The
dissemination of tumor metastasis in the peritoneal cavity,
also called peritoneal metastasis (PM) or carcinomatosis, represents
a late stage of gastrointestinal and gynecological cancer with very
poor prognosis, even when cytoreductive surgery is effective, due
to residual microscopic disease. Photodynamic therapy (PDT) in the
management of peritoneal metastasis has been clinically limited by
the low tumor selectivity of photosensitizers (PS) and important adverse
effects. Here, we propose extracellular nanovesicles (EVs) derived
from mesenchymal stem/stromal cells (MSCs) as the fourth generation
of immune active PS vectors that are able to target peritoneal metastasis
with superior selectivity, potentiate PDT cytotoxicity at the tumor
site without affecting healthy tissues, modulate the tumor microenvironment
of immunocompetent colorectal and ovarian carcinomatosis models, and
promote an antitumor immune response. A pioneering strategy was developed
for high yield, large-scale production of MSC-EVs encapsulating the
drug meta(tetrahydroxyphenyl)chlorin (mTHPC) (EVs-mTHPC)
that is compatible with requirements of clinical translation and also
preserves the topology and integrity of naturally produced EVs. Intraperitoneal
injection of EVs-mTHPC showed an impressive enhancement of tumoral
selectivity in comparison to the free drug and to the liposomal formulation
Foslip (mean ratio of PS in tumors/organs of 40 for EVs-mTHPC versus 1.5 for the free PS and 5.5 for Foslip). PDT mediated
by EVs-mTHPC permitted an important tumoral necrosis (55% of necrotic
tumoral nodules versus 18% for Foslip (p < 0.0001)) and promoted antitumor immune cell infiltration, mainly
proinflammatory M1-like CD80+ and CD8+ T cell effector. Intratumor
proliferation was significantly decreased after PDT with EVs-mTHPC.
Overall EVs vectorization of mTHPC afforded important tumoral selectivity
while overcoming the PDT toxicity of the free drug and prolonged mice
survival in the colorectal carcinomatosis model. MSC-EVs produced
by our scalable manufacturing method appears like the clinically relevant
fourth-generation PDT vehicle to overcome current limitations of PDT
in the treatment of peritoneal metastasis and promote a hot tumor
immune environment in PM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.