{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:26:41Z","timestamp":1790378801689,"version":"4.1.0"},"reference-count":76,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and ICT","award":["NRF-2019R1A2C1089141"],"award-info":[{"award-number":["NRF-2019R1A2C1089141"]}]},{"name":"Ministry of Science and ICT","award":["NRF-2019R1C1C1006300"],"award-info":[{"award-number":["NRF-2019R1C1C1006300"]}]},{"name":"Ministry of Science and ICT","award":["NRF-2022R1A4A2000776"],"award-info":[{"award-number":["NRF-2022R1A4A2000776"]}]},{"name":"Ministry of Science and ICT","award":["KFRM 21A0501L1"],"award-info":[{"award-number":["KFRM 21A0501L1"]}]},{"name":"Korea government (the Ministry of Science and ICT, the Ministry of Health &amp; Welfare)","award":["NRF-2019R1A2C1089141"],"award-info":[{"award-number":["NRF-2019R1A2C1089141"]}]},{"name":"Korea government (the Ministry of Science and ICT, the Ministry of Health &amp; Welfare)","award":["NRF-2019R1C1C1006300"],"award-info":[{"award-number":["NRF-2019R1C1C1006300"]}]},{"name":"Korea government (the Ministry of Science and ICT, the Ministry of Health &amp; Welfare)","award":["NRF-2022R1A4A2000776"],"award-info":[{"award-number":["NRF-2022R1A4A2000776"]}]},{"name":"Korea government (the Ministry of Science and ICT, the Ministry of Health &amp; Welfare)","award":["KFRM 21A0501L1"],"award-info":[{"award-number":["KFRM 21A0501L1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with high-risk non-metastatic renal cell carcinoma (RCC) are at risk of metastatic relapse following nephrectomy. Cabozantinib (CZ), a potent multitarget tyrosine kinase inhibitor, interferes with angiogenesis and immunosuppression associated with surgery-induced metastasis. Here, we explored the therapeutic potential of CZ-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CZ-PLGA-NPs) as an adjuvant strategy for targeting post-nephrectomy metastasis. A clinically relevant subline recapitulating post-nephrectomy lung metastasis of high-risk human RCC, namely Renca-SRLu5-Luc, was established through in vivo serial selection of luciferase-expressing murine RCC Renca-Luc cells. CZ was encapsulated into PLGA-NPs via the conventional single emulsion technique. The multifaceted preclinical antimetastatic efficacy of CZ-PLGA-NPs was assessed in Renca-SRLu5-Luc cells. CZ-PLGA-NPs with a smooth surface displayed desirable physicochemical properties, good CZ encapsulation efficiency, as well as controlled and sustained CZ release. CZ-PLGA-NPs exhibited remarkable dose-dependent toxicity against Renca-SRLu5-Luc cells by inducing G2\/M cell cycle arrest and apoptosis. CZ-PLGA-NPs attenuated in vitro colony formation, migration, and invasion by abrogating AKT and ERK1\/2 activation. An intravenous injection of CZ-PLGA-NPs markedly reduced lung metastatic burden and prolonged lifespan with favorable safety in the Renca-SRLu5-Luc experimental lung metastasis model. The novel CZ-PLGA-NPs system with multifaceted antimetastatic effects and alleviating off-target toxicity potential is a promising adjunctive agent for patients with surgically resected high-risk RCC.<\/jats:p>","DOI":"10.3390\/ijms232012634","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T22:49:46Z","timestamp":1666306186000},"page":"12634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma"],"prefix":"10.3390","volume":"23","author":[{"given":"Hye Won","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang 10408, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Seung","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-Yong","family":"Yeom","sequence":"additional","affiliation":[{"name":"Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Na","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cho Rim","family":"Kim","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae-Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Engineering Chemistry, College of Engineering, Chungbuk National University, Cheongju 28644, Korea"},{"name":"Department of Industrial Cosmetic Science and Department of Synchrotron Radiation Science and Technology, College of Bio-Health University System, Chungbuk National University, Cheongju 28644, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4614-0530","authenticated-orcid":false,"given":"Wooram","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6300-9377","authenticated-orcid":false,"given":"Young Bin","family":"Choy","sequence":"additional","affiliation":[{"name":"Institute of Medical & Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Korea"},{"name":"Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Korea"},{"name":"Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-3418","authenticated-orcid":false,"given":"Chun Gwon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, SKKU Institute for Convergence, Sungkyunkwan University, Suwon 16419, Korea"},{"name":"Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon 16419, Korea"},{"name":"Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Il","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/S0094-0143(03)00056-9","article-title":"Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease","volume":"30","author":"Janzen","year":"2003","journal-title":"Urol. