A Comparative Study of Passive and Active Tumor Targeting Using Nanoparticles as Drug Delivery Systems
Abstract
Nanoparticle-mediated drug targeting is an active
area of cancer research and hold enormous potential in improving anticancer
efficacy by providing tumor tissue specificity.
Herein, tumor targeting capabilities of nanoparticles between passive targeting
approach via the enhanced
permeability and retention (EPR) effect and active
targeting approach via the biotin receptors were compared to determine
targeting efficiency rates. For this reason, Fe3O4@SiO2(FITC)-DOX
(for passive targeting) and Fe3O4@SiO2(FITC)-BTN/DOX
(for active targeting) multifunctional nanoparticles combining imaging and therapy were used. Fluorescence microscopy and
flow cytometry were employed to both visualize and quantify the accumulation of
nanoparticles into the tumor cells. The results demonstrated that active
targeting strategy considerably enhanced nanoparticle accumulation in the cervical carcinoma HeLa cells with
a 2-fold increase in comparison to passive targeting. Targeted nanoparticles
exhibited higher cytotoxicity in cancer cells with an approximately 2.5-fold
better half maximal inhibitory concentration (IC50) value than
untargeted nanoparticles. Moreover, it was found that targeted nanoparticles increased
the number of apoptotic cells by nearly 21.1% as compared to untargeted
nanoparticles. These observations show that active tumor targeting drug
delivery systems could be more promising for enhancing the chemotherapeutic
effects of anticancer drugs as compared to passive tumor targeting drug
delivery systems.
References
- [1] L. Y. Rizzo, B. Theek, G. Storm, F. Kiessling and T. Lammers, “Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications”, Curr. Opin. Biotechnol., 24 (6), pp. 1159–1166, 2013. [2] I. Ojima, X. Geng, X. Wu, C. Qu, C. P. Borella, H. Xie, S. D. Wilhelm, B. A. Leece, L. M. Bartle, V. S. Goldmacher and R. V. J. Chari, “Tumor-Specific Novel Taxoid-Monoclonal Antibody Conjugates”, J. Med. Chem., 45, pp. 5620–5623, 2002. [3] S. Jaracz, J. Chen, L. V. Kuznetsova and I. Ojima, “Recent advances in tumor-targeting anticancer drug conjugates”, Bioorg. Med. Chem., 13, pp. 5043–5054, 2005. [4] S. M. Moghimi, A. C. Hunter and J. C. Murray, “Nanomedicine: current status and future prospects”, FASEB J., 19, pp. 311–330, 2005. [5] H. Maeda, J. Wu, T. Sawa, Y. Matsumura and K. Hori, “Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review”, J. Control. Release, 65 (1–2), pp. 271–284, 2000. [6] F. Danhier, O. Feron and V. Préat, “To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery, J. Control. Release”, 148 (2), pp. 135–146, 2010. [7] G. Russell-Jones, K. McTavish, J. McEwan, J. Rice and D. Nowotnik, “Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumors”, J. Inorg. Biochem., 98, pp. 1625–1633, 2004. [8] C. P. Leamon and J.A. Reddy, “Folate-targeted chemotherapy”, Adv. Drug Deliv. Rev., 56, pp. 1127–1141, 2004. [9] G. Russell-Jones, K. McTavish and J. McEwan, “Preliminary studies on the selective accumulation of vitamin-targeted polymers within tumors”, J. Drug Target., 19(2), pp. 133–139, 2011. [10] S. Chen, X. Zhao, J. Chen, J. Chen, L. Kuznetsova, S. S. Wong and I. Ojima, “Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release”, Bioconjug. Chem., 21, pp. 979–987, 2010. [11] C. Daglioglu, “Enhancing tumor cell response to multidrug resistance with pH-sensitive quercetin and doxorubicin conjugated multifunctional nanoparticles”, Colloids Surf. B Biointerfaces, 156, pp. 175–185, 2017. [12] C. Daglioglu, “Environmentally responsive dual-targeting nanoparticles: improving drug accumulation in cancer cells as a way of preventing anticancer drug efflux”, J. Pharma. Sci., (epub ahead of print) DOI: http://dx.doi.org/10.1016/j.xphs.2017.10.029, 2017. [13] G. Minotti, P. Menna, E. Salvatorelli, G. Cairo and L. Gianni, “Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity”, Pharmacol. Rev., 56, pp. 185–229, 2004. [14] C. Daglioglu and B. Okutucu, “Synthesis and characterization of AICAR and DOX conjugated multifunctional nanoparticles as a platform for synergistic inhibition of cancer cell growth”, Bioconjug. Chem., 27, pp. 1098−1111, 2016. [15] C. Daglioglu and B. Okutucu, “Therapeutic effects of AICAR and DOX conjugated multifunctional nanoparticles in sensitization and elimination of cancer cells via survivin targeting”, Pharm. Res., 34, pp. 175−84, 2017.
