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Functionalized Folic Acid-Conjugated Amphiphilic Alternating Copolymer Actively Targets 3D Multicellular Tumour Spheroids and Delivers the Hydrophobic Drug to the Inner Core

1
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
2
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, 18 Stuart St, Botterell Hall Rm 827, Kingston, ON K7L3N6, Canada
3
Department of Biology, Queen’s University, Kingston, ON K7L3N6, Canada
4
Synthesis of Peptides and Polymer Microspheres Laboratory, Institute of Macromolecular Compounds, Russian Academy of Sciences, St Petersburg 199004, Russia
5
Department of Biomaterials and Biotechnologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
6
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya Str. 8-2, Moscow 119991, Russia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Nanomaterials 2018, 8(8), 588; https://doi.org/10.3390/nano8080588
Received: 28 June 2018 / Revised: 21 July 2018 / Accepted: 30 July 2018 / Published: 2 August 2018
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Abstract

Engineering of a “smart” 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 “smart” 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 “smart” 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 “smart” 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. View Full-Text
Keywords: multicellular tumour spheroids; cyclo-RGDfK(TPP) peptide; folate; amphiphilic alternating copolymer; targeted drug delivery; paclitaxel; 5-fluorouracil; curcumin; pH-responsive multicellular tumour spheroids; cyclo-RGDfK(TPP) peptide; folate; amphiphilic alternating copolymer; targeted drug delivery; paclitaxel; 5-fluorouracil; curcumin; pH-responsive
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Li, X.; Sambi, M.; DeCarlo, A.; Burov, S.V.; Akasov, R.; Markvicheva, E.; Malardier-Jugroot, C.; Szewczuk, M.R. Functionalized Folic Acid-Conjugated Amphiphilic Alternating Copolymer Actively Targets 3D Multicellular Tumour Spheroids and Delivers the Hydrophobic Drug to the Inner Core. Nanomaterials 2018, 8, 588.

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