{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T01:40:06Z","timestamp":1769823606822,"version":"3.49.0"},"reference-count":76,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-15-00468"],"award-info":[{"award-number":["23-15-00468"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A promising strategy for pancreatic cancer therapy involves developing nanocarriers capable of simultaneously delivering various antitumor substances with diverse physicochemical properties, often resulting in synergistic effects. In the present work, novel biocomposites were developed using amphiphilic N-vinylpyrrolidone polymer incorporating bortezomib (BTZ) and modified with either the DR5-selective TRAIL cytokine (DR5-B) or its fusion with the iRGD effector peptide (DR5-B-iRGD), resulting in AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD formulations. The release of BTZ was most extensive at acidic pH 5.6, mimicking endolysosomal compartments, while at near-neutral pH 7.4 and alkaline pH 8.2 the release was slower and less complete, indicating a smart pH-responsive behavior suitable for triggered release in the tumor microenvironment. Both AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD significantly inhibited the growth of pancreatic adenocarcinoma cell lines PANC-1, BxPC-3, and MIA PaCa-2 and induced more rapid internalization of the DR5 receptor in MIA PaCa-2 cells than unmodified particles and free DR5-B or DR5-B-iRGD. Importantly, AmphPVP-BTZ-DR5-B-iRGD exhibited a more pronounced DR5 internalization rate and cytotoxic effect than AmphPVP-BTZ-DR5-B owing to the presence of fusion protein with internalizing iRGD peptide. Both biocomposites induced cell death via the apoptotic pathway while exhibiting minimal cytotoxic effects on healthy cells. Therefore, biocomposites incorporating BTZ and functionalized with DR5-selective TRAIL variants DR5-B or DR5-B-iRGD represent a promising avenue for future studies in pancreatic cancer animal models.<\/jats:p>","DOI":"10.3390\/ijms262311620","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amphiphilic Poly(N-vinylpyrrolidone) Biocomposites with Bortezomib and DR5-Selective TRAIL Variants: A Promising Approach to Pancreatic Cancer Treatment"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2918-185X","authenticated-orcid":false,"given":"Ekaterina","family":"Kukovyakina","sequence":"first","affiliation":[{"name":"Department of Technology of Chemical, Pharmaceutical and Cosmetic Substances, D. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-9091","authenticated-orcid":false,"given":"Alina A.","family":"Isakova","sequence":"additional","affiliation":[{"name":"Department of Technology of Chemical, Pharmaceutical and Cosmetic Substances, D. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia"},{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"},{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6355-7282","authenticated-orcid":false,"given":"Dmitry","family":"Bagrov","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2308-2574","authenticated-orcid":false,"given":"Marine","family":"Gasparian","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8140-2754","authenticated-orcid":false,"given":"Andrey","family":"Kuskov","sequence":"additional","affiliation":[{"name":"Department of Technology of Chemical, Pharmaceutical and Cosmetic Substances, D. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3145-3726","authenticated-orcid":false,"given":"Anne","family":"Yagolovich","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Li, T., Lin, C., and Wang, W. (2025). Global, Regional, and National Burden of Pancreatic Cancer from 1990 to 2021, Its Attributable Risk Factors, and Projections to 2050: A Systematic Analysis of the Global Burden of Disease Study 2021. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13597-z"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16022","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic Cancer","volume":"2","author":"Kleeff","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.18063\/cp.v3i3.323","article-title":"Gemcitabine for Pancreatic Cancer Therapy","volume":"3","author":"Srivani","year":"2024","journal-title":"CP"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123125","DOI":"10.1016\/j.lfs.2024.123125","article-title":"Bortezomib in Cancer Therapy: Mechanisms, Side Effects, and Future Proteasome Inhibitors","volume":"358","author":"Sogbein","year":"2024","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1358\/dot.2005.41.5.893706","article-title":"Preclinical and Clinical Development of the Proteasome Inhibitorbortezomib in Cancer Treatment","volume":"41","author":"Montagut","year":"2005","journal-title":"Drugs Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11060-010-0143-7","article-title":"Phase 