Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH‐responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor‐specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.
The
codelivery of drugs at specific optimal ratios to cancer cells
is vital for combination chemotherapy. However, most of the current
strategies are unable to coordinate the loading and release of drug
combinations to acquire precise and controllable synergistic ratios.
In this work, we designed an innovative dual-drug backboned and reduction-sensitive
polyprodrug PEG-P(MTO-ss-CUR) containing the anticancer drugs mitoxantrone
(MTO) and curcumin (CUR) at an optimal synergistic ratio to reverse
drug resistance. Due to synchronous drug activation and polymer backbone
degradation, drug release at the predefined ratio with a synergistic
anticancer effect was demonstrated by in vitro and in vivo experiments. Therefore, the dual-drug delivery system
developed in this work provides a novel and efficient strategy for
combination chemotherapy.
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.
Adoptive cellular
therapy utilizing chimeric antigen receptor redirected
T (CAR-T) cells has shown impressive therapeutic effects on hematological
malignancies. In contrast, the efficacy of CAR-T therapies in treating
solid tumors is still poor, which is largely due to inefficient penetration
into solid tumors and the immunosuppressive tumor microenvironment.
Herein, we engineered hyaluronidase (HAase) and the checkpoint blocking
antibody α-PDL1 on the CAR-T cell surface via highly efficient
and biocompatible bioorthogonal click chemistry to improve their therapeutic
effects on solid tumors. The modified HAase degrades hyaluronic acid
and destroys the tumor extracellular matrix, allowing CAR-T cells
to penetrate deeply into solid tumors, as evidenced by in
vitro infiltration experiments and in vivo biodistribution studies. In addition, in vitro cytotoxicity
studies showed stronger antitumor activity of α-PDL1-decorated
cells than traditional CAR-T cells. Importantly, HAase- and α-PDL1-engineered
CAR-T cells showed better therapeutic efficacy on two solid tumor
models and did not cause significant systemic side effects. In this
work, we provide a simple, efficient, and biologically safe chemical
strategy to engineer traditional CAR-T cells for enhanced therapeutic
efficacy on solid tumors, which can be extended to other adoptive
cellular immunotherapies and holds great potential for clinical application.
Developing
novel activatable photosensitizers with excellent plasma
membrane targeting ability is urgently needed for smart photodynamic
therapy (PDT). Herein, a tumor acidity-activatable photosensitizer
combined with a two-step bioorthogonal pretargeting strategy to anchor
photosensitizers on the plasma membrane for effective PDT is developed.
Briefly, artificial receptors are first anchored on the cell plasma
membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve
the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate
in tumor tissue and disassemble upon protonation of their tertiary
amines in response to the acidic tumor environment, exposing the contained
DBCO and Ce6. The selective, highly specific click reactions between
DBCO and azide groups enable Ce6 to be anchored on the tumor cell
surface. Upon laser irradiation, the cell membrane is severely damaged
by the cytotoxic reactive oxygen species, resulting in remarkable
cellular apoptosis. Taken together, the membrane-localized PDT by
our bioorthogonal pretargeting strategy to anchor activatable photosensitizers
on the plasma membrane provides a simple but effective method for
enhancing the therapeutic efficacy of photosensitizers in anticancer
therapy.
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