A new approach towards developing a smart and multifunctional peptide-based drug delivery system for selective targeting and treatment of invasive/metastatic breast cancer.

Main Article Content

Walhan Alshaer
Hamdi Nsairat
Malek Zihlif

Keywords

Estrogen receptor, Metastasis, Metalloproteinases, Endoxifen, Targeted drug delivery

Abstract

Cancer remains one of the leading causes of morbidity and mortality worldwide. Breast cancer is the most frequently diagnosed cancer and causes cancerrelated deaths in women. In cancer, targeted drugs are often divided into two strategies: “passive targeting” and “active targeting”. Passive targeting suffers from low selectivity and poor retention in tumors. Such limitations lead to the development of an active targeting strategy. Active targeting describes the specific interaction between drugs or drug carriers and target cells, which usually occurs through receptor-ligand interactions. Here, we propose to develop a peptide-based drug conjugate as a novel targeted drug delivery system that enhances selectivity, localization, and activity of antitumor therapeutics on metastatic and invasive breast cancer cells by using endoxefin (END) as a targeting ligand for estrogen receptor, Metalloproteinase peptide-substrate (MMP2) for trigger release of drug, and doxorubicin (DOX) as an antitumor therapeutic.

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References

REFERENCES
1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262. PubMed PMID:25651787.
2. Heath JR, Davis ME. Nanotechnology and cancer. Annu Rev Med. 2008;59:251-65. Epub 2007/10/17. doi:10.1146/annurev.med.59.061506.185523. PubMed PMID:17937588; PubMed Central PMCID:PMC3706454.
3. Kim KY. Nanotechnology platforms and physiological challenges for cancer therapeutics. Nanomedicine. 2007;3(2):103-10. Epub 2007/04/20. doi:S1549-9634(07)00044-5 [pii] 10.1016/j.nano.2006.12.002. PubMed PMID:17442621.
4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi:10.1016/j.cell.2011.02.013. PubMed PMID:21376230.
5. Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini PL. 2011: the immune hallmarks of cancer. Cancer Immunol Immunother. 2011;60(3):319-26. doi:10.1007/s00262-010-0968-0. PubMed PMID:21267721; PubMed Central PMCID:PMC3042096.
6. Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer. 2009;9(8):576-86. doi:10.1038/nrc2683. PubMed PMID:19629072.
7. El-Masry TA, El-Nagar MMF, Oriquat GA, Alotaibi BS, Saad HM, El Zahaby EI, et al. Therapeutic efficiency of Tamoxifen/Orlistat nanocrystals against solid ehrlich carcinoma via targeting TXNIP/HIF1-α/MMP-9/P27 and BAX/Bcl2/P53 signaling pathways. Biomedicine & Pharmacotherapy. 2024;180:117429. doi:https://doi.org/10.1016/j.biopha.2024.117429.
8. Brauch H, Jordan VC. Targeting of tamoxifen to enhance antitumour action for the treatment and prevention of breast cancer: the ‘personalised’ approach? Eur J Cancer. 2009;45(13):2274-83. doi:10.1016/j.ejca.2009.05.032. PubMed PMID:19592233.
9. Hagedorn HG, Bachmeier BE, Nerlich AG. Synthesis and degradation of basement membranes and extracellular matrix and their regulation by TGF-beta in invasive carcinomas (Review). Int J Oncol. 2001;18(4):669-81. PubMed PMID:11251160.
10. Mendes O, Kim HT, Lungu G, Stoica G. MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clin Exp Metastasis. 2007;24(5):341-51. doi:10.1007/s10585-007-9071-0. PubMed PMID:17505812.
11. Negro A, Onisto M, Pellati D, Garbisa S. CNTF up-regulation of TIMP-2 in neuroblastoma cells. Brain Res Mol Brain Res. 1997;48(1):30-6. PubMed PMID:9379846.
12. Nguyen M, Arkell J, Jackson CJ. Active and tissue inhibitor of matrix metalloproteinase-free gelatinase B accumulates within human microvascular endothelial vesicles. J Biol Chem. 1998;273(9):5400-4. PubMed PMID:9479001.
13. Nielsen BS, Sehested M, Kjeldsen L, Borregaard N, Rygaard J, Dano K. Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab Invest. 1997;77(4):345-55. PubMed PMID:9354769.
14. Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina OP, Heikkila P, et al. Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol. 1999;17(8):768-74. doi:10.1038/11703. PubMed PMID:10429241.
15. Bohme D, Beck-Sickinger AG. Drug delivery and release systems for targeted tumor therapy. J Pept Sci. 2015;21(3):186-200. doi:10.1002/psc.2753. PubMed PMID:25703117.
16. Shi NQ, Gao W, Xiang B, Qi XR. Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage. Int J Nanomedicine. 2012;7:1613-21. doi:10.2147/IJN.S30104. PubMed PMID:22619516; PubMed Central PMCID:PMCPMC3356196.
17. Bae M, Cho S, Song J, Lee GY, Kim K, Yang J, et al. Metalloprotease-specific poly(ethylene glycol) methyl ether-peptide-doxorubicin conjugate for targeting anticancer drug delivery based on angiogenesis. Drugs Exp Clin Res. 2003;29(1):15-23.
18. Lee GY, Park K, Kim SY, Byun Y. MMPs-specific PEGylated peptide-DOX conjugate micelles that can contain free doxorubicin. Eur J Pharm Biopharm. 2007;67(3):646-54. doi:10.1016/j.ejpb.2007.03.023. PubMed PMID:17499491.
19. Chau Y, Dang NM, Tan FE, Langer R. Investigation of targeting mechanism of new dextran-peptide-methotrexate conjugates using biodistribution study in matrix-metalloproteinase-overexpressing tumor xenograft model. J Pharm Sci. 2006;95(3):542-51. doi:10.1002/jps.20548. PubMed PMID:16419048.
20. Chau Y, Padera RF, Dang NM, Langer R. Antitumor efficacy of a novel polymer-peptide-drug conjugate in human tumor xenograft models. Int J Cancer. 2006;118(6):1519-26. doi:10.1002/ijc.21495. PubMed PMID:16187287.
21. Chau Y, Tan FE, Langer R. Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX. Bioconjug Chem. 2004;15(4):931-41. doi:10.1021/bc0499174. PubMed PMID:15264885.
22. Lafi Z, Alshaer W, Gharaibeh L, Alqudah DA, AlQuaissi B, Bashaireh B, et al. Synergistic combination of doxorubicin with hydralazine and disulfiram against MCF-7 breast cancer cell line. PLoS One. 2023;18(9):e0291981. Epub 2023/09/28. doi:10.1371/journal.pone.0291981. PubMed PMID:37768997; PubMed Central PMCID:PMCPMC10538757.
23. Alherz FA, El-Masry TA, Oriquat GA, Elekhnawy E, Al-Shaalan NH, Gaballa MMS, et al. Hesperidin Nanoformulation: A Potential Strategy for Reducing Doxorubicin-Induced Renal Damage via the Sirt-1/HIF1-α/VEGF/NF-κB Signaling Cascade. Pharmaceuticals (Basel). 2024;17(9). Epub 2024/09/28 22:42. doi:10.3390/ph17091144. PubMed PMID:39338308; PubMed Central PMCID:PMCPMC11435365.

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