4 research outputs found
Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells
Antibody
fragment (Fab′)-installed polyion complex (PIC)
micelles were constructed to improve targetability of small interfering
RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized
a block copolymer of azide-functionalized polyÂ(ethylene glycol) and
polyÂ(l-lysine) and prepared PIC micelles with siRNA. Then,
a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF)
Fab′ was conjugated to azido groups on the micellar surface.
A fluorescence correlation spectroscopic analysis revealed that 1,
2, or 3 molecule(s) of Fab′(s) were installed onto one micellar
nanoparticle according to the feeding ratio of Fab′ (or DBCO)
to micelle (or azide). The resulting micelles exhibited ∼40
nm in hydrodynamic diameter, similar to that of the parent micelles
before Fab′ conjugation. Flow cytometric analysis showed that
three molecules of Fab′-installed PIC micelles (3Â(Fab′)-micelles)
had the highest binding affinity to cultured pancreatic cancer BxPC3
cells, which are known to overexpress TF on their surface. The 3Â(Fab′)-micelles
also exhibited the most efficient gene silencing activity against
polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore,
the 3Â(Fab′)-micelles exhibited high penetrability and the highest
cellular internalization amounts in BxPC3 spheroids compared with
one or two molecule(s) of Fab′-installed PIC micelles. These
results demonstrate the potential of anti-TF Fab′-installed
PIC micelles for active targeting of stroma-rich pancreatic tumors
pH-Controlled Gas-Generating Mineralized Nanoparticles: A Theranostic Agent for Ultrasound Imaging and Therapy of Cancers
We report a theranostic nanoparticle that can express ultrasound (US) imaging and simultaneous therapeutic functions for cancer treatment. We developed doxorubicin-loaded calcium carbonate (CaCO<sub>3</sub>) hybrid nanoparticles (DOX-CaCO<sub>3</sub>-MNPs) through a block copolymer templated <i>in situ</i> mineralization approach. The nanoparticles exhibited strong echogenic signals at tumoral acid pH by producing carbon dioxide (CO<sub>2</sub>) bubbles and showed excellent echo persistence. <i>In vivo</i> results demonstrated that the DOX-CaCO<sub>3</sub>-MNPs generated CO<sub>2</sub> bubbles at tumor tissues sufficient for echogenic reflectivity under a US field. In contrast, the DOX-CaCO<sub>3</sub>-MNPs located in the liver or tumor-free subcutaneous area did not generate the CO<sub>2</sub> bubbles necessary for US contrast. The DOX-CaCO<sub>3</sub>-MNPs could also trigger the DOX release simultaneously with CO<sub>2</sub> bubble generation at the acidic tumoral environment. The DOX-CaCO<sub>3</sub>-MNPs displayed effective antitumor therapeutic activity in tumor-bearing mice. The concept described in this work may serve as a useful guide for development of various theranostic nanoparticles for US imaging and therapy of various cancers
Chemical Tumor-Targeting of Nanoparticles Based on Metabolic Glycoengineering and Click Chemistry
Tumor-targeting strategies for nanoparticles have been predominantly based on optimization of physical properties or conjugation with biological ligands. However, their tumor-targeting abilities remain limited and insufficient. Furthermore, traditional biological binding molecules have intrinsic limitations originating from the limited amount of cellular receptors and the heterogeneity of tumor cells. Our two-step <i>in vivo</i> tumor-targeting strategy for nanoparticles is based on metabolic glycoengineering and click chemistry. First, an intravenous injection of precursor-loaded glycol chitosan nanoparticles generates azide groups on tumor tissue specifically by the enhanced permeation and retention (EPR) effect followed by metabolic glycoengineering. These ‘receptor-like’ chemical groups then enhance the tumor-targeting ability of drug-containing nanoparticles by copper-free click chemistry <i>in vivo</i> during a second intravenous injection. The advantage of this protocol over traditional binding molecules is that there are significantly more binding molecules on the surface of most tumor cells regardless of cell type. The subsequent enhanced tumor-targeting ability can significantly enhance the cancer therapeutic efficacy in animal studies
Tumor-Targeting Transferrin Nanoparticles for Systemic Polymerized siRNA Delivery in Tumor-Bearing Mice
Transferrin (TF) is widely used as
a tumor-targeting ligand for
the delivery of anticancer drugs because the TF receptor is overexpressed
on the surface of various fast-growing cancer cells. In this article,
we report on TF nanoparticles as an siRNA delivery carrier for in
vivo tumor-specific gene silencing. To produce siRNA carrying TF nanoparticles
(NPs), both TF and siRNA were chemically modified with sulfhydryl
groups that can build up self-cross-linked siRNA-TF NPs. Self-polymerized
5′-end thiol-modified siRNA (poly siRNA, psi) and thiolated
transferrin (tTF) were spontaneously cross-linked to form stable NPs
(psi-tTF NPs) under optimized conditions, and they could be reversibly
degraded to release functional monomeric siRNA molecules under reductive
conditions. Receptor-mediated endocytosis of TF induced rapid tumor-cell-specific
uptake of the psi-tTF NPs, and the internalized NPs resulted in a
downregulation of the target protein in red-fluorescent-protein-expressing
melanoma cancer cells (RFP/B16F10) with negligible cytotoxicity. After
systemic administration, the psi-tTF NPs showed marked accumulation
at the tumor, leading to successful target-gene silencing in vivo.
This psi-tTF NP system provided a safe and effective strategy for
in vivo systemic siRNA delivery for cancer therapy