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Pankreas Kanserinde Hedefsel Nanopartikül Tedavisi ve Klinik Denemeler

Year 2019, , 506 - 511, 01.12.2019
https://doi.org/10.17343/sdutfd.619021

Abstract

Mortalitesi en yüksek kanser türleri arasında yer alan pankreas kanserinin günümüzde klinik tedavisinde kullanılan kemoterapötik ajanlar, hastalarda sağkalım süresini uzatmada ve pankreas kanserinin ölümcül etkilerini ortadan kaldırmakta yetersiz kalmaktadır. Çeşitli kemoterapötik ajanların, albumin gibi proteinlerle kombine edilerek tedavi için hastalara verilmesi sonucu sağkalım süresinin yaklaşık 1 - 2 ay uzadığı fakat ciddi yan etkilerin meydana geldiği gözlenmiştir. Pankreas kanserinin daha etkin tedavisinin sağlanması için selektif olarak sağlıklı hücreden ziyade hedefsel olarak kanser hücresine yönelik terapötik yaklaşımlara ihtiyaç duyulmaktadır. Tam da bu noktada hedefsel tedavilerin sağlanmasında nanopartikülün önemi son yıllarda öne çıkmakta olup yapılan çalışmalar, nanopartikül ile kaplı hem hidrofilik hem de hidrofobik karakterdeki ilaçların ayrı ayrı veya beraberce verilebildiği yeni tedavi yaklaşımlarının pankreas kanserinde umut verici sonuçlara ulaştığını göstermiştir. Genel olarak solid tümörler için günümüzde faz aşamasında veya faz aşamasını geçmiş olan nanopartikül bazlı hedefsel ilaç denemeleri bulunmakla birlikte, bunlardan 15-20 tanesi Faz 2 ve Faz 3 aşamasında olup klinik denemeleri devam etmektedir. Kolesterol, fosfokolin gibi nötral lipidlerden, katyonik lipidlerden ve polietilenglikol (PEG) ile konjuge edilmiş lipidlerden oluşan nanotaşıyıcılar, hedefsel olarak pankreas kanseri hücrelerine ilaç taşınmasında etkin rol oynamaktadırlar. Bu nanotaşıyıcıların yüzeyine kovalent bir şekilde yerleştirilen aptamer, folat, tripeptit, antikor gibi moleküller hedefe spesifik ilaç iletimini sağlamaktadır. Nanolipozomlar ile taşınan siRNA veya miRNA gibi oligonükleotidler, peptit ve proteinler, hidrofilik ve hidrofobik ilaçlar direkt olarak kanser hücrelerinin içerisine hedefe yönelik olarak ulaşabilmektedirler. Bu sayede nanopartikül aracılı hedefsel tedavi ile, daha az dozda ilaç alımı ve ilaçların vücut içerisindeki toksik etkisinin azaltılması da sağlanmış olur. Yapılan çalışmalar sonucunda elde edilen olumlu veriler ışığında, hedefe yönelik nanopartikül bazlı tedavi türlerinin geliştirilmesi pankreatik kanser tedavisinde yeni bir umut olacaktır. 

References

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  • 13) Gonzalez-Villasana V, Rodriguez-Aguayo C, Arumugam T, Cruz-Monserrate Z, Fuentes-Mattei E, Deng D et al. Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2014; 13(11): 2583-94.
  • 14) Hu P, Chen X, Sun J, Bie P, Zhang LD. siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo. Biosci Rep 2015; 35(1): pii:e00170.
  • 15) Gurbuz N, Ashour AA, Alpay SN, Ozpolat B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One 2014; 9(9): e110067.
  • 16) Ashour AA, Gurbuz N, Alpay SN, Abdel-Aziz AA, Mansour AM, Huo L, Ozpolat B. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J Cell Mol Med 2014; 18(11): 2235-51.
  • 17) Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells. Apoptosis 2014; 19(1): 241-58.
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  • 22) Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, Maitra A. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther 2011; 10(8): 1470-80.
  • 23) Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008; 7(16): 2591-600.
  • 24) Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 2008; 105: 13421–6.
  • 25) Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf. 2001;24(12):903-20.
  • 26) Su M, Chen L, Hitre E, Lee W, Bai L, Papai Z et al. EndoTAG-1 Plus Gemcitabine Versus Gemcitabine Alone in Patients With Measurable Locally Advanced and/or Metastatic Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment. SynCore Biotechnology Co., Ltd. ClinicalTrials.gov Identifier: NCT03126435. 2018.
  • 27) Ang C, DiMaio CJ. A Phase 2 Study of siG12D LODER in Combination With Chemotherapy in Patients With Locally Advanced Pancreatic Cancer (PROTACT). Silenseed Ltd. ClinicalTrials.gov Identifier: NCT01676259. 2018.
  • 28) Senzer N, Nemunaitis J, Nemunaitis D, Bedell C, Edelman G, Barve M et al. Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors. Mol Ther 2013; 21(5): 1096-1103.
  • 29) Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res 2008; 68(23): 9788-98.
  • 30) Schultheis B, Strumberg D, Santel A, Vank C, Gebhardt F, Keil O et al. First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. J Clin Oncol 2014; 32(36): 4141-8.
  • 31) Gurbuz N, Ozpolat B. MicroRNA-based Targeted Therapeutics in Pancreatic Cancer. Anticancer Res 2019; 39(2): 529-32.
Year 2019, , 506 - 511, 01.12.2019
https://doi.org/10.17343/sdutfd.619021