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1200\/JCO.2004.09.104","article-title":"Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: An international multicenter study","volume":"22","author":"Patard","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1097\/01.ju.0000165572.38887.da","article-title":"Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system","volume":"174","author":"Lam","year":"2005","journal-title":"J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Mattila, K.E., Vainio, P., and Jaakkola, P.M. (2022). Prognostic Factors for Localized Clear Cell Renal Cell Carcinoma and Their Application in Adjuvant Therapy. Cancers, 14.","DOI":"10.3390\/cancers14010239"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/j.mayocp.2019.01.045","article-title":"Adjuvant Therapy in High-Risk Renal Cell Cancer: A Systematic Review and Meta-analysis","volume":"94","author":"Riaz","year":"2019","journal-title":"Mayo Clin. Proc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.eururo.2021.03.011","article-title":"New Insights into Adjuvant Therapy in Renal Cell Carcinoma: Is the Chapter of VEGF Inhibitors Definitely Closed?","volume":"80","author":"Peyraud","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102207","DOI":"10.1016\/j.ctrv.2021.102207","article-title":"Adjuvant therapy in renal cell carcinoma: Current knowledges and future perspectives","volume":"97","author":"Larroquette","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7341294","DOI":"10.1155\/2022\/7341294","article-title":"The Efficacy of Adjuvant Targeted Therapy in Patients with Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis","volume":"2022","author":"Yiu","year":"2022","journal-title":"Comput. Math. Methods Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e339","DOI":"10.1016\/j.clgc.2018.12.011","article-title":"Adjuvant Tyrosine Kinase Inhibitors in Treatment of Renal Cell Carcinoma: A Meta-Analysis of Available Clinical Trials","volume":"17","author":"Massari","year":"2019","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100759","DOI":"10.1016\/j.currproblcancer.2021.100759","article-title":"High-risk Surgically Resected Renal Cell Carcinoma: Is There a Role for Adjuvant VEGF-TKI Inhibitors?","volume":"45","author":"Fallara","year":"2021","journal-title":"Curr. Probl. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1007\/s00345-020-03550-z","article-title":"Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma","volume":"39","author":"Martini","year":"2021","journal-title":"World J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1016\/S0140-6736(16)00559-6","article-title":"Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial","volume":"387","author":"Haas","year":"2016","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1056\/NEJMoa1611406","article-title":"Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy","volume":"375","author":"Ravaud","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.eururo.2017.09.008","article-title":"Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results","volume":"73","author":"Motzer","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1093\/annonc\/mdy454","article-title":"Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: Results from the phase III, randomized ATLAS trial","volume":"29","author":"Kwon","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.eururo.2020.12.029","article-title":"Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma: Final Overall Survival Analysis of the Phase 3 PROTECT Trial","volume":"79","author":"Motzer","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/ajco.13314","article-title":"Adjuvant therapy for high-risk renal cell carcinoma after nephrectomy how many trials are positive? Only one or more than one","volume":"16","author":"Ravaud","year":"2020","journal-title":"Asia Pac. J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.euo.2018.03.012","article-title":"Adjuvant Antiangiogenic Agents in Post-nephrectomy Renal Cell Carcinoma: A Systematic Review and Meta-analysis","volume":"1","author":"Sonbol","year":"2018","journal-title":"Eur. Urol. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.urolonc.2021.07.022","article-title":"Adjuvant therapy with tyrosine kinase inhibitors for localized and locally advanced renal cell carcinoma: An updated systematic review and meta-analysis","volume":"39","author":"Laukhtina","year":"2021","journal-title":"Urol. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ucl.2020.04.007","article-title":"Adjuvant Therapy for Localized High-Risk Renal Cell Carcinoma","volume":"47","author":"Wood","year":"2020","journal-title":"Urol. Clin. N. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12301","DOI":"10.2147\/OTT.S174149","article-title":"Review of Adjuvant Therapies in Renal Cell Carcinoma: Evidence to Date","volume":"13","author":"Tacconi","year":"2020","journal-title":"Onco Targets Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.5489\/cuaj.5187","article-title":"Kidney Cancer Research Network of Canada consensus statement on the role of adjuvant therapy after nephrectomy for high-risk, non-metastatic renal cell carcinoma: A comprehensive analysis of the literature and meta-analysis of randomized controlled trials","volume":"12","author":"Karakiewicz","year":"2018","journal-title":"Can. Urol. Assoc. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79.e1","DOI":"10.1016\/j.urolonc.2017.10.001","article-title":"Adjuvant therapy for locally advanced renal cell carcinoma: A meta-analysis and systematic review","volume":"36","author":"Bai","year":"2018","journal-title":"Urol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4064","DOI":"10.1200\/JCO.20.01800","article-title":"Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial","volume":"38","author":"Eisen","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1056\/NEJMoa2106391","article-title":"Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma","volume":"385","author":"Choueiri","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100312","DOI":"10.1016\/j.esmoop.2021.100312","article-title":"Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: Results from a pharmacokinetics\/pharmacodynamics study","volume":"6","author":"Cerbone","year":"2021","journal-title":"ESMO Open"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.critrevonc.2013.07.008","article-title":"Surgery, wound healing, and metastasis: Recent insights and clinical implications","volume":"89","author":"Ceelen","year":"2014","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nrclinonc.2016.128","article-title":"Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?","volume":"14","author":"Martin","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/0008-5472.CAN-16-1536","article-title":"Surgery for Cancer: A Trigger for Metastases","volume":"77","author":"Tohme","year":"2017","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s12943-019-1058-3","article-title":"Surgical stress and cancer progression: The twisted tango","volume":"18","author":"Chen","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Market, M., Tennakoon, G., and Auer, R.C. (2021). Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111378"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4030","DOI":"10.1245\/s10434-020-09371-z","article-title":"Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection","volume":"28","author":"Tang","year":"2021","journal-title":"Ann. Surg. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shurin, M.R., Baraldi, J.H., and Shurin, G.V. (2021). Neuroimmune Regulation of Surgery-Associated Metastases. Cells, 10.","DOI":"10.3390\/cells10020454"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1200\/JCO.22.00868","article-title":"Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline","volume":"40","author":"Rathmell","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.eururo.2019.02.011","article-title":"European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update","volume":"75","author":"Ljungberg","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1158\/1078-0432.CCR-19-1135","article-title":"PD-L1 Expression and Clinical Outcomes to Cabozantinib, Everolimus, and Sunitinib in Patients with Metastatic Renal Cell Carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN","volume":"25","author":"Flaifel","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1158\/1535-7163.MCT-18-1399","article-title":"Cabozantinib in Combination with Immunotherapy for Advanced Renal Cell Carcinoma and Urothelial Carcinoma: Rationale and Clinical Evidence","volume":"18","author":"Bergerot","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1002\/cncr.33169","article-title":"Quality-adjusted survival with first-line cabozantinib or sunitinib for advanced renal cell carcinoma in the CABOSUN randomized clinical trial (Alliance)","volume":"126","author":"Chen","year":"2020","journal-title":"Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Comandone, A., Vana, F., Comandone, T., and Tucci, M. (2021). Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results. Cancers, 13.","DOI":"10.3390\/cancers13235896"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ejca.2020.09.030","article-title":"Real-world evidence of cabozantinib in patients with metastatic renal cell carcinoma: Results from the CABOREAL Early Access Program","volume":"142","author":"Albiges","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1080\/14737140.2021.1919090","article-title":"Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: A comprehensive review of the preclinical evidence","volume":"21","author":"Santoni","year":"2021","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1080\/14656566.2021.1959548","article-title":"An up-to-date evaluation of cabozantinib for the treatment of renal cell carcinoma","volume":"22","author":"Marchetti","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"755433","DOI":"10.3389\/fonc.2021.755433","article-title":"Immunogenic Cell Death and Immunomodulatory Effects of Cabozantinib","volume":"11","author":"Scirocchi","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17588359221107112","DOI":"10.1177\/17588359221107112","article-title":"Cabozantinib for the treatment of solid tumors: A systematic review","volume":"14","author":"Maroto","year":"2022","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1200\/JCO.2016.70.7398","article-title":"Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial","volume":"35","author":"Choueiri","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1200\/JCO.2017.75.2170","article-title":"Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial","volume":"36","author":"Cella","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/cam4.3717","article-title":"Cabozantinib real-world effectiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium","volume":"10","author":"Gan","year":"2021","journal-title":"Cancer Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100358","DOI":"10.1016\/j.mtbio.2022.100358","article-title":"Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy","volume":"16","author":"Xu","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Huang, D., Sun, L., Huang, L., and Chen, Y. (2021). Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect. J. Pers. Med., 11.","DOI":"10.3390\/jpm11020124"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Subhan, M.A., Yalamarty, S.S.K., Filipczak, N., Parveen, F., and Torchilin, V.P. (2021). Recent Advances in Tumor Targeting via EPR Effect for Cancer Treatment. J. Pers. Med., 11.","DOI":"10.3390\/jpm11060571"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ejigah, V., Owoseni, O., Bataille-Backer, P., Ogundipe, O.D., Fisusi, F.A., and Adesina, S.K. (2022). Approaches to Improve Macromolecule and Nanoparticle Accumulation in the Tumor Microenvironment by the Enhanced Permeability and Retention Effect. Polymers, 14.","DOI":"10.3390\/polym14132601"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103677","DOI":"10.1016\/j.critrevonc.2022.103677","article-title":"Nanomedicine tactics in cancer treatment: Challenge and hope","volume":"174","year":"2022","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.msec.2019.01.066","article-title":"Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer","volume":"98","author":"Kalyane","year":"2019","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ijpharm.2019.05.064","article-title":"Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach","volume":"566","author":"Park","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"973666","DOI":"10.3389\/fchem.2022.973666","article-title":"Poly lactic-co-glycolic acid-based nanoparticles as delivery systems for enhanced cancer immunotherapy","volume":"10","author":"Gao","year":"2022","journal-title":"Front. