Ferroptosis provides an innovative theoretical basis
and method
for tumor therapy but is limited by the low efficiency of conventional
iron delivery systems. Herein, an efficient supramolecular iron delivery
system (SIDS) is demonstrated upon the hydrolysis of FeCl3, condensation of amino acids, and self-assembly of iron-containing
components. The as-assembled SIDS possesses a shuttle-like core/shell
structure with β-FeOOH as the core and Fe3+/polyamino
acid coordinated networks as shells. The iron content of SIDS is up
to 42 wt %, which is greatly higher than that of ferritin. The iron-containing
protein-mimic structure and shuttle-like morphology of SIDS facilitate
tumor accumulation and cell internalization. Once exposed to the tumor
microenvironment with overexpressed glutathione (GSH), the SIDS will
disassemble, accompanied by the depletion of GSH and the release of
Fe2+, leading to dual amplified ferroptosis. Primary studies
indicate that SIDS exhibits outstanding antitumor efficacy on bladder
cancer.
Clinically,
the surgical treatment of bladder cancer often faces
the problem of tumor recurrence, and the surgical treatment combined
with postoperative chemotherapy to inhibit tumor recurrence also faces
high toxicity and side effects. Therefore, the need for innovative
bladder cancer treatments is urgent. For the past few years, with
the development of nano science and technology, imaging-guided therapy
using nanomaterials with both imaging and therapy functions has shown
great advantages and can not only identify the locations of the tumors
but also exhibit biodistributions of nanomaterials in the tumors,
significantly improving the accuracy and efficacy of treatment. In
this work, we synthesized Fe(III)-doped polyaminopyrrole nanoparticles
(FePPy-NH2 NPs). With low cytotoxicity and a blood circulation
half-life of 7.59 h, high levels of FePPy-NH2 NPs accumulated
in bladder tumors, with an accumulation rate of up to 5.07%ID/g. The
coordination of Fe(III) and the amino group in the structure can be
used for magnetic resonance imaging (MRI), whereas absorption in the
near-infrared region can be applied to photoacoustic imaging (PAI)
and photothermal therapy (PTT). MRI and PAI accurately identified
the location of the tumor, and based on the imaging data, laser irradiation
was employed accurately. With a high photothermal conversion efficiency
of 44.3%, the bladder tumor was completely resected without recurrence.
Hematological analysis and histopathological analysis jointly confirmed
the high level of safety of the experiment.
Nanovaccine-based immunotherapy has been considered as a major pillar to stimulate the host immune system to recognize and eradicate tumor cells as well as establish a long-term immune memory to prevent tumor relapse and metastasis. However, the weak specificity and low crosspresentation of antigens, as well as the immunosuppressive microenvironments of tumor tissues, are still the major obstacles on exerting the therapeutic performance of tumor nanovaccines sufficiently. Herein, we design and construct cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-loaded aluminum hydroxyphosphate nanoparticles covered by Fe-Shikonin metal-phenolic networks (MPNs) (Alum-CpG@Fe-Shikonin NPs) as personalized in situ nanovaccines for antitumor immunity. Upon internalization by tumor cells, the shell of Fe-Shikonin MPNs will disassemble into Fe 2+ and Shikonin to elicit the immunogenic cell death of tumor cells through ferroptosis and necroptosis. Then, dying tumor cell-released autologous tumor cell lysates will be absorbed by Alum NPs and codelivered with CpG ODN to professional antigen-presenting cells temporally and spatially to activate multistep cascade antitumor immune responses, including dendritic cell maturation, antigen cross-presentation, natural killer cell and cytotoxic T lymphocyte infiltrations, and tumor-associated macrophage repolarization. Benefiting from the synergistic effects of Alum NPs, CpG ODN, and Fe-Shikonin MPNs, our Alum-CpG@Fe-Shikonin NPs exhibit drastic cytotoxicity and accurate selectivity on eradicating primary tumor, strong abscopal effect on inhibiting distant tumor, and a long-term immune memory effect on preventing tumor metastasis and recurrence. Because our report provides a feasible strategy to in situ make full use of autologous tumor cell lysates, which present an entire spectrum of the patient's personal epitopes without complicated ex vivo processes, such as extraction, purification, and sequencing, it may promote the development of personalized nanovaccines for antitumor immunity.
Phototherapy,
such as photodynamic therapy (PDT) and photothermal
therapy (PTT), refers to the therapeutic strategy using a visible
or near-infrared (NIR) laser to generate free radicals or heat for
noninvasive and localized tumor treatment. However, limited by the
low photoconversion efficiency of therapeutic agents, a single treatment
method can hardly lead to complete tumor ablation, even when enhancing
the power density of the laser and/or prolonging the irradiation duration.
In this work, copper ion and ruthenium complex codoped polydopamine
nanoparticles (Cu(II)/LRu/PDA NPs) are designed for PDT/PTT dual-mode
therapy. The doped LRu in the NPs can generate reactive oxygen species
under visible laser irradiation and enable PDT. Because of the strong
absorption in the NIR region, PDA can not only generate heat for PTT
under irradiation but also be used for photoacoustic tomography (PAT)
imaging. Meanwhile, the doping of Cu(II) in the NPs through the coordination
with PDA facilitates T1-weighted magnetic resonance imaging
(MRI). Thus, MR/PAT imaging-guided PDT/PTT dual-mode therapy is achieved.
The in vivo experiments indicate that the Cu(II)/LRu/PDA NPs can accumulate
in HeLa tumors with a retention rate up to 8.34%ID/g. MR/PAT imaging
can clearly identify the location and boundary of the tumors, permitting
precise guidance for phototherapy. Under the combined effect of PDT
and PTT, a complete ablation of HeLa tumors is achieved. The current
work provides an alternative nanoplatform for performing PDT/PTT dual-mode
therapy, which can be further guided by MR/PAT imaging.
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