Cancer
radiotherapy suffers from drawbacks such as radiation resistance
of hypoxic cells, excessive radiation that causes damage of adjacent
healthy tissues, and concomitant side effects. Hence, radiotherapy
sensitizers with improved radiotherapeutic performance and requiring
a relatively small radiation dose are highly desirable. In this study,
a nanosystem based on poly(lactic-co-glycolic acid)
(PLGA) and ultrasmall black phosphorus quantum dots (BPQDs) is designed
and prepared to accomplish precise tumor radiosensitization. The PLGA
nanoparticles act as carriers to package the BPQDs to avoid off-target
release and rapid degradation during blood circulation. The nanosystem
that targets the polypeptide peptide motif Arg-Gly-Asp-Gys actively
accumulates in tumor tissues. The 2,3-dimethylmaleic anhydride shell
decomposes in an acidic microenvironment, and the nanoparticles become
positively charged, thereby favoring cellular uptake. Furthermore,
glutathione (GSH) deoxidizes the disulfide bond of cystamine and sequentially
triggers release of BPQDs, rendering tumor cells sensitive to radiotherapy.
The treatment utilizing the PLGA‑SS‑D@BPQDs
nanosystem and X-ray induces cell apoptosis triggered by overproduction
of reactive oxygen species. In the in vivo study,
the nanosystem shows excellent radiotherapy sensitization efficiency
but negligible histological damage of the major organs. This study
provides insights into the design and fabrication of surface-charge-switching
and pH-responsive nanosystems as potent radiosensitizers to achieve
excellent radiotherapy sensitization efficacy and negligible toxic
side effects.
Rational design of smart nanosystems with high biological safety is a critical milestone for realizing precise imagingguided cancer theranostics. Herein, a bioinspired nanosystem was designed by camouflaging SPIO@DOX-ICG nanoparticles with cancer cell membrane (CCM) to realize precise cancer treatment through simultaneous chemotherapy, hyperthermia-therapy, and radiotherapy. CCM surface decoration preserves the cancer adhesion molecules and surface antigens in the nanosystem, endowing the nanosystem with tumor-homing ability and high biocompatibility. Guided by dual-modal imaging, the nanosystem specifically accumulated in the tumor region and achieved synergistic anticancer effects after combined treatment, without causing toxic side effects in major organs. Interestingly, the combined treatment also antagonized tumor hypoxia and reprogrammed the polarization of tumor associated macrophages to the antitumor M1 phenotype. Taken together, this study offers a smart strategy for designing a bioinspired tumor-homing nanosystem for precise cancer therapy.
Rationale
: Current therapies for hepatocellular carcinoma (HCC) are hampered by treatment failure and recurrence due to the remaining treatment-resistant liver cancer stem cells (CSCs). Stemness and epithelial-mesenchymal transition (EMT) are regarded as two fundamental characteristics of liver CSCs necessary for cancer progression; thus, drugs that simultaneously target both characteristics should prove effective in eliminating HCC and impeding recurrence. In this study, we developed new arsenic trioxide (ATO)-based nanoparticles (NPs), which are expected to be more effective than the current HCC therapy, and explored their potential mechanism.
Methods
: A “one-pot” reverse emulsification approach was employed to prepare the ZnAs@SiO
2
NPs. HCC cell lines, MHCC97L and Hep3b, were used to analyze the antitumor activity of ZnAs@SiO
2
NPs
in vitro
and
in vivo
by quantifying cell growth and metastasis as well as to study the effect on stemness and EMT. SHP-1 siRNA was used to validate the role of the SHP-1/JAK2/STAT3 signaling pathway in mediating inhibition of stemness and EMT by ZnAs@SiO
2
.
Results
: Compared with the current ATO treatment, ZnAs@SiO
2
NPs promoted apoptosis and significantly inhibited proliferation, migration, and invasion of both MHCC97L and Hep3b cells. In the
in vivo
assay, ZnAs@SiO
2
NPs inhibited tumor growth by 2.2-fold and metastasis by 3.5-fold as compared to ATO. The ZnAs@SiO
2
NPs also inhibited tumor spheroid formation
in vitro
and tumor initiation
in vivo
and induced significant changes in the expression of stemness markers (CD133, Sox-2, and Oct-4) and EMT markers (E-cadherin, Vimentin, and Slug) both
in vitro
and
in vivo.
These effects of ZnAs@SiO
2
that correlated with prognosis of HCC were mediated by the SHP-1/JAK2/STAT3 signaling.
Conclusions
: ZnAs@SiO
2
NPs can effectively suppress tumor initiation, growth, metastasis, and inhibit stemness and EMT through regulation of SHP-1/JAK2/STAT3 signaling pathway in liver cancer cells
in vitro
and
in vivo
. Thus, ZnAs@SiO
2
NPs have immense potential for HCC treatment in the future.
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