Hypoxia, a common feature of most
solid tumors, causes severe tumor
resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity
and bioorthogonal chemistry-mediated on-site size transformation clustered
nanosystem is designed to overcome hypoxic resistance and enhance
chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive
group poly(2-azepane ethyl methacrylate) with a rapid response rate
and highly efficient bioorthogonal click chemistry to form large-sized
aggregates in tumor tissue to enhance accumulation and retention.
Subsequently, another tumor-acidity responsive group of the maleic
acid amide with a slow response rate was cleaved allowing the aggregates
to slowly dissociate into ultrasmall nanoparticles with better tumor
penetration ability for the delivery of doxorubicin (DOX) and nitric
oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced
DOX resistance and boost the antitumor immune response through a reprogrammed
tumor immune microenvironment. This tumor-acidity and bioorthogonal
chemistry-mediated on-site size transformation clustered nanosystem
not only helps to counteract a hypoxia-induced chemoresistance and
enhance antitumor immune responses but also provides a general drug
delivery strategy for enhanced tumor accumulation and penetration.
The
normoxic and hypoxic microenvironments in solid tumors cause cancer
cells to show different sensitivities to various treatments. Therefore,
it is essential to develop different therapeutic modalities based
on the tumor microenvironment. In this study, we designed size-switchable
nanoparticles with self-destruction and tumor penetration characteristics
for site-specific phototherapy of cancer. This was achieved by photodynamic
therapy in the perivascular normoxic microenvironment due to high
local oxygen concentrations and photothermal therapy (PTT) in the
hypoxic microenvironment, which are not in proximity to blood vessels
due to a lack of effective approaches for heat transfer. In brief,
a poly(amidoamine) dendrimer with photothermal agent indocyanine green
(PAMAM-ICG) was conjugated to the amphiphilic polymer through a singlet
oxygen-responsive thioketal linker and then loaded with photosensitizer
chlorin e6 (Ce6) to construct a nanotherapy platform (denoted as SNPICG/Ce6). After intravenous injection, SNPICG/Ce6 was accumulated at the perivascular sites of the tumor. The singlet
oxygen produced by Ce6 can ablate the tumor cells in the normoxic
microenvironment and simultaneously cleave the thioketal linker, allowing
the release of small PAMAM-ICGs with improved tumor penetration for
PTT in the hypoxic microenvironment. This tailored site-specific phototherapy
in normoxic and hypoxic microenvironments provides an effective strategy
for cancer therapy.
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