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Shell-sheddable dendritic polyglycerol sulfates loaded with sunitinib for inhibition of tumor angiogenesis
Hanna Koeppe1, Daniel Horn1, Johanna Scholz1
1Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
Abstract:
Induced angiogenesis, a specific hallmark of cancer, plays a vital role in tumor progression and can be targeted by inhibitors like sunitinib. Sunitinib is a small hydrophobic molecule suffering from low bioavailability and a short half-life in the bloodstream. To overcome these drawbacks, suitable drug delivery systems need to be developed. In this work dendritic polyglycerol (dPG), a well-known polymer, was functionalized with a sheddable shell. Therefore, aliphatic chains of different lengths (C5, C9, C11) were coupled to dPG through a cleavable ester bond. To restore water solubility and improve tumor targeting, the surface was decorated with sulfate groups. The resulting shell-sheddable dPG sulfates were characterized and evaluated regarding their loading capacity and biocompatibility in cell culture. The nine-carbon chain derivative (dPG-TNS) was selected as the best candidate for further experiments due to its high drug loading capacity (20 wt%), and a sustained release in vitro. The cellular biocompatibility of the blank carrier up to 1 mg/mL was confirmed after 24 h incubation on HeLa cells. Furthermore, the shell-cleavability of dPG-TNS under different physiological conditions was shown in a degradation study over four weeks. The activity of sunitinib-loaded dPG-TNS was demonstrated in a tube formation assay on Human umbilical vein endothelial cells (HUVECs). Our results suggest that the drug-loaded nanocarrier is a promising candidate to be further investigated in tumor treatments, as it shows similar efficacy to free sunitinib while overcoming its limitations.
Insights
Researchers developed a novel dendritic polyglycerol nanocarrier to improve sunitinib delivery for cancer treatment. This nanocarrier enhances drug loading and sustained release, overcoming sunitinib
Area of Science:
- Nanotechnology and Drug Delivery
- Polymer Chemistry
- Cancer Therapeutics
Background:
- Induced angiogenesis is crucial for tumor progression and a target for cancer drugs like sunitinib.
- Sunitinib exhibits poor bioavailability and short half-life, necessitating advanced drug delivery systems.
- Dendritic polyglycerol (dPG) is a versatile polymer for developing nanocarriers.
Purpose of the Study:
- To engineer a shell-sheddable dendritic polyglycerol sulfate nanocarrier for improved sunitinib delivery.
- To evaluate the drug loading capacity, biocompatibility, and release kinetics of the nanocarrier.
- To assess the therapeutic efficacy of sunitinib-loaded nanocarriers in an angiogenesis model.
Main Methods:
- Functionalization of dPG with aliphatic chains (C5, C9, C11) via cleavable ester bonds and surface decoration with sulfate groups.
- Characterization of shell-sheddable dPG sulfates for drug loading (sunitinib), biocompatibility (HeLa cells), and degradation studies.
- In vitro evaluation of sunitinib-loaded dPG-TNS efficacy using a tube formation assay on Human umbilical vein endothelial cells (HUVECs).
Main Results:
- The dPG-TNS nanocarrier (C9 chain) demonstrated high sunitinib loading (20 wt%) and sustained in vitro release.
- Blank dPG-TNS showed excellent biocompatibility on HeLa cells up to 1 mg/mL.
- Sunitinib-loaded dPG-TNS exhibited comparable anti-angiogenic activity to free sunitinib in the HUVEC tube formation assay.
Conclusions:
- Shell-sheddable dPG sulfates represent a promising nanocarrier system for enhancing sunitinib's therapeutic potential in cancer treatment.
- The developed nanocarrier effectively overcomes the limitations of free sunitinib, including poor bioavailability and short half-life.
- Further investigation of this drug-loaded nanocarrier is warranted for advanced tumor therapy applications.
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