Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region
Abstract
Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against αvβ3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLM tumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl]C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C-liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor.
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Due to overexpression of αvβ3 integrin receptors on tumor vasculature, nanoparticles decorated with RGD peptide have more access to targeted tumor tissues.
“For example, due to the overexpression of αvβ3 integrin receptors on tumor vasculature, the nanoparticles decorated with arginine-glycine-glutamic acid (RGD) peptide, a ligand for αvβ3 integrin receptors, have more access to the targeted tumor tissues [163–165].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [165]
Cites
Phosphorus Assay in Column Chromatography
Bartlett, G. R. (1959) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)70226-3 · Cited by 12,802 · see citing works
Liposomal drug delivery systems: From concept to clinical applications
Allen, T. M., & Cullis, P. R. (2013) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.037 · Cited by 4,839 · see citing works
RGD modified polymers: biomaterials for stimulated cell adhesion and beyond
Hersel, U., Dahmen, C., & Kessler, H. (2003) · Biomaterials · doi:10.1016/s0142-9612(03)00343-0 · Cited by 2,590 · see citing works
Albelda, S. M., Mette, S. A., Elder, D. E., Stewart, R., Damjanovich, L., Herlyn, M., & Buck, C. A. (1990) · PubMed · Cited by 760 · see citing works
Mas‐Moruno, C., Rechenmacher, F., & Kessler, H. (2010) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152010794728639 · Cited by 649 · see citing works
Multifunctional and stimuli-sensitive pharmaceutical nanocarriers
Torchilin, V. (2009) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.09.026 · Cited by 583 · see citing works
Andresen, T. L., Jensen, S. S., & Jørgensen, K. (2005) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.12.001 · Cited by 580 · see citing works
Reynolds, A. R., Hart, I. R., Watson, A. R., Welti, J. C., Silva, R. G., Robinson, S. D., Violante, G. D., Gourlaouen, M., Salih, M., Jones, M., et al. (2009) · Nature Medicine · doi:10.1038/nm.1941 · Cited by 494 · see citing works
Temming, K., Schiffelers, R. M., Molema, G., & Kok, R. J. (2005) · Drug Resistance Updates · doi:10.1016/j.drup.2005.10.002 · Cited by 467 · see citing works
Gabizon, A. (2004) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2004.01.011 · Cited by 464 · see citing works
Ligand-targeted particulate nanomedicines undergoing clinical evaluation: Current status
van der Meel, R., Vehmeijer, L. J. C., Kok, R. J., Storm, G., & van Gaal, E. V. B. (2013) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2013.08.012 · Cited by 398 · see citing works
Allen, C. J., Santos, N. D., Gallagher, R., Chiu, G. N. C., Shu, Y., Li, W. M., Johnstone, S. A., Janoff, A. S., Mayer, L. D., Webb, M. S., et al. (2002) · Bioscience Reports · doi:10.1023/a:1020186505848 · Cited by 388 · see citing works
Anti-tumor efficacy of tumor vasculature-targeted liposomal doxorubicin
Schiffelers, R. M. (2003) · Journal of Controlled Release · doi:10.1016/s0168-3659(03)00240-2 · Cited by 307 · see citing works
Forssen, E. A., & Willis, M. C. (1998) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00083-5 · Cited by 287 · see citing works
Zitzmann, S., Ehemann, V., & Schwab, M. (2002) · PubMed · Cited by 265 · see citing works
Tseng, Y., Liu, J., & Hong, R. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.4.864 · Cited by 241 · see citing works
The Role of αvβ3 in Prostate Cancer Progression
Cooper, C. R., Chay, C. H., & Pienta, K. J. (2002) · Neoplasia · doi:10.1038/sj.neo.7900224 · Cited by 238 · see citing works
Schleich, N., Po, C., Jacobs, D., Ucakar, B., Gallez, B., Danhier, F., & Préat, V. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.07.059 · Cited by 238 · see citing works
Li, L., ten Hagen, T. L. M., Hossann, M., Süss, R., van Rhoon, G. C., Eggermont, A. M. M., Haemmerich, D., & Koning, G. A. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.03.011 · Cited by 211 · see citing works
Self-citationWang, F., Chen, L., Zhang, R., Chen, Z., & Zhu, L. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.10.012 · Cited by 190 · see citing works
Seynhaeve, A. L. B., Hoving, S., Schipper, D., Vermeulen, C. E., de Wiel‐Ambagtsheer, G. A., van Tiel, S. T., Eggermont, A. M. M., & ten Hagen, T. L. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1599 · Cited by 175 · see citing works
Seynhaeve, A. L. B., Dicheva, B. M., Hoving, S., et al. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.08.034 · Cited by 156 · see citing works
Targeting colon cancer cells using PEGylated liposomes modified with a fibronectin-mimetic peptide
