Cancer
remains a serious clinical disease awaiting new effective
treatment strategies. Autophagy modulation has emerged as a novel
and promising pharmacologic target critical to future drug development
and anti-cancer therapy applications. Herein, we constructed an in
situ autophagy disruption generator to break the balance of autophagy
flow for tumor-targeting therapy. Hollow mesoporous manganese trioxide
(Mn2O3) nanoparticles (NPs) were synthesized
and conjugated with hyaluronic acid (HA) to form tumor-targeting drug
carriers. Then, traditional autophagy inhibitor hydroxychloroquine
(HCQ) was loaded into the hollow core of HA-Mn2O3, to form a multifunctional theranostics platform (HA-Mn2O3/HCQ). This nanoplatform displayed specific localization
and retention in lysosomes after entering tumor cells. The synchronous
release of HCQ and manganese ion (Mn2+) induced lysosomal
alkalization and osmotic pressure elevation. Significantly greater
lysosomal deacidification and autophagy blockade effect emerged after
treatment by this nanoplatform, with in vitro tumor inhibition rate
of 92.2%. Imaging experiment proved that it could selectively deliver
HCQ to tumor sites and further degrade to realize simultaneous release
of Mn2+ and HCQ. Micromorphological and immunofluorescence
analysis demonstrated that in situ high concentrations of these two
substances would achieve effective autophagy blockade. Pharmacodynamics
test showed that this nanogenerator displayed the best therapeutic
efficacy with 5.08-fold tumor inhibition ratio compared with the HCQ
group. Moreover, the generated Mn2+ can be used as T1 contrast
agent for visualizing tumor lesions and monitoring therapeutic effects.
Overall, the as-made multifunctional drug-delivery system might provide
a promising platform for cancer theranostics upon in situ autophagy
disruption.
Carbon dots (CDs) are one of the most highlighted carbon-based materials for biological applications, such as optical imaging nanoprobes, which are used for labeling cells in cancer treatment mainly due to their biocompatibility and unique optical properties. In this study, gadolinium (Gd)-complex-containing CDs were obtained through a one-step microwave method to develop multimodal nanoprobes integrating the advantages of optical and magnetic imaging. The obtained Gd-CDs exhibited highly fluorescent properties with excellent water solubility and biological compatibility. Natural apoferritin (AFn) nanocages, an excellent drug delivery carrier, are hollow in structure, with their pH-dependent, unfolding–refolding process at pH 2.0 and 7.4. The chemotherapeutic drug doxorubicin (DOX) can be highly effective and encapsulated into AFn cavity. A widely used tumor-targeting molecule, folic acid (FA), functionalized the surface of AFn to obtain an active tumor targeting effect on MCF-7 cells and malignant tumors in mice models. In this study, an AFn nanocarrier encapsulating high concentration of DOX labeled with magnetic and fluorescent Gd-CDs probe was developed. Gd-CDs exhibited a unique green photoluminescence and almost no toxicity compared with free GdCl
3
. Furthermore, Gd-doped CDs significantly increased the circulation time and decreased the toxicity of Gd
3+
in in vitro and in vivo magnetic resonance imaging, which demonstrated that the AFn nanocages labeled with Gd-CD compounds could serve as an excellent T
1
contrast agent for magnetic resonance imaging. The self-assembling multifunctional Gd-CDs/AFn (DOX)/FA nanoparticles have a great potential for cancer theranostic applications.
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