4 research outputs found
Reduction-Cleavable Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release Behavior for Reversing Drug Resistance
In
the treatment of cancer, multidrug resistance (MDR) has been the major
obstacle to the success of chemotherapy. The underlying mechanism
relies on the overexpression of drug-efflux transporters that prevent
the intracellular transport of the drug. In this study, reduction-cleavable
vesicles were designed and developed with efficient glutathione-mediated
drug-release behavior for reversing drug resistance. Polymeric vesicles
were self-assembled from triblock copolymers with disulfide-bond-linked
poly(ethylene glycol) (PEG) and poly(ε-benzyloxycarbonyl-l-lysine) (PzLL). Observations from transmission electron microscopy
(TEM) and confocal laser scanning microscopy (CLSM) outline an obvious
hollow structure surrounded by a thin outer layer, indicating the
successful formation of the vesicles. Using fluorescently detectable
doxorubicin hydrochloride (DOX·HCl) as the model drug, a significant
acceleration of drug release regulated by glutathione (GSH) was found
(>3-fold difference). Upon incubation of the DOX·HCl-loaded
polymeric vesicles with the HeLa cervical cancer cell line exposed
to glutathione, an enhanced nuclear accumulation of DOX·HCl was
observed, elicited by the preferred disassembly of the vesicle structure
under reducing conditions. Importantly, by using the gemcitabine hydrochloride
(GC·HCl)-resistant breast cancer cell line MDA-MB-231, it was
found that cell viability was significantly reduced after treatment
with GC·HCl-loaded polymeric vesicles, indicating that these
vesicles can help to reverse the drug resistance
Cleavable PEGylation and Hydrophobic Histidylation of Polylysine for siRNA Delivery and Tumor Gene Therapy
Polylysine with cleavable PEGylation
and hydrophobic histidylation (mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub>) was designed and developed for
efficient siRNA delivery and tumor therapy. mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> was used to carry
and deliver small interfering RNA (siRNA) for silencing endogenous
vascular endothelial growth factor (VEGF) expression and inhibiting
tumor growth in HepG2 tumor-bearing mice. In this gene vector, histidine(Bzl)
was selected for hydrophobic histidylation for the proton sponge ability
of the imidazole ring and hydrophobic benzyl group. Cleavable PEGylation
was introduced for in vivo circulation as well as selective PEG detachment
in response to intracellular reduction condition in order to release
the genetic payload. PEG detachment induced gene release was supported
by agarose gel electrophoresis retardation assay, undertaken in the
intracellular relevant reduction condition. In vitro transfection
evaluation of histidylated copolymers, using pEGFP as genetic model,
indicated significantly higher GFP expression than unmodified counterparts,
comparable to the gold standard PEI. The efficacy of hydrophobic histidylation
was found to be pronounced in mesenchymal stem cells (MSCs). In vivo
application of the VEGF-siRNA package by tailored mPEG-SS-Lys<sub><i>n</i></sub>-r-His<sub><i>m</i></sub> showed
distinct tumor suppression in terms of macroscopic tumor volume and
molecular analysis
“Minimalist” Nanovaccine Constituted from Near Whole Antigen for Cancer Immunotherapy
One of the major
challenges in vaccine design has been the over
dependence on incorporation of abundant adjuvants, which in fact is
in violation of the “minimalist” principle. In the present
study, a compact nanovaccine derived from a near whole antigen (up
to 97 wt %) was developed. The nanovaccine structure was stabilized
by free cysteines within each antigen (ovalbumin, OVA), which were
tempospatially exposed and heat-driven to form an extensive intermolecular
disulfide network. This process enables the engineering of a nanovaccine
upon integration of the danger signal (CpG-SH) into the network during
the synthetic process. The 50 nm-sized nanovaccine was developed comprising
approximately 500 antigen molecules per nanoparticle. The nanovaccine
prophylactically protected 70% of mice from tumorigenesis (0% for
the control group) in murine B16-OVA melanoma. Significant tumor inhibition
was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes.
This strategy can be adapted for the future design of vaccine for
a minimalist composition in clinical settings