3 research outputs found
Overcoming Multidrug Resistance by Base-Editing-Induced Codon Mutation
Multidrug
resistance (MDR) is the main obstacle in cancer chemotherapy.
ATP binding cassette (ABC) transporters on the MDR cell membrane can
transport a wide range of antitumor drugs out of cells, which is one
of the main causes of MDR. Therefore, disturbing ABC transporters
becomes the key to reversing MDR. In this study, we implement a cytosine
base editor (CBE) system to knock out the gene encoding ABC transporters
by base editing. When the CBE system works in MDR cells, the MDR cells
are manipulated, and the genes encoding ABC transporters can be inactivated
by precisely changing single in-frame nucleotides to induce stop (iSTOP)
codons. In this way, the expression of ABC efflux transporters is
reduced and intracellular drug retention is significantly increased
in MDR cells. Ultimately, the drug shows considerable cytotoxicity
to the MDR cancer cells. Moreover, the substantial downregulation
of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
implies the successful application of the CBE system in the knockout
of different ABC efflux transporters. The recovery of chemosensitivity
of MDR cancer cells to the chemotherapeutic drugs revealed that the
system has a satisfactory universality and applicability. We believe
that the CBE system will provide valuable clues for the use of CRISPR
technology to defeat the MDR of cancer cells
Antigen-Loaded Upconversion Nanoparticles for Dendritic Cell Stimulation, Tracking, and Vaccination in Dendritic Cell-Based Immunotherapy
A dendritic cell (DC) vaccine, which is based on efficient antigen delivery into DCs and migration of antigen-pulsed DCs to draining lymph nodes after vaccination, is an effective strategy in initiating CD8<sup>+</sup> T cell immunity for immunotherapy. Herein, antigen-loaded upconversion nanoparticles (UCNPs) are used to label and stimulate DCs, which could be precisely tracked after being injected into animals and induce an antigen-specific immune response. It is discovered that a model antigen, ovalbumin (OVA), could be adsorbed on the surface of dual-polymer-coated UCNPs <i>via</i> electrostatic interaction, forming nanoparticle–antigen complexes, which are efficiently engulfed by DCs and induce DC maturation and cytokine release. Highly sensitive <i>in vivo</i> upconversion luminescence (UCL) imaging of nanoparticle-labeled DCs is successfully carried out, observing the homing of DCs to draining lymph nodes after injection. In addition, strong antigen-specific immune responses including enhanced T cell proliferation, interferon gamma (IFN-γ) production, and cytotoxic T lymphocyte (CTL)-mediated responses are induced by a nanoparticle-pulsed DC vaccine, which is promising for DC-based immunotherapy potentially against cancer
Hyaluronidase To Enhance Nanoparticle-Based Photodynamic Tumor Therapy
Photodynamic therapy (PDT) is considered
as a safe and selective way to treat a wide range of cancers as well
as nononcological disorders. However, as oxygen is required in the
process of PDT, the hypoxic tumor microenvironment has largely limited
the efficacy of PDT to treat tumors especially those with relatively
large sizes. To this end, we uncover that hyaluronidase (HAase), which
breaks down hyaluronan, a major component of extracellular matrix
(ECM) in tumors, would be able to enhance the efficacy of nanoparticle-based
PDT for in vivo cancer treatment. It is found that the administration
of HAase would lead to the increase of tumor vessel densities and
effective vascular areas, resulting in increased perfusion inside
the tumor. As a result, the tumor uptake of nanomicelles covalently
linked with chlorine e6 (NM-Ce6) would be increased by ∼2 folds
due to the improved “enhanced permeability and retention”
(EPR) effect, while the tumor oxygenation level also shows a remarkable
increase, effectively relieving the hypoxia state inside the tumor.
Those effects taken together offer significant benefits in greatly
improving the efficacy of PDT delivered by nanoparticles. Taking advantage
of the effective migration of HAase from the primary tumor to its
drainage sentinel lymph nodes (SLNs), we further demonstrate that
this strategy would be helpful to the treatment of metastatic lymph
nodes by nanoparticle-based PDT. Lastly, both enhanced EPR effect
of NM-Ce6 and relieved hypoxia state of tumor are also observed after
systemic injection of modified HAase, proving its potential for clinical
translation. Therefore, our work presents a new concept to improve
the efficacy of nanomedicine by modulating the tumor microenvironment