Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer

doi:10.5246/jcps.2019.09.060

Abstract

Abstract:

The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression. Targeting to different cell populations might result in improved therapeutic effects on malignant tumors. Integrins high express on many kinds of tumor cells, and VEGF has a strong effect on tumor angiogenesis. Therefore, based on tumor cells and angiogenesis, we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab. We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model. The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin; cRGD-DOX nanoparticles showed less cytotoxic than free DOX; Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL. The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure; the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments. These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.

Key words: RGD-DOX, Self-assembled nanoparticles, Bevacizumab, Combination therapy, Breast cancer

CLC Number:

R943

Supporting:

Xueling Wang, Yanqin Liang, Yuan Zhang, Bing He, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang. Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(9): 627-640.

References

[1] Chen, W.Q.; Zheng, R.S.; Baade, P.D.; Zhang, S.W.; Zeng, H.M.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA Cancer J. Clin. 2016, 66, 115-132.

[2] Dissanayake, S.; Denny, W.A.; Gamage, S.; Sarojini, V. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides. J. Control. Release. 2017, 250, 62-76.

[3] Shi, J.J.; Votruba, A.R.; Farokhzad, O.C.; Langer, R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010, 10, 3223-3230.

[4] Allen, M.; Louise Jones, J. Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J. Pathol. 2011, 223, 162-176.

[5] Chen, B.L.; Dai, W.B.; He, B.; Zhang, H.; Wang, X.Q.; Wang, Y.G.; Zhang, Q. Current multistage drug delivery systems based on the tumor microenvironment. Theranostics. 2017, 7, 538-558.

[6] Zardavas, D.; Baselga, J.; Piccart, M. Emerging targeted agents in metastatic breast cancer. Nat. Rev. Clin. Oncol. 2013, 10, 191-210.

[7] Barker, H.E.; Paget, J.T.; Khan, A.A.; Harrington, K.J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer. 2015, 15, 409-425.

[8] Hanahan, D.; Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012, 21, 309-322.

[9] Giancotti, F.G.; Ruoslahti, E. Integrin signaling. Science. 1999, 285, 1028-1032.

[10] Desgrosellier, J.S.; Cheresh, D.A. Integrins in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer. 2010, 10, 9-22.

[11] Dissanayake, S.; Denny, W.A.; Gamage, S.; Sarojini, V. Recent developments in anticancer drug delivery using cell penetrating and tumor targeting peptides. J. Control. Release. 2017, 250, 62-76.

[12] Arosio, D.; Casagrande, C. Advancement in integrin facilitated drug delivery. Adv. Drug Deliv. Rev. 2016, 97, 111-143.

[13] Arap, W. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science. 1998, 279, 377-380.

[14] Dal Corso, A.; Caruso, M.; Belvisi, L.; Arosio, D.; Piarulli, U.; Albanese, C.; Gasparri, F.; Marsiglio, A.; Sola, F.; Troiani, S.; Valsasina, B.; Pignataro, L.; Donati, D.; Gennari, C. Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers. Chemistry. 2015, 21, 6921-6929.

[15] Dal Pozzo, A.; Ni, M.H.; Esposito, E.; Dallavalle, S.; Musso, L.; Bargiotti, A.; Pisano, C.; Vesci, L.; Bucci, F.; Castorina, M.; Foderà, R.; Giannini, G.; Aulicino, C.; Penco, S. Novel tumor-targeted RGD peptide-camptothecin conjugates: synthesis and biological evaluation. Bioorg. Med. Chem. 2010, 18, 64-72.

[16] Rao, N.; Lee, Y.F.; Ge, R.W. Novel endogenous angiogenesis inhibitors and their therapeutic potential. Acta Pharmacol. Sin. 2015, 36, 1177-1190.

[17] Wang, Z.W.; Dabrosin, C.; Yin, X.; Fuster, M.M.; Arreola, A.; Rathmell, W.K.; Generali, D.; Nagaraju, G.P.; El-Rayes, B.; Ribatti, D.; Chen, Y.C.; Honoki, K.; Fujii, H.; Georgakilas, A.G.; Nowsheen, S.; Amedei, A.; Niccolai, E.; Amin, A.; Ashraf, S.S.; Helferich, B.; Yang, X.J.; Guha, G.; Bhakta, D.; Ciriolo, M.R.; Aquilano, K.; Chen, S.; Halicka, D.; Mohammed, S.I.; Azmi, A.S.; Bilsland, A.; Keith, W.N.; Jensen, L.D. Broad targeting of angiogenesis for cancer prevention and therapy. Semin. Cancer Biol. 2015, 35 Suppl, S224-S243.

[18] Jain, R.K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005, 307, 58-62.

[19] Fukumura, D.; Jain, R.K. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc. Res. 2007, 74, 72-84.

[20] Ferrara, N.; Kerbel, R.S. Angiogenesis as a therapeutic target. Nature. 2005, 438, 967-974.

[21] Willett, C.G.; Duda, D.G.; di Tomaso, E.; Boucher, Y.; Ancukiewicz, M.; Sahani, D.V.; Lahdenranta, J.; Chung, D.C.; Fischman, A.J.; Lauwers, G.Y.; Shellito, P.; Czito, B.G.; Wong, T.Z.; Paulson, E.; Poleski, M.; Vujaskovic, Z.; Bentley, R.; Chen, H.X.; Clark, J.W.; Jain, R.K. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: A multidisciplinary phase II study. J. Clin. Oncol. 2009, 27, 3020-3026.

[22] Jain, R.K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 2013, 31, 2205-2218.

[23] Fan, Y.C.; Du, W.W.; He, B.; Fu, F.Y.; Yuan, L.; Wu, H.N.; Dai, W.B.; Zhang, H.; Wang, X.Q.; Wang, J.C.; Zhang, X.; Zhang, Q. The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin. Biomaterials. 2013, 34, 2277-2288.

[24] Jain, R.K.; Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 2010, 7, 653-664.

[25] Rakocevic, J.; Orlic, D.; Mitrovic-Ajtic, O.; Tomasevic, M.; Dobric, M.; Zlatic, N.; Milasinovic, D.; Stankovic, G.; Ostojić, M.; Labudovic-Borovic, M. Endothelial cell markers from clinician’s perspective. Exp. Mol. Pathol. 2017, 102, 303-313.

[26] Pathmanathan, N.; Balleine, R.L. Ki67 and proliferation in breast cancer. J. Clin. Pathol. 2013, 66, 512-516.