5 research outputs found
Photosensitizer-Encapsulated Ferritins Mediate Photodynamic Therapy against Cancer-Associated Fibroblasts and Improve Tumor Accumulation of Nanoparticles
Nanoparticles
have been widely tested as drug delivery carriers
or imaging agents, largely because of their ability to selectively
accumulate in tumors through the enhanced permeability and retention
(EPR) effect. However, studies show that many tumors afford a less
efficient EPR effect and that many nanoparticles are trapped in the
perivascular region after extravasation and barely migrate into tumor
centers. This is to a large degree attributed to the dense tumor extracellular
matrix (ECM), which functions as a physical barrier to prevent efficient
nanoparticle extravasation and diffusion. In this study, we report
a photodynamic therapy (PDT) approach to enhance tumor uptake of nanoparticles.
Briefly, we encapsulate ZnF<sub>16</sub>Pc, a photosensitizer, into
ferritin nanocages, and then conjugate to the surface of the ferritin
a single chain viable fragment (scFv) sequence specific to fibroblast
activation protein (FAP). FAP is a plasma surface protein widely upregulated
in cancer-associated fibroblasts (CAFs), which is a major source of
the ECM fiber components. We found that the scFv-conjugated and ZnF<sub>16</sub>Pc-loaded ferritin nanoparticles (scFv-Z@FRT) can mediate
efficient and selective PDT, leading to eradication of CAFs in tumors.
When tested in bilateral 4T1 tumor models, we found that the tumor
accumulation of serum albumin (BSA), 10 nm quantum dots (QDs), and
50 nm QDs was increased by 2-, 3.5-, and 18-fold after scFv-Z@FRT
mediated PDT. Our studies suggest a novel and safe method to enhance
the delivery of nanoparticles to tumors
RGD-Modified Apoferritin Nanoparticles for Efficient Drug Delivery to Tumors
Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each ferritin is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD–integrin α<sub>v</sub>β<sub>3</sub> interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein, we showed that after being precomplexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49 wt %). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation
Ferritin Nanocages To Encapsulate and Deliver Photosensitizers for Efficient Photodynamic Therapy against Cancer
Photodynamic therapy is an emerging treatment modality that is under intensive preclinical and clinical investigations for many types of disease including cancer. Despite the promise, there is a lack of a reliable drug delivery vehicle that can transport photosensitizers (PSs) to tumors in a site-specific manner. Previous efforts have been focused on polymer- or liposome-based nanocarriers, which are usually associated with a suboptimal PS loading rate and a large particle size. We report herein that a RGD4C-modified ferritin (RFRT), a protein-based nanoparticle, can serve as a safe and efficient PS vehicle. Zinc hexadecaÂfluoroÂphthaloÂcyanine (ZnF<sub>16</sub>Pc), a potent PS with a high <sup>1</sup>O<sub>2</sub> quantum yield but poor water solubility, can be encapsulated into RFRTs with a loading rate as high as ∼60 wt % (<i>i.e.</i>, 1.5 mg of ZnF<sub>16</sub>Pc can be loaded on 1 mg of RFRTs), which far exceeds those reported previously. Despite the high loading, the ZnF<sub>16</sub>Pc-loaded RFRTs (P-RFRTs) show an overall particle size of 18.6 ± 2.6 nm, which is significantly smaller than other PS–nanocarrier conjugates. When tested on U87MG subcutaneous tumor models, P-RFRTs showed a high tumor accumulation rate (tumor-to-normal tissue ratio of 26.82 ± 4.07 at 24 h), a good tumor inhibition rate (83.64% on day 12), as well as minimal toxicity to the skin and other major organs. This technology can be extended to deliver other metal-containing PSs and holds great clinical translation potential
Protein Nanocage Mediated Fibroblast-Activation Protein Targeted Photoimmunotherapy To Enhance Cytotoxic T Cell Infiltration and Tumor Control
Carcinoma-associated
fibroblasts (CAFs) are found in many types of cancer and play an important
role in tumor growth and metastasis. Fibroblast-activation protein
(FAP), which is overexpressed on the surface of CAFs, has been proposed
as a universal tumor targeting antigen. However, recent studies show
that FAP is also expressed on multipotent bone marrow stem cells.
A systematic anti-FAP therapy may lead to severe side effects and
even death. Hence, there is an urgent need of a therapy that can selectively
kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based
photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically,
we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer
carrier, and we conjugate to the surface of ferritin a FAP-specific
single chain variable fragment (scFv). With photoirradiation, the
enabled nano-PIT efficiently eliminates CAFs in tumors but causes
little damage to healthy tissues due to the localized nature of the
treatment. Interestingly, while not directly killing cancer cells,
the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent
mice. Further investigations found that the nano-PIT led to suppressed
C–X–C motif chemokine ligand 12 (CXCL12) secretion and
extracellular matrix (ECM) deposition, both of which are regulated
by CAFs in untreated tumors and mediate T cell exclusion that prevents
physical contact between T cells and cancer cells. By selective killing
of CAFs, the nano-PIT reversed the effect, leading to significantly
enhanced T cell infiltration, followed by efficient tumor suppression.
Our study suggests a new and safe CAF-targeted therapy and a novel
strategy to modulate tumor microenvironment (TME) for enhanced immunity
against cancer
Nanoscintillator-Mediated X‑ray Inducible Photodynamic Therapy for In Vivo Cancer Treatment
Photodynamic therapy is a promising
treatment method, but its applications
are limited by the shallow penetration of visible light. Here, we
report a novel X-ray inducible photodynamic therapy (X-PDT) approach
that allows PDT to be regulated by X-rays. Upon X-ray irradiation,
the integrated nanosystem, comprised of a core of a nanoscintillator
and a mesoporous silica coating loaded with photosensitizers, converts
X-ray photons to visible photons to activate the photosensitizers
and cause efficient tumor shrinkage