12 research outputs found
Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment
The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to over-come these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer
Drp1-Dependent Mitochondrial Fission Mediates Toxicity of Positively Charged Graphene in Microglia
The
unique physicochemical properties of graphene and its derivatives
enable their application in the diagnostics and therapy of central
nervous system (CNS) diseases. However, the potential impacts of surface
properties of functionalized graphene on microglia remain poorly understood.
Herein, we used graphene oxides (GO), polyethylene glycol (PEG)- and
polyethylenimine (PEI)-functionalized GO, which possess different
surface charges, to investigate their effects on microglia by focusing
on mitochondrial dynamics. The positively charged GO-PEI was found
to promote mitochondrial fission as observed in BV-2 cells with mitochondria
labeled by DsRed2-mito, indicating that alterations in mitochondrial
dynamics depend on the surface properties of graphene. Concurrent
to mitochondrial fragmentation, treatment with positively charged
GO-PEI induced an increase in mitochondrial recruitment of dynamin-related
protein (Drp1). Additionally, GO-PEI treatment also led to apoptotic
and autophagic cell death. However, Drp1 silencing by small interfering
RNA (siRNA) could effectively attenuate GO-PEI-induced apoptotic and
autophagic cell death, indicating that mitochondrial fragmentation
occurs upstream of GO-PEI-mediated toxicity in microglia. Overall,
our study indicated that positively charged GO-PEI might cause deleterious
influence on the central immune homeostasis by Drp1-dependent mitochondrial
fragmentation, and provide the strategies for the rational design
of graphene-based materials in neuroscience
Personalized cancer vaccines from bacteria-derived outer membrane vesicles with antibody-mediated persistent uptake by dendritic cells
Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen, thus efficiently facilitating antitumor adaptive immunity. Bacteria-derived outer membrane vesicles (OMVs) are an excellent candidate due to their abundance of pathogen associated molecular patterns. However, during the uptake of OMVs by dendritic cells (DCs), the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage, a phenomenon we refer to as “maturation-induced uptake obstruction” (MUO). Herein we decorated OMV with the DC-targeting αDEC205 antibody (OMV-DEC), which endowed the nanovaccine with an uptake mechanism termed as “not restricted to maturation via antibody modifying” (Normandy), thereby overcoming the MUO phenomenon. We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display. In summary, this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines, and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design
Surface Functionalization of Polymeric Nanoparticles with Umbilical Cord-Derived Mesenchymal Stem Cell Membrane for Tumor-Targeted Therapy
Multiple cell plasma
membranes have been utilized for surface functionalization of synthetic
nanomaterials and construction of biomimetic drug delivery systems
for cancer treatment. The natural characters and facile isolation
of original cells facilitate the biomedical applications of plasma
membranes in functionalizing nanocarriers. Human umbilical cord-derived
mesenchymal stem cells (MSCs) have been identified to show tropism
toward malignant lesions and have great advantages in ease of acquisition,
low immunogenicity, and high proliferative ability. Here, we developed
a poly(lactic-<i>co</i>-glycolic acid) (PLGA) nanoparticle
with a layer of plasma membrane from umbilical cord MSC coating on
the surface for tumor-targeted delivery of chemotherapy. Functionalization
of MSC plasma membrane significantly enhanced the cellular uptake
efficiency of PLGA nanoparticles, the tumor cell killing efficacy
of PLGA-encapsulated doxorubicin, and most importantly the tumor-targeting
and accumulation of the nanoparticles. As a result, this MSC-mimicking
nanoformulation led to remarkable tumor growth inhibition and induced
obvious apoptosis within tumor lesions. This study for the first time
demonstrated the great potential of umbilical cord MSC plasma membranes
in functionalizing nanocarriers with inherent tumor-homing features
and the high feasibility of such biomimetic nanoformulations in cancer
therapy
Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
Combination
therapeutic regimen is becoming a primary direction
for current cancer immunotherapy to broad the antitumor response.
Functional nanomaterials offer great potential for steady codelivery
of various drugs, especially small molecules, therapeutic peptides,
and nucleic acids, thereby realizing controllable drug release, increase
of drug bioavailability, and reduction of adverse effects. Herein,
a therapeutic peptide assembling nanoparticle that can sequentially
respond to dual stimuli in the tumor extracellular matrix was designed
for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (<sup>D</sup>PPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By
concurrent blockade of immune checkpoints and tryptophan metabolism,
the nanoformulation increased the level of tumor-infiltrated cytotoxic
T cells and in turn effectively inhibited melanoma growth. To achieve
this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl
isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2
(MMP-2), and <sup>D</sup>PPA-1, was synthesized and coassembled with
NLG919. The nanostructure swelled when it encountered the weakly acidic
tumor niche where DEAP molecules were protonated, and further collapsed
due to the cleavage of the peptide substrate by MMP-2 that is highly
expressed in tumor stroma. The localized release of <sup>D</sup>PPA-1
and NLG919 created an environment which favored the survival and activation
of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth
and increase of overall survival. Together, this study offers new
opportunities for dual-targeted cancer immunotherapy through functional
peptide assembling nanoparticles with design features that are sequentially
responsive to the multiple hallmarks of the tumor microenvironment