1 Clinical Trial of Bortezomib in Adults with Recurrent Malignant Glioma","volume":"100","author":"Phuphanich","year":"2010","journal-title":"J. Neuro-Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11658","DOI":"10.1158\/0008-5472.CAN-05-2370","article-title":"Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis","volume":"65","author":"Nawrocki","year":"2005","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11923","DOI":"10.1074\/jbc.M508533200","article-title":"PS-341 (Bortezomib) Induces Lysosomal Cathepsin B Release and a Caspase-2-Dependent Mitochondrial Permeabilization and Apoptosis in Human Pancreatic Cancer Cells","volume":"281","author":"Yeung","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S52","DOI":"10.1111\/jns.12338","article-title":"Bortezomib and Other Proteosome Inhibitors\u2014Induced Peripheral Neurotoxicity: From Pathogenesis to Treatment","volume":"24","author":"Velasco","year":"2019","journal-title":"J. Peripheral Nervous Sys."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s10637-017-0531-3","article-title":"Phase I Trial of Bortezomib Daily Dose: Safety, Pharmacokinetic Profile, Biological Effects and Early Clinical Evaluation in Patients with Advanced Solid Tumors","volume":"36","author":"Bahleda","year":"2018","journal-title":"Investig. New Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhao, R., Jiang, X., Li, Z., and Zhang, B. (2021). Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations. Biomolecules, 12.","DOI":"10.3390\/biom12010051"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1080\/03639045.2018.1483385","article-title":"Bortezomib-Loaded Solid Lipid Nanoparticles: Preparation, Characterization, and Intestinal Permeability Investigation","volume":"44","author":"Mahmoudian","year":"2018","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1007\/s00396-018-4406-8","article-title":"Novel Block Glycopolymers Prepared as Delivery Nanocarriers for Controlled Release of Bortezomib","volume":"296","author":"Zhang","year":"2018","journal-title":"Colloid. Polym. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26176","DOI":"10.1039\/D4RA03504F","article-title":"Bortezomib-Encapsulated Metal\u2013Phenolic Nanoparticles for Intracellular Drug Delivery","volume":"14","author":"Zhou","year":"2024","journal-title":"RSC Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.actbio.2018.09.022","article-title":"Hyaluronic Acid Shell and Disulfide-Crosslinked Core Micelles for in Vivo Targeted Delivery of Bortezomib for the Treatment of Multiple Myeloma","volume":"80","author":"Gu","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.nantod.2009.06.001","article-title":"Self-Assembled Polymer Nanostructures for Delivery of Anticancer Therapeutics","volume":"4","author":"Wiradharma","year":"2009","journal-title":"Nano Today"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1002\/jps.10397","article-title":"Amphiphilic Block Copolymers for Drug Delivery","volume":"92","author":"Adams","year":"2003","journal-title":"J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kuperkar, K., Patel, D., Atanase, L.I., and Bahadur, P. (2022). Amphiphilic Block Copolymers: Their Structures, and Self-Assembly to Polymeric Micelles and Polymersomes as Drug Delivery Vehicles. Polymers, 14.","DOI":"10.3390\/polym14214702"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9409","DOI":"10.1039\/D1NJ01473K","article-title":"Robust Fluorescent Amphiphilic Polymer Micelle for Drug Carrier Application","volume":"45","author":"Shi","year":"2021","journal-title":"N. J. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9325","DOI":"10.1039\/D3TB01371E","article-title":"Synthesis Approaches of Amphiphilic Copolymers for Spherical Micelle Preparation: Application in Drug Delivery","volume":"11","author":"Aliabadi","year":"2023","journal-title":"J. Mater. Chem. B"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gao, M., Yang, Y., Bergfel, A., Huang, L., Zheng, L., and Bowden, T.M. (2020). Self-Assembly of Cholesterol End-Capped Polymer Micelles for Controlled Drug Delivery. J. Nanobiotechnol., 18.","DOI":"10.1186\/s12951-020-0575-y"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20230049","DOI":"10.1515\/epoly-2023-0049","article-title":"Polymer-Based Nanocarriers for Biomedical and Environmental Applications","volume":"23","author":"Idris","year":"2023","journal-title":"e-Polymers"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8673","DOI":"10.2147\/IJN.S231477","article-title":"Biomedical Applications of Multifunctional Polymeric Nanocarriers: A Review of Current Literature","volume":"15","author":"Karabasz","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zieli\u0144ska, A., Carreir\u00f3, F., Oliveira, A.M., Neves, A., Pires, B., Venkatesh, D.N., Durazzo, A., Lucarini, M., Eder, P., and