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Gemcitabine-based monotherapy was the standard until multidrug regimens and nanomedicine-enabled combinations improved responses, yet treated patients still show very low 5-year survival and severe side effects. Advances in PDAC biology now support new drug combinations and nanocarriers to counter resistance, enhance stability and targeting, and potentially reduce toxicity. This systematic review focuses on disulfiram synergy with GEM and on nanosystems enabling multi-drug encapsulation and sustained release.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/breaking-through-the-limits-nanomedicine-at-the-service-of-new-drug-combinations-to-tackle-pancreatic-cancer/357250/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/breaking-through-the-limits-nanomedicine-at-the-service-of-new-drug-combinations-to-tackle-pancreatic-cancer/357250.png","ImageObject",300,407,{"name":92,"@type":93},"4398046744996","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is pancreatic ductal adenocarcinoma (PDAC) difficult to treat?","Question",{"text":113,"@type":114},"PDAC has poor prognosis because it is often diagnosed late and develops resistance to chemotherapy, limiting treatment efficacy and survival.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What major treatment shift occurred after gemcitabine monotherapy?",{"text":118,"@type":114},"After early 2010s evidence emerged for multidrug approaches such as FOLFIRINOX and gemcitabine combined with Nab-paclitaxel, which became reference therapies for PDAC.",{"name":120,"@type":111,"acceptedAnswer":121},"How do nanomedicine drug delivery systems help address current limitations?",{"text":122,"@type":114},"They can improve drug stability, enhance targeting, and potentially overcome resistance while reducing side effects, including via nanocarriers designed for sustained release and multi-drug encapsulation.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},357250,1790194281,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":66,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},4398046744996,"Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology  \nSYSTEMATIC REVIEW  OPEN ACCESS   \nBreaking Through the Limits: Nanomedicine at the Service of New Drug Combinations to Tackle Pancreatic Cancer  \nValeria Bincoletto1 | Ilaria Andreana1  | Barbara Stella1  | Nazanine Modjtahedi2 | Silvia Arpicco1 | Giorgia Urbinati3   \n1Department of Drug Science and Technology, University of Turin, Turin, Italy | 2Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, Lyon, France | 3Université Paris Cité, CNRS, INSERM, UTCBS, Paris, France  \nCorrespondence: Giorgia Urbinati ([giorgia.urbinati@u-paris.fr](giorgia.urbinati@u-paris.fr))  \nReceived: 17 July 2025 | Revised: 26 March 2026 | Accepted: 22 May 2026  \nEditor-in-Chief: Qiaobing Xu | Executive Editor: Gareth Williams  \nKeywords: combinatory treatments | disulfiram | gemcitabine | liposomes | nanomedicine | pancreatic cancer  \nABSTRACT  \nPancreatic ductal adenocarcinoma (PDAC) is among the most aggressive cancers, with a poor prognosis due to late diagnosis and resistance to chemotherapy. Gemcitabine (GEM) monotherapy was the gold standard treatment for PDAC until the early 2010s, when two combinatorial therapies, FOLFIRINOX and GEM combined with Nab-paclitaxel, showed the benefits of the multidrug approach and became the reference treatments for PDAC. Despite their undisputed efficacy, the overall survival of treated PDAC patients is very low, reaching approximately 12% at 5 years, and the side effects of these therapeutic protocols remain severe and not tolerated by all patients. Recent advances in understanding PDAC biology have led to new therapeutic strategies, including new drug combinations and nanomedicine. This review summarizes background information about past and present PDAC therapeutic regimens with their benefits and the drawbacks including the appearance of treatment resistance and focuses on two potential strategies to counteract the limitations of the actual therapies. First, we highlight the interest of combining disulfiram, a repurposed anti-alcoholism drug, with GEM, based on evidence of synergism between the two molecules. We then emphasize the use of drug delivery nanosystems for their ability to improve drug stability, targeting and to potentially overcome resistance and reduce side effects. Finally, we discuss the combination of multi-drug therapies and nanomedicine through the design of apposite drug delivery nanocarriers capable of encapsulating more than one drug and ensuring sustained release. This all-in-one approach should be promising for more effective therapies of this challenging disease.  \nThis article is categorized under:  \nTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Lipid-Based Structures  \n1 | Introduction  \nPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that remains a significant clinical challenge due to its late diagnosis and resistance to chemotherapy. Approximately 90% of PDAC cases are diagnosed at an advanced stage, with unresectable disease and after metastases have occurred. This late detection has a significant impact on the efficacy of the  \nanticancer therapies and therefore on the survival rate of the patients, which is nearly 12% at 5 years (Halbrook et al. 2023) . The median survival time for patients drops to less than 1 year when the disease is diagnosed at stage IV, regardless of the best available chemotherapy protocols (Springfeld et al. 2019) . Consequently, PDAC exhibits one of the poorest survival rates among all types of cancer (Hu and O'Reilly 2024), and unfortunately “old molecules” such as gemcitabine (GEM), a drug  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \n© 2026 The Author(s). WIREs Nanomedicine and Nanobiotechnol","cbCaifh36vsKjjfK","https://ap.wps.com/l/cbCaifh36vsKjjfK","pdf",3254369,"English","# Introduction\n## Challenges in PDAC diagnosis and chemotherapy resistance\n# Therapeutic strategies\n## Combinatorial drug regimens\n## Nanomedicine to improve stability, targeting, and resistance control\n# Disulfiram and gemcitabine strategy\n## Synergism rationale","[{\"question\":\"Why is pancreatic ductal adenocarcinoma (PDAC) difficult to treat?\",\"answer\":\"PDAC has poor prognosis because it is often diagnosed late and develops resistance to chemotherapy, limiting treatment efficacy and survival.\"},{\"question\":\"What major treatment shift occurred after gemcitabine monotherapy?\",\"answer\":\"After early 2010s evidence emerged for multidrug approaches such as FOLFIRINOX and gemcitabine combined with Nab-paclitaxel, which became reference therapies for PDAC.\"},{\"question\":\"How do nanomedicine drug delivery systems help address current limitations?\",\"answer\":\"They can improve drug stability, enhance targeting, and potentially overcome resistance while reducing side effects, including via nanocarriers designed for sustained release and multi-drug encapsulation.\"}]","Breaking Through the Limits - Nanomedicine at the Service of New Drug Combinations to Tackle Pancreatic Cancer | PDF",1790129481,48]