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

Year 2014, Volume: 73 Issue: 1, 9 - 19, 27.11.2014

Abstract

Cancer is a group of diseases in which normal cells are converted to cells capable of autonomous growth
and invasion. In the chemotherapeutic control of cancer, drugs are usually given systemically so they reach
toxic levels in cancer cells. This causes serious side effects in healthy cells. Another important problem with
chemotherapy is resistance developed to cytotoxic drugs (multi drug resistance). As a possible solution to
these problems, in the present study, two different microparticle fabrication methods were compared; double
emulsion 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 that
any change that hinder drug diffusion would result in increased drug content in microparticles. To asses
the cytotoxicities of synthesized microparticles, cell proliferation assays were performed with XTT reagent
on Doxorubicin resitant and sensitive breast cancer cell lines, MCF-7. DOX entrapped microparticles was
effective on both sensitive and DOX resistant MCF-7 cells. The concentration of drug in resistant cancer
cells was increased indicating a partial reversal of drug resistance. The results of this study will provide
new insights to the development of new drug delivery systems for cancer therapy.

References

  • 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.

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

Year 2014, Volume: 73 Issue: 1, 9 - 19, 27.11.2014

Abstract

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.

References

  • 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.
There are 24 citations in total.

Details

Primary Language English
Journal Section Research Articles
Authors

Gülseren Çağlar This is me

Serap Yalçın

Güngör Gündüz This is me

Ufuk Gündüz This is me

Publication Date November 27, 2014
Submission Date November 27, 2014
Published in Issue Year 2014 Volume: 73 Issue: 1

Cite

AMA Çağlar G, Yalçın S, Gündüz G, Gündüz U. Poly (DL-Lactic-Co-Glycolic Acid) Microparticle- Doxorubicin Formulations for Anti-cancer Drug Delivery. Eur J Biol. November 2014;73(1):9-19.