İlaç Taşıma Sistemleri olarak Nanopartiküller kullanılarak Pasif ve Aktif Tümör Hedeflemelerinin Karşılaştırmalı İncelenmesi
Abstract
Nanopartikül-aracılı ilaç
hedefleme kanser araştırmalarının aktif bir alanı olup, tümör dokusuna özgün
antikanser etkinliği artırmada çok önemli bir potansiyele sahiptir. Bu
çalışmada, hedefleme verimlilik oranlarının belirlenmesi için pasif ve aktif
hedefli nanopartiküllerin tümör hedefleme kabiliyetleri, sırasıyla artmış
geçirgenlik ve alıkonma (EPR) etkisi ve biyotin reseptörlerini hedefleme
yaklaşımları karşılaştırılarak incelendi. Bunun için, görüntüleme ve tedavi
edici özellikleri bir arada barından Fe3O4@SiO2(FITC)-DOX (pasif
hedefleme için) ve Fe3O4@SiO2(FITC)-BTN/DOX
(aktif hedefleme için) multifonksiyonel nanopartikülleri kullanıldı. Nanopartiküllerin
tümör hücrelerindeki birikiminin izlenmesi ve miktarsal ölçümü için floresan
mikroskopu ve akım sitometresi kullanıldı. Elde edilen sonuçlar, pasif
hedeflemeyle karşılaştırıldığında aktif hedefleme stratejisinin servikal
karsinoma HeLa hücrelerindeki nanopartikül birikimini 2 kat gibi önemli bir ölçüde
artırdığını gösterdi. Aktif hedefli nanopartiküller, pasif hedefli nanopartikülerden
yaklaşık 2.5 kat daha düşük yarı-maksimum inhibisyon konsantrasyonu (IC50)
değeri ile kanser hücrelerinde daha yüksek sitotoksisite sergiledi. Ayrıca, pasif hedefli
nanopartiküllerle karşılaştırıldığında, aktif hedefli nanopartiküllerin apoptotik
hücre sayısını yaklaşık % 21.1 oranında artırdığı bulundu. Bu gözlemler, aktif tümör
hedefli ilaç taşıma sistemlerinin, pasif tümör hedefli ilaç taşıma sistemleri
ile karşılaştırıldığında, antikanser ilaçların kemoterapötik etkilerini artırmada
daha umut verici olduğunu göstermektedir.
References
- [1] L. Y. Rizzo, B. Theek, G. Storm, F. Kiessling and T. Lammers, “Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications”, Curr. Opin. Biotechnol., 24 (6), pp. 1159–1166, 2013. [2] I. Ojima, X. Geng, X. Wu, C. Qu, C. P. Borella, H. Xie, S. D. Wilhelm, B. A. Leece, L. M. Bartle, V. S. Goldmacher and R. V. J. Chari, “Tumor-Specific Novel Taxoid-Monoclonal Antibody Conjugates”, J. Med. Chem., 45, pp. 5620–5623, 2002. [3] S. Jaracz, J. Chen, L. V. Kuznetsova and I. Ojima, “Recent advances in tumor-targeting anticancer drug conjugates”, Bioorg. Med. Chem., 13, pp. 5043–5054, 2005. [4] S. M. Moghimi, A. C. Hunter and J. C. Murray, “Nanomedicine: current status and future prospects”, FASEB J., 19, pp. 311–330, 2005. [5] H. Maeda, J. Wu, T. Sawa, Y. Matsumura and K. Hori, “Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review”, J. Control. Release, 65 (1–2), pp. 271–284, 2000. [6] F. Danhier, O. Feron and V. Préat, “To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery, J. Control. Release”, 148 (2), pp. 135–146, 2010. [7] G. Russell-Jones, K. McTavish, J. McEwan, J. Rice and D. Nowotnik, “Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumors”, J. Inorg. Biochem., 98, pp. 1625–1633, 2004. [8] C. P. Leamon and J.A. Reddy, “Folate-targeted chemotherapy”, Adv. Drug Deliv. Rev., 56, pp. 1127–1141, 2004. [9] G. Russell-Jones, K. McTavish and J. McEwan, “Preliminary studies on the selective accumulation of vitamin-targeted polymers within tumors”, J. Drug Target., 19(2), pp. 133–139, 2011. [10] S. Chen, X. Zhao, J. Chen, J. Chen, L. Kuznetsova, S. S. Wong and I. Ojima, “Mechanism-Based Tumor-Targeting Drug Delivery System. Validation of Efficient Vitamin Receptor-Mediated Endocytosis and Drug Release”, Bioconjug. Chem., 21, pp. 979–987, 2010. [11] C. Daglioglu, “Enhancing tumor cell response to multidrug resistance with pH-sensitive quercetin and doxorubicin conjugated multifunctional nanoparticles”, Colloids Surf. B Biointerfaces, 156, pp. 175–185, 2017. [12] C. Daglioglu, “Environmentally responsive dual-targeting nanoparticles: improving drug accumulation in cancer cells as a way of preventing anticancer drug efflux”, J. Pharma. Sci., (epub ahead of print) DOI: http://dx.doi.org/10.1016/j.xphs.2017.10.029, 2017. [13] G. Minotti, P. Menna, E. Salvatorelli, G. Cairo and L. Gianni, “Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity”, Pharmacol. Rev., 56, pp. 185–229, 2004. [14] C. Daglioglu and B. Okutucu, “Synthesis and characterization of AICAR and DOX conjugated multifunctional nanoparticles as a platform for synergistic inhibition of cancer cell growth”, Bioconjug. Chem., 27, pp. 1098−1111, 2016. [15] C. Daglioglu and B. Okutucu, “Therapeutic effects of AICAR and DOX conjugated multifunctional nanoparticles in sensitization and elimination of cancer cells via survivin targeting”, Pharm. Res., 34, pp. 175−84, 2017.
Details
| Subjects | Engineering |
|---|---|
| Journal Section | Articles |
| Authors | |
| Publication Date | January 31, 2018 |
| Submission Date | November 7, 2017 |
| Published in Issue | Year 2018 Volume: 6 Issue: 1 |