Garg, A., Tisdale, A. W., Haidari, E. S., & Kokkoli, E. (2008) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2008.09.016 · Cited by 151 · see citing works
Dicheva, B. M., ten Hagen, T. L. M., Li, L., et al. (2012) · Nano Letters · doi:10.1021/nl3014154 · Cited by 125 · see citing works
The development of site-specific drug delivery nanocarriers based on receptor mediation
Wang, X., Li, S., Shi, Y., Chuan, X., Li, J., Zhong, T., Zhang, H., Dai, W., He, B., & Zhang, Q. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.05.028 · Cited by 113 · see citing works
Heckmann, D., Meyer, A., Marinelli, L., Zahn, G., Stragies, R., & Kessler, H. (2007) · Angewandte Chemie International Edition · doi:10.1002/anie.200700008 · Cited by 102 · see citing works
Amin, M., Badiee, A., & Jaafari, M. R. (2013) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2013.10.018 · Cited by 101 · see citing works
Self-citationDesign and Chemical Synthesis of Integrin Ligands
Heckmann, D., & Kessler, H. (2007) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(07)26020-3 · Cited by 88 · see citing works
Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery
Kim, H., Nam, K., & Kim, S. W. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.05.021 · Cited by 87 · see citing works
Targeted Multifunctional Lipid-Based Nanocarriers for Image-Guided Drug Delivery
Koning, G. A., & Krijger, G. C. (2007) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/187152007781058613 · Cited by 86 · see citing works
Self-citationNallamothu, R., Wood, G. C., Pattillo, C. B., et al. (2006) · AAPS PharmSciTech · doi:10.1208/pt070232 · Cited by 82 · see citing works
Zhang, X., Yao, S., Liu, C., et al. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.11.003 · Cited by 73 · see citing works
Increasing αvβ3 Selectivity of the Anti‐Angiogenic Drug Cilengitide by N‐Methylation
Mas‐Moruno, C., Beck, J. G., Doedens, L., et al. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201102971 · Cited by 69 · see citing works
In vivo imaging of tumour angiogenesis in mice with the αvβ3 integrin-targeted tracer 99mTc-RAFT-RGD
Sancey, L., Ardisson, V., Riou, L. M., Ahmadi, M., Batlle, D. M., Boturyn, D., Dumy, P., Fagret, D., Ghezzi, C., & Vuillez, J.-P. (2007) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-007-0497-z · Cited by 66 · see citing works
Gruber, G., Hess, J., Stiefel, C., Aebersold, D. M., Zimmer, Y., Greiner, R. H., Studer, U. E., Altermatt, H. J., Hlushchuk, R., & Djonov, V. (2004) · British Journal of Cancer · doi:10.1038/sj.bjc.6602278 · Cited by 66 · see citing works
Ragelle, H., Colombo, S., Pourcelle, V., Vanvarenberg, K., Vandermeulen, G., Bouzin, C., Marchand‐Brynaert, J., Féron, O., Foged, C., & Véronique Préat, A. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.05.274 · Cited by 61 · see citing works
Diou, O., Fattal, E., Delplace, V., Mackiewicz, N., Nicolas, J., Mériaux, S., Valette, J., Pujolle-Robic, C., & Tsapis, N. (2013) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2013.12.003 · Cited by 53 · see citing works
Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin
Shahin, M., Soudy, R., El-Sikhry, H. E., et al. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.10.007 · Cited by 44 · see citing works
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Li, L., Hu, S., & Chen, X. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.031 · Cited by 415 · see citing works
Mosafer, J., Teymouri, M., Abnous, K., Tafaghodi, M., & Ramezani, M. (2017) · Materials Science and Engineering: C · doi:10.1016/j.msec.2016.11.053 · Cited by 60 · see citing works
- Authors
- Amin, M., Mansourian, M., Koning, G. A., Badiee, A., Jaafari, M. R., & ten Hagen, T. L. M.
- Affiliations
- Mashhad University of Medical Sciences (IR)
- Erasmus MC (NL)
- Corresponding author
- Jaafari, Mahmoud Reza
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 220
- Issue
- Pt A
- Pages
- 308-315
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W2194137888
- Cited by
- 83
- References
- 38
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 11 · 2020: 9 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 8
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- RGD peptide, liposomal drug delivery, integrin αvβ3, tumor targeting, PEGylated liposomes, doxorubicin, tumor vasculature, reticuloendothelial system, opsonization, tissue distribution, tumor cell targeting, B16F0 melanoma, intravital microscopy
- MeSH terms
- Intravital Microscopy, Animals, Antibiotics, Antineoplastic, Doxorubicin, Drug Carriers, Drug Compounding, Drug Stability, Humans, Injections, Intravenous, Melanoma, Experimental, Mice, Inbred BALB C, Mice, Inbred C57BL, Peptides, Cyclic, Polyethylene Glycols, Skin Neoplasms, Tissue Distribution, Colorectal Neoplasms, Microscopy, Confocal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Hydrophobic and Hydrophilic Interactions, Human Umbilical Vein Endothelial Cells
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