Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 5, Issue 10, Pages 5453-5469Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.9b01226
Keywords
Lanthanide; Tumor penetration; Polydopamine; Spheroids; Zebrafish; Theranostic
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 105-2221-E-011-133-MY3, 105-E-2221-011-151-MY3]
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Integrating anticancer drugs and diagnostic agents in a polymer nanosystem is an emerging and promising strategy for improving cancer treatment. However, the development of multifunctional nano articles (NPs) for an all-in-one platform characterized by specific targeting, therapeutic efficiency, and imaging feedback remains an unmet clinical need. In this study, pH-responsive mixed-lanthanide-based multifunctional NPs were fabricated based on simple metal ligand interactions for simultaneous cancer cell imaging and drug delivery. We investigated two new systems of alginate-polydopamine complexed with either terbium/europium or dysprosium/erbium oxide NPs (Tb/Eu@AlgPDA or Dy/Er@AlgPDA NPs). Tb/Eu@AlgPDA NPs were then functionalized with the tumor-targeting ligand folic acid (FA) and loaded with the anticancer drug doxorubicin (DOX) to form FA-Tb/Eu@AlgPDA-DOX NPs. Using such systems, the mussel-inspired property of PDA was introduced to improve tumor targetability and penetration, in addition to active targeting (via FA-folate receptor interactions). Determining the photoluminescence efficiency showed that the Tb/Eu@AlgPDA system was superior to the Dy/Er@AlgPDA system, presenting intense and sharp emission peaks on the fluorescence spectra. In addition, compared to Dy/Er@A1gPDA NPs (82.4%), Tb/Eu@AlgPDA NPs exhibited negligible cytotoxicity with >93.3% HeLa cell viability found in MTT assays at NP concentrations of up to 0.50 mg/mL and high biocompatibility when incubated with zebrafish (Danio rerio) embryos and larvae. The FA-Tb/Eu@AlgPDA-DOX system exhibited a pH-responsive and sustained drug-release pattern. In a spheroid model of HeLa cells, the FA-Tb/Eu@AlgPDA-DOX system showed a better penetration efficiency and spheroid growth-inhibitory effect than free DOX. After incubation with zebrafish embryos, the FA-Tb/Eu@AlgPDA-DOX system also showed improved antitumor efficacies versus the other experimental groups in HeLa tumor cell xenografted zebrafish. Therefore, our results suggested that FA-Tb/Eu@AlgPDA-DOX NPs are promising multifunctional nanocarriers with therapeutic capacity for tumor targeting and penetration.
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