{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T01:50:04Z","timestamp":1771379404768,"version":"3.50.1"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Nebraska Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate P-DOX-iRGD that not only significantly suppressed primary tumor growth but also substantially inhibited pulmonary metastasis in an orthotopic mouse model of breast cancer. In addition, treatment with P-DOX-iRGD markedly reduced breast cancer-induced splenomegaly and liver hematopoiesis. Interestingly, contrasting results were seen for the free form and polymeric form of DOX in vitro and in vivo, which may be attributed to the enhanced permeability and retention (EPR) effect.<\/jats:p>","DOI":"10.3390\/pharmaceutics14081725","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T23:28:41Z","timestamp":1660865321000},"page":"1725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tumor Microenvironment-Responsive Polymeric iRGD and Doxorubicin Conjugates Reduce Spontaneous Lung Metastasis in an Orthotopic Breast Cancer Model"],"prefix":"10.3390","volume":"14","author":[{"given":"Zheng-Hong","family":"Peng","sequence":"first","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"},{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry\/CCCD, Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0018-1684","authenticated-orcid":false,"given":"Chinmay M.","family":"Jogdeo","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8846-4023","authenticated-orcid":false,"given":"Ying","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri M.","family":"Sheinin","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"},{"name":"Department of Pathology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jind\u0159ich","family":"Kope\u010dek","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry\/CCCD, Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4710-861X","authenticated-orcid":false,"given":"David","family":"Oupick\u00fd","sequence":"additional","affiliation":[{"name":"Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 69198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1126\/science.1203543","article-title":"A perspective on cancer cell metastasis","volume":"331","author":"Chaffer","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature03799","article-title":"Genes that mediate breast cancer metastasis to lung","volume":"436","author":"Minn","year":"2005","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/nm.3391","article-title":"Tumor metastasis: Moving new biological insights into the clinic","volume":"19","author":"Wan","year":"2013","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.3892\/or_00000963","article-title":"Chemotherapy for breast cancer","volume":"24","author":"Hassan","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2748","article-title":"Integrins in cancer: Biological implications and therapeutic opportunities","volume":"10","author":"Desgrosellier","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1038\/sj.onc.1206347","article-title":"\u03b1v integrins regulate cell proliferation through integrin-linked kinase (ILK) in ovarian cancer cells","volume":"22","author":"Maubant","year":"2003","journal-title":"Oncogene"},{"key":"ref_7","first-page":"2625","article-title":"Vascular integrin alpha (v) beta3: A new prognostic indicator in breast cancer","volume":"4","author":"Gasparini","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1073\/pnas.040337597","article-title":"Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity","volume":"97","author":"Gagnon","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/1535-7163.MCT-14-0366","article-title":"Tumor-penetrating iRGD peptide inhibits metastasis","volume":"14","author":"Sugahara","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jconrel.2013.12.006","article-title":"A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity","volume":"175","author":"Pang","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jconrel.2014.03.057","article-title":"EPR: Evidence and fallacy","volume":"190","author":"Nichols","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"952","DOI":"10.3389\/fphar.2017.00952","article-title":"Modulating the tumor microenvironment to enhance tumor nanomedicine delivery","volume":"8","author":"Zhang","year":"2017","journal-title":"Front. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6726","DOI":"10.1021\/jacs.5b00922","article-title":"Enhancing Accumulation and Penetration of HPMA Copolymer-Doxorubicin Conjugates in 2D and 3D Prostate Cancer Cells via iRGD Conjugation with an MMP-2 Cleavable Spacer","volume":"137","author":"Peng","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1007\/s00109-015-1279-x","article-title":"Nanoparticles coated with the tumor-penetrating peptide iRGD reduce experimental breast cancer metastasis in the brain","volume":"93","author":"Hamilton","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zuo, H. (2019). iRGD: A promising peptide for cancer imaging and a potential therapeutic agent for various cancers. J. Oncol., 9367845.","DOI":"10.1155\/2019\/9367845"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pulaski, B.A., and Ostrand-Rosenberg, S. (2001). Mouse 4T1 Breast Tumor Model. Current Protocols in Immunology, John Wiley & Sons, Inc.","DOI":"10.1002\/0471142735.im2002s39"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrc1670","article-title":"Breast cancer metastasis: Markers and models","volume":"5","author":"Weigelt","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/jso.2930230311","article-title":"Breast carcinoma: Pattern of metastasis at autopsy","volume":"23","author":"Lee","year":"1983","journal-title":"J. Surg. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1200\/jco.2010.28.15_suppl.1131","article-title":"Recurrence and survival after pulmonary metastasis in triple-negative breast cancer","volume":"28","author":"Gadiyaram","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.yexmp.2006.06.007","article-title":"Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors","volume":"82","author":"DuPre","year":"2007","journal-title":"Exp. Mol. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.intimp.2009.03.015","article-title":"Gemcitabine directly inhibits myeloid derived suppressor cells in BALB\/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice","volume":"9","author":"Le","year":"2009","journal-title":"Int. Immunopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tao, K., Fang, M., Alroy, J., and Sahagian, G.G. (2008). Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-228"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120218","DOI":"10.1016\/j.biomaterials.2020.120218","article-title":"Chitosan\/\u03b3-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer","volume":"257","author":"Castro","year":"2020","journal-title":"Biomaterials"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1725\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:11:32Z","timestamp":1760141492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/8\/1725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,18]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["pharmaceutics14081725"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14081725","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,18]]}}}