Silva, A.M. (2020). Polymeric Nanoparticles: Production, Characterization, Toxicology and Ecotoxicology. Molecules, 25.","DOI":"10.3390\/molecules25163731"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1016\/j.jnoncrysol.2007.02.061","article-title":"Self-Assembling Nanoscaled Drug Delivery Systems Composed of Amphiphilic Poly-N-Vinylpyrrolidones","volume":"353","author":"Kuskov","year":"2007","journal-title":"J. Non-Cryst. Solids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"205139","DOI":"10.1088\/0953-8984\/19\/20\/205139","article-title":"Amphiphilic Poly-N-Vinylpyrrolidone Nanocarriers with Incorporated Model Proteins","volume":"19","author":"Kuskov","year":"2007","journal-title":"J. Phys. Condens. Matter"},{"key":"ref_28","first-page":"85","article-title":"Amphiphilic Poly-N-Vinylpyrrolidone Nanoparticles as Carriers for Non-Steroidal Anti-Inflammatory Drugs: Characterization and in Vitro Controlled Release of Indomethacin","volume":"26","author":"Kuskov","year":"2010","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","first-page":"621","article-title":"Interaction of Polymer Aggregates Based on Stearoyl-Poly-N-Vinylpyrrolidone with Blood Components","volume":"69","author":"Villemson","year":"2004","journal-title":"Biochemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1134\/S0003683808060112","article-title":"Novel Liposomal Forms of Antifungal Antibiotics Modified by Amphiphilic Polymers","volume":"44","author":"Yamskov","year":"2008","journal-title":"Appl. Biochem. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yan, S., Na, J., Liu, X., and Wu, P. (2024). Different Targeting Ligands-Mediated Drug Delivery Systems for Tumor Therapy. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16020248"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ragheb, M.A., Ragab, M.S., Mahdy, F.Y., Elsebaie, M.S., Saber, A.M., AbdElmalak, Y.O., Elsafoury, R.H., Elatreby, A.A., Rochdi, A.M., and El-Basyouni, A.W. (2025). Folic Acid-Modified Chitosan Nanoparticles for Targeted Delivery of a Binuclear Co(II) Complex in Cancer Therapy. Int. J. Biol. Macromol., 311.","DOI":"10.1016\/j.ijbiomac.2025.144034"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Wu, H., Ding, X., Chen, Y., Cai, Y., Yang, Z., and Jin, J. (2023). EGFR-Targeted Humanized Single Chain Antibody Fragment Functionalized Silica Nanoparticles for Precision Therapy of Cancer. Int. J. Biol. Macromol., 253.","DOI":"10.1016\/j.ijbiomac.2023.127538"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Al-Obaidy, R., Haider, A.J., Al-Musawi, S., and Arsad, N. (2023). Targeted Delivery of Paclitaxel Drug Using Polymer-Coated Magnetic Nanoparticles for Fibrosarcoma Therapy: In Vitro and in Vivo Studies. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-30221-x"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Alizadeh Zeinabad, H., and Szegezdi, E. (2022). TRAIL in the Treatment of Cancer: From Soluble Cytokine to Nanosystems. Cancers, 14.","DOI":"10.3390\/cancers14205125"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1007\/s10495-009-0349-3","article-title":"Generation of New TRAIL Mutants DR5-A and DR5-B with Improved Selectivity to Death Receptor 5","volume":"14","author":"Gasparian","year":"2009","journal-title":"Apoptosis"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yagolovich, A., Isakova, A., Artykov, A., Vorontsova, Y., Mazur, D., Antipova, N., Pavlyukov, M., Shakhparonov, M., Gileva, A., and Markvicheva, E. (2022). DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012687"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-023-01668-1","article-title":"Multifunctional Nanoparticle-Mediated Combining Therapy for Human Diseases","volume":"9","author":"Li","year":"2024","journal-title":"Sig Transduct. Target. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Al Bostami, R.D., Abuwatfa, W.H., and Husseini, G.A. (2022). Recent Advances in Nanoparticle-Based Co-Delivery Systems for Cancer Therapy. Nanomaterials, 12.","DOI":"10.3390\/nano12152672"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, D., Liu, X., Lu, X., and Tian, J. (2023). Nanoparticle Drug Delivery Systems for Synergistic Delivery of Tumor Therapy. