20 research outputs found
Reactive oxygen species activated by mitochondria-specific camptothecin prodrug for enhanced chemotherapy
Camptothecin (CPT) has attracted much attention due to its potent antitumor activities. However, the undesirable physicochemical properties, including poor water-solubility, unstable lactone ring and severe adverse effects limit its further application. In this study, two water-soluble prodrugs, CPT-lysine (CPTK) and CPT-arginine (CPTR), were designed and synthesized by conjugating lysine or arginine with CPT, improving its solubility, pharmacokinetic properties and tumor penetration. Importantly, the introduction of arginine into CPTR contributed to the mitochondria-specific delivery, which increased mitochondrial reactive oxygen species (ROS) generation, induced mitochondria dysfunction and enhanced cell apoptosis and in vivo anti-cancer effect. This strategy is believed to hold great potential for organelle-specific synergistic anti-tumor therapy
Production and clinical development of nanoparticles for gene delivery
Gene therapy is a promising strategy for specific treatment of numerous gene-associated human diseases by intentionally altering the gene expression in pathological cells. A successful clinical application of gene-based therapy depends on an efficient gene delivery system. Many efforts have been attempted to improve the safety and efficiency of gene-based therapies. Nanoparticles have been proved to be the most promising vehicles for clinical gene therapy due to their tunable size, shape, surface, and biological behaviors. In this review, the clinical development of nanoparticles for gene delivery will be particularly highlighted. Several promising candidates, which are closest to clinical applications, will be briefly reviewed. Then, the recent developments of nanoparticles for clinical gene therapy will be identified and summarized. Finally, the development of nanoparticles for clinical gene delivery in future will be prospected
Linear-like polypeptide-based micelle with pH-sensitive detachable PEG to deliver dimeric camptothecin for cancer therapy
Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin (CPT). However, many challenges for CPT delivery remain, including low drug loading efficiency, premature drug leakage, and poor cellular internalization. Herein, we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy. This self-assembled micelle possesses the following essential components for CPT: (1) pH-sensitive PEG (OHC-PEG-CHO) for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles, which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake; (2) polypeptide polylysine-polyphenylalanine (PKF) synthesized via ring-opening polymerization for micelle formation and CPT analogue loading; (3) dimeric CPT (DCPT) with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites. Interestingly, the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles. Also, the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation. In conclusion, this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy
pH-Triggered Sheddable Shielding System for Polycationic Gene Carriers
For improving the therapeutic efficiency of tumors and decreasing undesirable side effects, ternary complexes were developed by coating pH-sensitive PEG-b-PLL-g-succinylsulfathiazole (hereafter abbreviated as PPSD) with DNA/PEI polyplexes via electrostatic interaction. PPSD can efficiently shield the surface charge of DNA/PEI. The gene transfection efficiency of ternary complexes was lower than that of DNA/PEI at pH 7.4; however, it recovered to the same level as that of DNA/PEI at pH 6.0, attributed to the pH-triggered release of DNA/PEI from ternary complexes. Cell uptake results also exhibited the same trend as transfection at different pH values. The suitable ability for pH-triggered shielding/deshielding estimated that PPSD demonstrates potential as a shielding system for use in in vivo gene delivery
Ultrasensitive pH Triggered Charge/Size Dual-Rebound Gene Delivery System
A facile
strategy is developed to construct an ultrasensitive pH
triggered charge/size dual-rebound gene delivery system for efficient
tumor treatment. The therapeutic gene is complexed by polyethylenimine
(PEI) and poly-l-glutamate (PLG), further in situ tightened
by aldehyde modified polyethylene glycol (PEG) via Schiff base reaction.
The generated Schiff base bonds are stable in neutral pH but cleavable
in tumor extracellular pH. This gene delivery system possesses following
favorable properties: (1) the tunable gene delivery system is constructed
by chemical bench-free āgreenā and fast process which
is favored by clinician, (2) PEG cross-linking shields the surface
positive charges and tightens the complex particles, leading to decreased
cytotoxicity, improved stability, and prolonged circulation, (3) PEG
shielding can be rapidly peeled off by acidic pH as soon as arriving
tumors, (4) dual charge/size ultrasensitively rebounding to higher
positive potential and bigger size enhances tumor cell uptake efficiency.
A series of experiments both in vitro and in vivo are carried out
to investigate this gene delivery system in detail. An antiangiogenesis
therapeutic gene is carried for the treatment of CT26 tumors in mice,
achieving superior antitumor efficacy which is well proved by sufficient
biological evidence. The system has great potentials for cancer therapy
in the future
Additional file 1 of Co-delivery of dimeric camptothecin and chlorin e6 via polypeptide-based micelles for chemo-photodynamic synergistic therapy
Additional file 1: Figure S1. Particle size and PDI of PKF-Ce6 blank micelles. Figure S2. Pharmacokinetics profiles of Ce6 after administration in mice (n=3). Figure S3. H&E staining of major organs (heart, liver, spleen, lung and kidneys) collected from one mouse after treatment, scale bar is 20 Ī¼m. Table S1. Particle size of PCD micelles with different ratio of Ce6 to DCPT. Table S2. Pharmacokinetic parameters of DCPT, PCD and PPCD after administration in mice (n=3). Table S3. Pharmacokinetic parameters of Ce6, PCD and PPCD after administration in mice (n=3)
A pH-Responsive Detachable PEG Shielding Strategy for Gene Delivery System in Cancer Therapy
In
this study, a pH-responsive detachable polyethylene glycol (PEG)
shielding strategy was designed for gene delivery in cancer therapy.
Polyethylenimine/DNA complex (PEI/DNA) was in situ shielded by aldehyde
group-modified PEG derivatives. The aldehyde groups of PEG could react
with the amino groups of PEI by Schiff base reaction. The Schiff base
bond was stable in neutral pH but labile in slightly acidic pH, which
made the PEG sheddable in tumors. PEG-coated nanoparticles (NPs) had
distinct advantages compared to their mPEG counterpart, possessing
decreased zeta potential, more compressed size, and enhanced stability.
PEG/PEI/DNA NPs showed not only high tumor cell uptake and transfection
efficiency in vitro but also efficient accumulation and gene expression
in solid tumors in vivo. This pH-responsive detachable PEG shielding
system has the potential to be applied to other polycationic nanoparticles
that contain amino groups on their surfaces, which will have broad
prospects in cancer therapy
pH Triggered Size Increasing Gene Carrier for Efficient Tumor Accumulation and Excellent Antitumor Effect
High
efficiency and serum resistant capacity are important for gene carrier
in vivo usage. In this study, transfection efficiency and cell toxicity
of polyethylenimine (PEI) (branched, Mw = 25K) was remarkably improved,
when mixed with polyanion (polyethylene glycol-polyglutamic acid (PEGāPLG)
or polyglutamic acid (PLG)). Different composite orders of PEI, polyanion,
and gene, for example, PEI is first complexed with DNA, and then with
polyanion, or PEI is first complexed with polyanion, and then with
DNA, were studied. Results showed that only the polyanion/PEI complexes
exhibited additional properties, such as decreased pH, resulting in
increased particle size, as well as enhanced serum resistance capability
and improved tumor accumulation. The prepared gene carrier showed
excellent antitumor effect, with no damage on major organs, which
is suitable for in vivo gene antitumor therapy