. Sentezlenen mikroparçacıklar sitotoksisitesini belirlemek için, hücre çoğalma testi, XTT kullanılarak Doksorubisin dirençli ve duyarlı meme kanseri hücre hatlarında, MCF-7, kullanılmıştır. Doksorubisin tutuklanmış mikroparçacıklar hem duyarlı hemde Doksorubisin dirençli MCF-7 hücrelerinde etkili olmuştur. Dirençli kanser hücrelerinde ilacın konsantrasyonu kısmi olarak ilaç dirençliliğinin geri çevrilmesini artırmıştır. Bu çalışmanın sonuçları, kanser tedavisi için yeni ilaç taşıma sistemlerinin geliştirilmesine katkı sağlayacaktır.

Anahtar Kelimeler:

PLGA, Doksorubisin, MCF-7, mikroparçacık, ilaç taşınması

Poly (DL-Lactic-Co-Glycolic Acid) Microparticle- Doxorubicin Formulations for Anti-cancer Drug Delivery

Cancer is a group of diseases in which normal cells are converted to cells capable of autonomous growthand invasion. In the chemotherapeutic control of cancer, drugs are usually given systemically so they reachtoxic levels in cancer cells. This causes serious side effects in healthy cells. Another important problem withchemotherapy is resistance developed to cytotoxic drugs (multi drug resistance). As a possible solution tothese problems, in the present study, two different microparticle fabrication methods were compared; doubleemulsion solvent evaporation (SE) method for encapsulation of Doxorubicin into PLGA microparticles.The most appropriate method was the SE techniquies which lead to higher encapsulation efficiencies.Processing factors were evaluated for their effects on encapsulation efficiency and results indicated thatany change that hinder drug diffusion would result in increased drug content in microparticles. To assesthe cytotoxicities of synthesized microparticles, cell proliferation assays were performed with XTT reagenton Doxorubicin resitant and sensitive breast cancer cell lines, MCF-7. DOX entrapped microparticles waseffective on both sensitive and DOX resistant MCF-7 cells. The concentration of drug in resistant cancercells was increased indicating a partial reversal of drug resistance. The results of this study will providenew insights to the development of new drug delivery systems for cancer therapy.

Keywords:

PLGA, DOX, MCF-7, microparticle, drug delivery.,

PDF

___

Ambudkar S.V., Dey S., Hrycyna C.A., Ramachandra M., Pastan I., Gottesman M.M. (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annual Revıew of Pharmacology and Toxıcology, 39: 361-98.
Barraud L., Merle P., Soma E., Lefrançois L., Guerret S., Chevallier M., Dubernet C., Couvreur P., Trépo C., Vitvitski L. (2005) Increase of DOX sensitivity by DOX-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo. Journal of Hepatology, 42: 736-43.
Bertram J.S. (2000) The molecular biology of cancer. Molecular Aspects of Medicine, 21: 167-223.
Bilati U., Allémann E., Doelker E. (2005) Poly(D,L-lactide-co-glycolide) proteinloaded nanoparticles prepared by the double emulsion method--processing and formulation issues for enhanced entrapment efficiency. Journal of Microencapsulation, 22: 205-14.
Bilati U., Allémann E., Doelker E. (2005) Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles. European Journal of Pharmaceutıcs and Bıopharmaceutıcs, 59: 375-88.
Budhian A., Siegel S.J., Winey K.I. (2007) Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content. International Journal of Pharmaceutics, 336: 367-75.
Cao N., Feng S.S. (2008) DOX conjugated to D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS): conjugation chemistry, characterization, in vitro and in vivo evaluation. Biomaterials, 29: 3856-65.
Cetin M., Vural I., Atila A., Kadıoğlu Y. (2010) Preparation and characterization of anticancer drug-loaded implantable PLGA microparticles. Turk J Chem, 34: 509 – 516.
Chavanpatil M.D., Patil Y., Panyam J. (2006) Susceptibility of nanoparticleencapsulated paclitaxel to P-glycoproteinmediated drug efflux. International Journal of Pharmaceutics, 320: 150-6.
Gabizon A., Catane R., Uziely B., Kaufman B., Safra T., Cohen R., Martin F., Huang A., Barenholz Y. (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of DOX encapsulated in polyethylene-glycol coated liposomes. Cancer Research, 54: 987-92.
Hanahan D., Weinberg R.A. (2011) Hallmarks of cancer: the next generation.Cell 144: 646Iyer A.K., Khaled G., Fang J., Maeda H. (2006) Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discovery Today, 11: 812-8.
Jabr-Milane L.S., van Vlerken L.E., Yadav S., Amiji M.M. (2008) Multi functional nanocarriers to overcome tumor drug resistance. Cancer Treatment Reviews, 34:592-602.
Jiang H.H., Kim T.H., Lee S., Chen X., Youn Y.S., Lee K.C.( 2011) PEGylated TNF related apoptosis inducing ligand (TRAIL) for effective tumor combination therapy. Biomaterials, 32 (33): 8529–8537.
Khodadust R., Unsoy G., Yalçın S., Gündüz G., Gündüz U. (2013) PAMAM Dendrimer
Coated Iron Oxide Nanoparticles: Synthesis and Characterization of Different Generations. Journal of Nanoparticle Research, 15: 1488
Luan X., Skupin M., Siepmann J., Bodmeier R. (2006) Key parameters affecting the initial release (burst) and encapsulation efficiency of peptide-containing poly(lactide-coglycolide) microparticles. International
Journal of Pharmaceutics, 324: 168-75. Phillips G.D.L., Li G., Dugger D.L., Crocker L.M., Parsons K.L., Mai E., Blättler W.A., Lambert J.M., Chari R.V., Lutz R.J., Wong W.L., Jacobson F.S., Koeppen H., Schwall R.H., Kenkare-Mitra S.R., Spencer S.D., Sliwkowski M.X. (2008) Targeting HER2positive breast cancer with trastuzumabDM1, an antibody-cytotoxic drug conjugate. Cancer Research, 68: 9280-90.
Ravivarapu H.B., Lee H., DeLuca P.P. (2000)
Enhancing initial release of peptide from poly(d,l-lactide-co-glycolide) (PLGA) microspheres by addition of a porosigen and increasing drug load. Pharmaceutıcal Development and Technology, 5: 287-96. Sahoo S.K., Panda A.K., Labhasetwar V. (2005) Characterization of porous PLGA/
PLA microparticles as a scaffold for three dimensional growth of breast cancer cells. Biomacromolecules, 6: 1132-9.
Takemura G., Fujiwara H. (2007) DOX-induced cardiomyopathy fromthe cardiotoxic mechanisms to management. Progress in
Cardıovascular Diseases, 49: 330–52. Tewes F., Munnier E., Antoon B., Ngaboni Okassa L., Cohen-Jonathan S., Marchais H., Douziech-Eyrolles L., Soucé M., Dubois P., Chourpa I. (2007) Comparative study of DOX-loaded poly(lactide-coglycolide) nanoparticles prepared by single and double emulsion methods.
European Journal of Pharmaceutıcs and Bıopharmaceutıcs, 66: 488-92. Unsoy G., Yalçın S., Khodadust R., Gündüz G., Gündüz U. (2012) Synthesis optimization and characterization of chitosan coated iron oxide nanoparticles produced for biomedical applications. Journal of
Nanoparticle Research, 14: 964.

ISSN: 2602-2575
Yayın Aralığı: Yılda 2 Sayı
Başlangıç: 1940
Yayıncı: İstanbul Üniversitesi Yayınevi

Arşiv