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Russo, E., Spallarossa, A., Tasso, B., Villa, C., and Brullo, C. (2021). Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126538"},{"key":"ref_57","first-page":"1973","article-title":"The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment","volume":"6","author":"Yang","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"963413","DOI":"10.3389\/fnut.2022.963413","article-title":"Biopolymeric nanoparticles based effective delivery of bioactive compounds toward the sustainable development of anticancerous therapeutics","volume":"9","author":"Pathak","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Kim, K.T., Lee, J.Y., Kim, D.D., Yoon, I.S., and Cho, H.J. (2019). Recent Progress in the Development of Poly(lactic-co-glycolic acid)-Based Nanostructures for Cancer Imaging and Therapy. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11060280"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"122002","DOI":"10.1088\/2053-1591\/ac3f5e","article-title":"PLGA-based drug delivery system for combined therapy of cancer: Research progress","volume":"8","author":"Ruirui","year":"2021","journal-title":"Mater. Res. Express"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.3389\/fphar.2018.01260","article-title":"PLGA-Based Nanoparticles in Cancer Treatment","volume":"9","author":"Rezvantalab","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E553","DOI":"10.1111\/j.1464-410X.2012.11246.x","article-title":"Late recurrence of renal cell carcinoma >5 years after surgery: Clinicopathological characteristics and prognosis","volume":"110","author":"Park","year":"2012","journal-title":"BJU Int."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.juro.2010.09.100","article-title":"Clinical characteristics and outcomes of patients with recurrence 5 years after nephrectomy for localized renal cell carcinoma","volume":"185","author":"Adamy","year":"2011","journal-title":"J. Urol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1158\/1078-0432.CCR-20-1610","article-title":"Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses","volume":"27","author":"Aggen","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s11255-017-1707-7","article-title":"Establishment of a bioluminescent Renca cell line for renal carcinoma research","volume":"50","author":"Ding","year":"2018","journal-title":"Int. Urol. Nephrol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"bio058566","DOI":"10.1242\/bio.058566","article-title":"Development of a highly pulmonary metastatic orthotopic renal cell carcinoma murine model","volume":"10","author":"Park","year":"2021","journal-title":"Biol. Open"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"663517","DOI":"10.3389\/fonc.2021.663517","article-title":"Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity","volume":"11","author":"Liu","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_68","first-page":"e51485","article-title":"Modeling spontaneous metastatic renal cell carcinoma (mRCC) in mice following nephrectomy","volume":"86","author":"Tracz","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"282ra250","DOI":"10.1126\/scitranslmed.3010722","article-title":"Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib","volume":"7","author":"Jedeszko","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1016\/S0142-9612(00)00115-0","article-title":"The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices","volume":"21","author":"Jain","year":"2000","journal-title":"Biomaterials"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"119642","DOI":"10.1016\/j.lfs.2021.119642","article-title":"Progresses in polymeric nanoparticles for delivery of tyrosine kinase inhibitors","volume":"278","author":"Barar","year":"2021","journal-title":"Life Sci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Milligan, J.J., and Saha, S. (2022). A Nanoparticle\u2019s Journey to the Tumor: Strategies to Overcome First-Pass Metabolism and Their Limitations. Cancers, 14.","DOI":"10.3390\/cancers14071741"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Gerner, B., and Scherf-Clavel, O. (2021). Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug-Drug Interaction with Rifampin and Liver Impairment. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060778"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kim, M.C., Jin, Z., Kolb, R., Borcherding, N., Chatzkel, J.A., Falzarano, S.M., and Zhang, W. (2021). Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13225856"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20434","DOI":"10.18632\/oncotarget.3886","article-title":"Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1","volume":"6","author":"Hwang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"43692","DOI":"10.18632\/oncotarget.18460","article-title":"Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model","volume":"8","author":"Borgna","year":"2017","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:58:28Z","timestamp":1760144308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":76,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012634"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012634","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,20]]}}}