Photodynamic
therapy (PDT) shows a promising synergy with chemotherapy
in the therapeutic outcome of malignant cancers. The minimal invasiveness
and nonsystemic toxicity are appealing advantages of PDT, but combination
with chemotherapy brings in the nonselective toxicity. We designed
a polymeric nanoparticle system that contains both a chemotherapeutic
agent and a photosensitizer to seek improvement for chemo-photodynamic
therapy. First, to address the challenge of efficient co-delivery,
polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to
load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by
a π–π stacking interaction, with high loading (41.9
wt %) and the optimal nanoparticle size (50 nm). Second, light given
in PDT treatment not only excites Ce6 to produce cytotoxic reactive
oxygen species (ROS) but also spatiotemporally activates a cascade
reaction to release the loaded drugs. Finally, we report a self-destructive
polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone
to facilitate drug release upon ROS stimulus. This is achieved by
grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate.
When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target
delivery toxicity is mostly avoided. An oral squamous cell carcinoma
that is clinically relevant to PDT was used as the cancer model. We
put forward a polymeric system with improved efficiency for chemo-photodynamic
therapy and reduced off-target toxicity.
The
anti-PD-L1 immunotherapy has shown promise in treating
cancer.
However, certain patients with metastatic cancer have low response
and high relapse rates. A main reason is systemic immunosuppression
caused by exosomal PD-L1, which can circulate in the body and inhibit
T cell functions. Here, we show that Golgi apparatus-Pd-l1
–/– exosome hybrid membrane coated nanoparticles
(GENPs) can significantly reduce the secretion of PD-L1. The GENPs
can accumulate in tumors through homotypic targeting and effectively
deliver retinoic acid, inducing disorganization of the Golgi apparatus
and a sequence of intracellular events including alteration of endoplasmic
reticulum (ER)-to-Golgi trafficking and subsequent ER stress, which
finally disrupts the PD-L1 production and the release of exosomes.
Furthermore, GENPs could mimic exosomes to access draining lymph nodes.
The membrane antigen of PD-l1
–/– exosome on GENPs can activate T cells through a vaccine-like effect,
strongly promoting systemic immune responses. By combining GENPs with
anti-PD-L1 treatment in the sprayable in situ hydrogel,
we have successfully realized a low recurrence rate and substantially
extended survival periods in mice models with incomplete metastatic
melanoma resection.
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