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Anionic Polymerization of an Amphiphilic Copolymer for Preparation of Block Copolymer Micelles Stabilized by π-π Stacking Interactions
Published on: October 10, 2016
Functionalized Folic Acid-Conjugated Amphiphilic Alternating Copolymer Actively Targets 3D Multicellular Tumour
Xia Li1, Manpreet Sambi2, Alexandria DeCarlo3
1Department of Chemistry and Chemical Engineering, Sawyer Mod 5, Rm 5512, Royal Military College of Canada, 11 General Crerar Crescent, Kingston, ON K7K 7B4, Canada. xiali.summer@gmail.com.
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.
Insights
A novel smart drug delivery system using folic acid-conjugated copolymer effectively targets and penetrates 3D pancreatic and breast tumors. This system encapsulates hydrophobic drugs, releasing them to kill cancer cells, reducing tumor volume.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Cancer Research
Background:
- Targeted cancer therapy requires specific biomarkers for drug delivery systems.
- Current 2D cell models limit the assessment of drug delivery systems' efficacy in complex 3D tumor microenvironments.
- Penetrating the inner core of tumors and achieving selective targeting remain significant challenges in cancer treatment.
Purpose of the Study:
- To evaluate a novel folic acid-conjugated copolymer (FA-DABA-SMA) for targeted drug delivery.
- To assess the copolymer's ability to penetrate and target 3D pancreatic and breast tumor spheroids.
- To investigate the encapsulation, release, and efficacy of hydrophobic anticancer drugs delivered by the FA-DABA-SMA system.
Main Methods:
- Fabrication and characterization of folic acid-conjugated amphiphilic alternating copolymer (FA-DABA-SMA) with a biodegradable linker (DABA).
- Encapsulation efficiency of hydrophobic drugs (curcumin, paclitaxel, 5-fluorouracil) within FA-DABA-SMA nanoparticles.
- In vitro evaluation of drug release profiles, pH-dependent properties, and tumor targeting in 3D pancreatic and breast cancer spheroids.
- Assessment of cancer cell killing efficacy using the WST-1 assay on 2D cell cultures.
Main Results:
- FA-DABA-SMA nanoparticles successfully encapsulated hydrophobic drugs of varying molecular weights.
- The drug delivery system demonstrated effective penetration into the inner core of 3D tumor spheroids.
- Significant reduction in tumor spheroid volumes was observed in a dose- and time-dependent manner.
- The system showed efficient drug release and potent cancer cell killing in vitro.
Conclusions:
- The functionalized FA-DABA-SMA copolymer represents a promising "smart" drug delivery platform for targeted cancer therapy.
- This system overcomes limitations of 2D models by effectively targeting and penetrating 3D tumor spheroids.
- The ability to encapsulate and release hydrophobic drugs offers a strategy for enhanced chemotherapy efficacy.
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