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1111991"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1134\/S199542121703008X","article-title":"Amphiphilic Poly-n-Vinyl-2-Pyrrolidone: Synthesis, Properties, Nanoparticles","volume":"10","author":"Kulikov","year":"2017","journal-title":"Polym. Sci. Ser. D"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Artyukhov, A.A., Nechaeva, A.M., Shtilman, M.I., Chistyakov, E.M., Svistunova, A.Y., Bagrov, D.V., Kuskov, A.N., Docea, A.O., Tsatsakis, A.M., and Gurevich, L. (2022). Nanoaggregates of Biphilic Carboxyl-Containing Copolymers as Carriers for Ionically Bound Doxorubicin. Materials, 15.","DOI":"10.3390\/ma15207136"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yagolovich, A., Kuskov, A., Kulikov, P., Bagrov, D., Petrova, P., Kukovyakina, E., Isakova, A., Khan, I., Pokrovsky, V., and Nosyrev, A. (2024). Assessment of the Effects of Amphiphilic Poly (N-vinylpyrrolidone) Nanoparticles Loaded with Bortezomib on Glioblastoma Cell Lines and Zebrafish Embryos. Biomed. Rep., 20.","DOI":"10.3892\/br.2024.1725"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"313081","DOI":"10.1155\/2013\/313081","article-title":"Detection Limits of DLS and UV-Vis Spectroscopy in Characterization of Polydisperse Nanoparticles Colloids","volume":"2013","author":"Tomaszewska","year":"2013","journal-title":"J. Nanomater."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Artykov, A.A., Yagolovich, A.V., Dolgikh, D.A., Kirpichnikov, M.P., Trushina, D.B., and Gasparian, M.E. (2021). Death Receptors DR4 and DR5 Undergo Spontaneous and Ligand-Mediated Endocytosis and Recycling Regardless of the Sensitivity of Cancer Cells to TRAIL. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.733688"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2000298","DOI":"10.1002\/marc.202000298","article-title":"Multicompartment Polymeric Nanocarriers for Biomedical Applications","volume":"41","author":"Nayanathara","year":"2020","journal-title":"Macromol. Rapid Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s11671-023-03899-1","article-title":"Preparation and Anti-Triple-Negative Breast Cancer Cell Effect of a Nanoparticle for the Codelivery of Paclitaxel and Gemcitabine","volume":"18","author":"Yang","year":"2023","journal-title":"Discov. Nano"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.2147\/IJN.S164611","article-title":"Codelivery of Temozolomide and siRNA with Polymeric Nanocarrier for Effective Glioma Treatment","volume":"13","author":"Peng","year":"2018","journal-title":"Int. J. Nanomed."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"K\u00e1ntor, I., Dreav\u0103, D., Todea, A., P\u00e9ter, F., May, Z., Bir\u00f3, E., Babos, G., and Feczk\u00f3, T. (2021). Co-Entrapment of Sorafenib and Cisplatin Drugs and iRGD Tumour Homing Peptide by Poly[\u03b5-Caprolactone-Co-(12-Hydroxystearate)] Copolymer. Biomedicines, 10.","DOI":"10.3390\/biomedicines10010043"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1021\/acs.nanolett.9b00374","article-title":"Codelivery Nanosystem Targeting the Deep Microenvironment of Pancreatic Cancer","volume":"19","author":"Chen","year":"2019","journal-title":"Nano Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1021\/mp500847s","article-title":"Codelivery of Small Molecule Hedgehog Inhibitor and miRNA for Treating Pancreatic Cancer","volume":"12","author":"Kumar","year":"2015","journal-title":"Mol. Pharmaceutics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2350","DOI":"10.1021\/mp3002792","article-title":"Micellar Delivery of Cyclopamine and Gefitinib for Treating Pancreatic Cancer","volume":"9","author":"Chitkara","year":"2012","journal-title":"Mol. Pharmaceutics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8758356","DOI":"10.1155\/2022\/8758356","article-title":"Codelivery of Doxorubicin\/PI3K Inhibitor Nanomicelle Linked with Phenylboronic Acid for Enhanced Cytotoxicity to Pancreatic Cancer","volume":"2022","author":"Zeng","year":"2022","journal-title":"J. Nanomater."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Farooqi, A.A., Turgambayeva, A., Kamalbekova, G., Suleimenova, R., Latypova, N., Ospanova, S., Ospanova, D., Abdikadyr, Z., and Zhussupov, S. (2024). TRAIL as a Warrior in Nano-Sized Trojan Horse: Anticancer and Anti-Metastatic Effects of Nano-Formulations of TRAIL in Cell Culture and Animal Model Studies. Medicina, 60.","DOI":"10.3390\/medicina60121977"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Nguyen, T.T.K., Woo, S.M., Seo, S.U., Banstola, A., Kim, H., Duwa, R., Vu, A.T.T., Hong, I.-S., Kwon, T.K., and Yook, S. (2025). Enhanced Anticancer Efficacy of TRAIL-Conjugated and Odanacatib-Loaded PLGA Nanoparticles in TRAIL Resistant Cancer. Biomaterials, 312.","DOI":"10.1016\/j.biomaterials.2024.122733"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41419-023-05820-1","article-title":"Therapeutic Efficacy of a MMAE-Based Anti-DR5 Drug Conjugate Oba01 in Preclinical Models of Pancreatic Cancer","volume":"14","author":"Zheng","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_57","first-page":"1027","article-title":"Phase II Study of Panobinostat and Bortezomib in Patients with Pancreatic Cancer Progressing on Gemcitabine-Based Therapy","volume":"32","author":"Wang","year":"2012","journal-title":"Anticancer. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"215","DOI":"10.14715\/cmb\/2020.66.3.35","article-title":"TRAIL Mediated Signaling as a Double-Edged Sword in Pancreatic Cancer: Analysis of Brighter and Darker Sides of the Pathway","volume":"66","author":"Farooqi","year":"2020","journal-title":"Cell. Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.jconrel.2020.05.046","article-title":"DR5-Targeted, Chemotherapeutic Drug-Loaded Nanoparticles Induce Apoptosis and Tumor Regression in Pancreatic Cancer in Vivo Models","volume":"324","author":"Johnston","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Nikitovic, D., Kukovyakina, E., Berdiaki, A., Tzanakakis, A., Luss, A., Vlaskina, E., Yagolovich, A., Tsatsakis, A., and Kuskov, A. (2024). Enhancing Tumor Targeted Therapy: The Role of iRGD Peptide in Advanced Drug Delivery Systems. Cancers, 16.","DOI":"10.3390\/cancers16223768"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1134\/S0006297915080143","article-title":"Mutations Enhancing Selectivity of Antitumor Cytokine TRAIL to DR5 Receptor Increase Its Cytotoxicity against Tumor Cells","volume":"80","author":"Gasparian","year":"2015","journal-title":"Biochem. Mosc."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, C., Kuo, J.C.-T., Huang, Y., Hu, Y., Deng, L., Yung, B.C., Zhao, X., Zhang, Z., Pan, J., and Ma, Y. (2023). Optimized Liposomal Delivery of Bortezomib for Advancing Treatment of Multiple Myeloma. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15122674"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/nbt.3330","article-title":"Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery","volume":"33","author":"Blanco","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/s41467-018-03705-y","article-title":"Progress and Challenges towards Targeted Delivery of Cancer Therapeutics","volume":"9","author":"Rosenblum","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1021\/mp300684a","article-title":"Size-Dependent Tumor Penetration and in Vivo Efficacy of Monodisperse Drug\u2013Silica Nanoconjugates","volume":"10","author":"Tang","year":"2013","journal-title":"Mol. Pharmaceutics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-1-60761-609-2_3","article-title":"Enhanced Permeability and Retention (EPR) Effect for Anticancer Nanomedicine Drug Targeting","volume":"Volume 624","author":"Grobmyer","year":"2010","journal-title":"Cancer Nanotechnology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/cdd.2015.174","article-title":"Onto Better TRAILs for Cancer Treatment","volume":"23","author":"Lemke","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13075-015-0529-1","article-title":"Proteasome Inhibitors as Experimental Therapeutics of Autoimmune Diseases","volume":"17","author":"Verbrugge","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/smll.200901158","article-title":"Effect of Surface Properties on Nanoparticle\u2013Cell Interactions","volume":"6","author":"Verma","year":"2010","journal-title":"Small"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1134\/S0006297919060051","article-title":"A New Efficient Method for Production of Recombinant Antitumor Cytokine TRAIL and Its Receptor-Selective Variant DR5-B","volume":"84","author":"Yagolovich","year":"2019","journal-title":"Biochem. Mosc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.chemphyslip.2016.10.005","article-title":"In Vitro Release Kinetics Model Fitting of Liposomes: An Insight","volume":"201","author":"Jain","year":"2016","journal-title":"Chem. Phys. Lipids"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.ijpharm.2011.03.051","article-title":"Higuchi Equation: Derivation, Applications, Use and Misuse","volume":"418","author":"Siepmann","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_74","unstructured":"Bruschi, K.L. (2015). Mathematical Models of Drug Release. Strategies to Modify the Drug Release from Pharmaceutical Systems, Elsevier."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"105026","DOI":"10.1016\/j.ejps.2019.105026","article-title":"Interpreting Non-Linear Drug Diffusion Data: Utilizing Korsmeyer-Peppas Model to Study Drug Release from Liposomes","volume":"138","author":"Wu","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Arunachalam, K., and Sreeja, P.S. (2025). MTT Assay Protocol. Advanced Cell and Molecular Techniques, Springer US. Springer Protocols Handbooks.","DOI":"10.1007\/978-1-0716-4518-5"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11620\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T13:03:51Z","timestamp":1764594231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11620"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,30]]},"references-count":76,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311620"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311620","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,30]]}}}