Abstract

References

  • 1) American Cancer Society. Cancer facts & figures 2014 . Atlanta, Georgia: American Cancer Society; 2014. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed March 28, 2014
  • 2) Wang P, Meng ZQ, Chen Z, Lin JH, Zhou ZH, Chen H et al. Survival rate of pancreatic cancer in elderly patients. Hepatogastroenterology 2008; 55: 681–6.
  • 3) Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369(18): 1691–703.
  • 4) Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015; 107(2): pii:dju413.
  • 5) Díaz MR, Vivas-Mejia PE. Nanoparticles as Drug Delivery Systems in Cancer Medicine: Emphasis on RNAi-Containing Nanoliposomes. Pharmaceuticals (Basel) 2013; 6(11): 1361-80.
  • 6) Kanlikilicer P, Ozpolat B, Aslan B, Bayraktar R, Gurbuz N, Rodriguez-Aguayo C et al. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models. Mol Ther Nucleic Acids 2017; 15(9): 251-62.
  • 7) Aslan B, Ozpolat B, Sood AK, Lopez-Berestein G. Nanotechnology in cancer theraphy. J Drug Target 2013; 21(10): 904-13.
  • 8) Gündoğdu R, Çelik V. RNA interferans(RNAi). Erciyes Üniversitesi Fen Bilimleri Enstitüsü Fen Bilimleri Dergisi 2009; 25(1): 34-47.
  • 9) Oylar Ö, Tekin İ. Kanserin teşhis ve tedavisinde nanoteknolojinin önemi. Uludağ Üniversitesi Mimarlık ve Mühendislik Fakültesi Dergisi 2011; 16(1): 147-54.
  • 10) Gondi CS, Rao JS. Concepts in in vivo siRNA delivery for cancer therapy. J Cell Physiol 2009; 220(2): 285-91.
  • 11) Ozpolat B, Sood AK, Lopez-Berestein G. Nanomedicine based approaches for the delivery of siRNA in cancer. J Intern Med 2010; 267(1): 44-53.
  • 12) Pittella F, Cabral H, Maeda Y, Mi P, Watanabe S, Takemoto H et al. Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles. J Control Release 2014; 28(178): 18-24.
  • 13) Gonzalez-Villasana V, Rodriguez-Aguayo C, Arumugam T, Cruz-Monserrate Z, Fuentes-Mattei E, Deng D et al. Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2014; 13(11): 2583-94.
  • 14) Hu P, Chen X, Sun J, Bie P, Zhang LD. siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo. Biosci Rep 2015; 35(1): pii:e00170.
  • 15) Gurbuz N, Ashour AA, Alpay SN, Ozpolat B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One 2014; 9(9): e110067.
  • 16) Ashour AA, Gurbuz N, Alpay SN, Abdel-Aziz AA, Mansour AM, Huo L, Ozpolat B. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J Cell Mol Med 2014; 18(11): 2235-51.
  • 17) Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells. Apoptosis 2014; 19(1): 241-58.
  • 18) Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, Chen C. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg 2009; 33(4): 698-709.
  • 19) Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ 2010; 17(2): 193-9.
  • 20) Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 2009; 4(8): e6816.
  • 21) Kent OA, Fox-Talbot K, Halushka MK. RREB1 repressed miR-143/145 modulates KRAS signaling through downregulation of multiple targets. Oncogene 2013; 32(20): 2576-85.
  • 22) Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, Maitra A. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther 2011; 10(8): 1470-80.
  • 23) Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 2008; 7(16): 2591-600.
  • 24) Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci USA 2008; 105: 13421–6.
  • 25) Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf. 2001;24(12):903-20.
  • 26) Su M, Chen L, Hitre E, Lee W, Bai L, Papai Z et al. EndoTAG-1 Plus Gemcitabine Versus Gemcitabine Alone in Patients With Measurable Locally Advanced and/or Metastatic Adenocarcinoma of the Pancreas Failed on FOLFIRINOX Treatment. SynCore Biotechnology Co., Ltd. ClinicalTrials.gov Identifier: NCT03126435. 2018.
  • 27) Ang C, DiMaio CJ. A Phase 2 Study of siG12D LODER in Combination With Chemotherapy in Patients With Locally Advanced Pancreatic Cancer (PROTACT). Silenseed Ltd. ClinicalTrials.gov Identifier: NCT01676259. 2018.
  • 28) Senzer N, Nemunaitis J, Nemunaitis D, Bedell C, Edelman G, Barve M et al. Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors. Mol Ther 2013; 21(5): 1096-1103.
  • 29) Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res 2008; 68(23): 9788-98.
  • 30) Schultheis B, Strumberg D, Santel A, Vank C, Gebhardt F, Keil O et al. First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. J Clin Oncol 2014; 32(36): 4141-8.
  • 31) Gurbuz N, Ozpolat B. MicroRNA-based Targeted Therapeutics in Pancreatic Cancer. Anticancer Res 2019; 39(2): 529-32.
There are 31 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Reviews
Authors

Kaya Kaya This is me

Sude İyiöz This is me

Bensu Kayacan This is me

Hatice Abit This is me

Şeyma Ceren Şenyiğit This is me

Furkan İlker Özbalcı This is me

Nilgün Gürbüz

Publication Date December 1, 2019
Submission Date September 12, 2019
Acceptance Date November 19, 2019
Published in Issue Year 2019

Cite

Vancouver Kaya K, İyiöz S, Kayacan B, Abit H, Şenyiğit ŞC, Özbalcı Fİ, Gürbüz N. Pankreas Kanserinde Hedefsel Nanopartikül Tedavisi ve Klinik Denemeler. Med J SDU. 2019;26(4):506-11.

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