Without
coordinated strategies to mitigate the immunosuppressive
nature of the tumor microenvironment, cancer immunotherapy generally
offers limited clinical benefit for established tumors. Tumor-associated
macrophages (TAMs) are the critical driver of this immunosuppressive
tumor microenvironment, which also promotes tumor metastasis. Here
we successfully reprogrammed TAMs to an antitumor M1 phenotype using
precision nanoparticle-based reactive oxygen species photogeneration,
which demonstrated superior efficiency and efficacy over lipopolysaccharide
stimulation. Meanwhile, antigen presentation and T-cell-priming by
TAMs were enhanced by inhibiting lysosomal proton pump and proteolytic
activity or by promoting tumor associated antigen release in the cytoplasm.
The reprogrammed TAMs orchestrate cytotoxic lymphocyte (CTL) recruitment
in the tumor and direct memory T-cells toward tumoricidal responses.
This strategy could effectively eradicate tumors, inhibit metastasis,
and further prevent their recurrence, which holds tremendous promise
to realize potent cancer immunotherapy.
A mild and efficient method was developed for the copper-catalyzed additions of H-phosphonate diesters to boronic acids under the copper catalyst system Cu(2)O/1,10-phenanthroline. To the best of our knowledge this finding is the first example of a copper-catalyzed synthesis of aryl phosphonates from arylboronic acids and H-phosphonate dialkyl esters.
A convenient and quantitative radioiodination method by copper-mediated cross-coupling of aryl boronic acids was developed. The mild labeling conditions, ready availability of the boronic acid substrate, simple operation, broad functional group tolerance and excellent radiochemical yield (RCY) make this a practical strategy for radioiodine labeling without further purification.
Although
emerging evidence suggests that the pathogenesis of Parkinson’s
disease (PD) is closely related to the aggregation of alpha-synuclein
(α-syn) in the midbrain, the clearance of α-syn remains
an unmet clinical need. Here, we develop a simple and efficient strategy
for fabricating the α-syn nanoscavenger for PD via a reprecipitation self-assembly procedure. The curcumin analogue-based
nanoscavenger (NanoCA) is engineered to be capable of a controlled-release
property to stimulate nuclear translocation of the major autophagy
regulator, transcription factor EB (TFEB), triggering both autophagy
and calcium-dependent exosome secretion for the clearance of α-syn.
Pretreatment of NanoCA protects cell lines and primary neurons from
MPP+-induced neurotoxicity. More importantly, a rapid arousal
intranasal delivery system (RA-IDDS) was designed and applied for
the brain-targeted delivery of NanoCA, which affords robust neuroprotection
against behavioral deficits and promotes clearance of monomer, oligomer,
and aggregates of α-syn in the midbrain of an MPTP mouse model
of PD. Our findings provide a clinically translatable therapeutic
strategy aimed at neuroprotection and disease modification in PD.
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