{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:18:27Z","timestamp":1761718707468,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2018,8,2]],"date-time":"2018-08-02T00:00:00Z","timestamp":1533168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2015-05301"],"award-info":[{"award-number":["RGPIN-2015-05301"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Engineering of a \u201csmart\u201d drug delivery system to specifically target tumour cells has been at the forefront of cancer research, having been engineered for safer, more efficient and effective use of chemotherapy for the treatment of cancer. However, selective targeting and choosing the right cancer surface biomarker are critical for a targeted treatment to work. Currently, the available delivery systems use a two-dimensional monolayer of cancer cells to test the efficacy of the drug delivery system, but designing a \u201csmart\u201d drug delivery system to be specific for a tumour in vivo and to penetrate the inner core remains a major design challenge. These challenges can be overcome by using a study model that integrates the three-dimensional aspect of a tumour in a culture system. Here, we tested the efficacy of a functionalized folic acid-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) to specifically target and penetrate the inner core of three-dimensional avascular human pancreatic and breast tumour spheroids in culture. The copolymer was quantitatively analyzed for its hydrophobic drug encapsulation efficiency using three different chemical drug structures with different molecular weights. Their release profiles and tumour targeting properties at various concentrations and pH environments were also characterized. Using the anticancer drug curcumin and two standard clinical chemotherapeutic hydrophobic drugs, paclitaxel and 5-fluorouracil, we tested the ability of FA-DABA-SMA nanoparticles to encapsulate the differently sized drugs and deliver them to kill monolayer pancreatic cancer cells using the WST-1 cell proliferation assay. The findings of this study revealed that the functionalized folic acid-conjugated amphiphilic alternating copolymer shows unique properties as an active \u201csmart\u201d tumor-targeting drug delivery system with the ability to internalize hydrophobic drugs and release the chemotherapeutics for effective killing of cancer cells. The novelty of the study is the first to demonstrate a functionalized \u201csmart\u201d drug delivery system encapsulated with a hydrophobic drug effectively targeting and penetrating the inner core of pancreatic and breast cancer spheroids and reducing their volumes in a dose- and time-dependent manner.<\/jats:p>","DOI":"10.3390\/nano8080588","type":"journal-article","created":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T03:03:15Z","timestamp":1533265395000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Functionalized Folic Acid-Conjugated Amphiphilic Alternating Copolymer Actively Targets 3D Multicellular Tumour Spheroids and Delivers the Hydrophobic Drug to the Inner Core"],"prefix":"10.3390","volume":"8","author":[{"given":"Xia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Engineering, Sawyer Mod 5, Rm 5512, Royal Military College of Canada, 11 General Crerar Crescent, Kingston, ON K7K 7B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manpreet","family":"Sambi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, 18 Stuart St, Botterell Hall Rm 827, Kingston, ON K7L3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandria","family":"DeCarlo","sequence":"additional","affiliation":[{"name":"Department of Biology, Queen\u2019s University, Kingston, ON K7L3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-5680","authenticated-orcid":false,"given":"Sergey V.","family":"Burov","sequence":"additional","affiliation":[{"name":"Synthesis of Peptides and Polymer Microspheres Laboratory, Institute of Macromolecular Compounds, Russian Academy of Sciences, St Petersburg 199004, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"Akasov","sequence":"additional","affiliation":[{"name":"Department of Biomaterials and Biotechnologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"},{"name":"Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, Moscow 119991, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Markvicheva","sequence":"additional","affiliation":[{"name":"Department of Biomaterials and Biotechnologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecile","family":"Malardier-Jugroot","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Engineering, Sawyer Mod 5, Rm 5512, Royal Military College of Canada, 11 General Crerar Crescent, Kingston, ON K7K 7B4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-5481","authenticated-orcid":false,"given":"Myron R.","family":"Szewczuk","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, 18 Stuart St, Botterell Hall Rm 827, Kingston, ON K7L3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41392-017-0004-3","article-title":"Controlled Drug Delivery Vehicles for Cancer Treatment and Their Performance","volume":"3","author":"Senapati","year":"2018","journal-title":"Signal Transduct. 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