43 research outputs found
Endosomal-Escape Polymers Based on Multicomponent Reaction-Synthesized Monomers Integrating Alkyl and Imidazolyl Moieties for Efficient Gene Delivery
As
one of the toughest tasks in the course of intracellular therapeutics
delivery, endosomal escape must be effectively achieved, particularly
for intracellular gene transport. In this report, novel endosomal-escape
polymers were designed and synthesized from monomers by integrating
alkyl and imidazolyl via Passerini reaction and reversible additionâfragmentation
chain transfer polymerization (RAFT). After introducing the endosomal-escape
polymers with proper degrees of polymerization (DPs) into polyÂ(2-dimethylaminoethyl
methacrylate) (PDMAEMA) as the gene delivery vectors, the block copolymers
exhibited significantly enhanced hemolytic activity at endosomal pH,
and the plasmid DNA (pDNA)-loaded polyplexes showed efficient endosomal
escape compared with PDMAEMA, ultimately achieving dramatically increased
gene transfection efficacy. These results suggest that the polymers
that integrate alkyl and imidazolyl moieties for efficient endosomal
escape have wide potential applications for intracellular gene delivery
Biomaterials: Simultaneous Nanoâ and Microscale Control of Nanofibrous Microspheres SelfâAssembled from StarâShaped Polymers (Adv. Mater. 26/2015)
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112246/1/adma201570177.pd
Integrated Nanoparticles To Synergistically Elevate Tumor Oxidative Stress and Suppress Antioxidative Capability for Amplified Oxidation Therapy
The
improved antioxidant system
of cancer cells renders them well-adaptive to the intrinsic oxidative
stress in tumor tissues. On the other hand, cancer cells are more
sensitive to elevated tumor oxidative stress as compared with normal
cells due to their deficient reactive oxygen species-eliminating systems.
Oxidation therapy of cancers refers to the strategy of killing cancer
cells through selectively increasing the oxidative stress in tumor
tissues. In this article, to amplify the oxidation therapy, we develop
integrated nanoparticles with the properties to elevate tumor oxidative
stress and concurrently suppress the antioxidative capability of cancer
cells. The amphiphilic block copolymer micelles of polyÂ(ethylene glycol)-<i>b</i>-polyÂ[2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)Âbenzyl)Âoxy)Âcarbonyl)Âoxy)Âethyl
methacrylate] (PEG-<i>b</i>-PBEMA) are integrated with palmitoyl
ascorbate (PA) to form hybrid micelles (PA-Micelle). PA molecules
at pharmacologic concentrations serve as a prooxidant to upregulate
the hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) level in tumor
sites and the PBEMA segment exhibits H<sub>2</sub>O<sub>2</sub>-triggered
release of quinone methide for glutathione depletion to suppress the
antioxidative capability of cancer cells, which synergistically and
selectively kill cancer cells for tumor growth suppression. Given
the significantly low side toxicity against normal tissues, this novel
integrated nanoparticle design represents a novel class of nanomedicine
systems for high-efficiency oxidation therapy with the potentials
to be translated to clinical applications
Cationic telluroviologen derivatives as typeâI photosensitizers for tumor photodynamic theranostics
Abstract The hypoxia of the tumor microenvironment (TME) seriously restricts the photodynamic therapy (PDT) effect of conventional typeâII photosensitizers, which are highly dependent on O2. In this work, a new typeâI photosensitizer (TPEâTeVâPPh3) consisting of a tetraphenylethylene group (TPE) as a bioimaging moiety, triphenylâphosphine (PPh3) as a mitochondriaâtargeting group, and telluroviologen (TeV2+) as a reactive oxygen species (O2â˘â, â˘OH) generating moiety is developed. The luminescence intensity of TPEâTeVâPPh3 increased significantly after specific oxidation by excess H2O2 in the TME without responding to normal tissues via the formation of TeâO bond, which can be used for monitoring abnormal H2O2, positioning, and imaging of tumors. TPEâTeVâPPh3 with highly reactive radicals generation and stronger hypoxia tolerance realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition. Therefore, TPEâTeVâPPh3 with low phototoxicity in normal tissue achieves tumor imaging and effective PDT toward solid tumors in response to high concentrations of H2O2 in the TME, which provides a new strategy for the development of typeâI photosensitizers
Multifunctional Mesoporous Hollow Cobalt Sulfide Nanoreactors for Synergistic Chemodynamic/Photodynamic/Photothermal Therapy with Enhanced Efficacy
The unique tumor microenvironment
(TME) characteristic of severe
hypoxia, overexpressed intracellular glutathione (GSH), and elevated
hydrogen peroxide (H2O2) concentration limit
the anticancer effect by monotherapy. In this report, glucose oxidase
(GOx)-encapsulated mesoporous hollow Co9S8 nanoreactors
are constructed with the coverage of polyphenol diblock polymers containing
poly(oligo(ethylene glycol) methacrylate) and dopamine moieties containing
methacrylate polymeric block, which are termed as GOx@PCoS. After
intravenous injection, tumor accumulation, and cellular uptake, GOx@PCoS
deplete GSH by Co3+ ions. GOx inside the nanoreactors produce
H2O2 via oxidation of glucose to enhance â˘OH-based
chemodynamic therapy (CDT) through the Fenton-like reaction under
the catalysis of Co2+. Moreover, Co3+ ions possess
catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia. Upon 808 nm laser
irradiation, GOx@PCoS exhibit photothermal and photodynamic effects
with a high photothermal conversion efficiency (45.06%) and generation
capacity of the toxic superoxide anion (â˘O2â) for photothermal therapy (PTT) and photodynamic therapy
(PDT). The synergetic antitumor effects can be realized by GSH depletion,
starvation, and combined CDT, PTT, and PDT with enhanced efficacy.
Notably, GOx@PCoS can also be used as a magnetic resonance imaging
(MRI) contrast agent to monitor the antitumor performance. Thus, GOx@PCoS
show great potentials to effectively modulate TME and perform synergistic
multimodal therapy
Facile Preparation and Radiotherapy Application of an Amphiphilic Block Copolymer Radiosensitizer
Radiosensitizer plays
an important role in the cancer radiotherapy
for efficient killing of hypoxic cancer cells at a low radiation dose.
However, the commercially available small molecular radiosensitizers
show low efficiency due to poor bioavailability in tumor tissues.
In this report, we develop a novel amphiphilic block copolymer radiosensitizer,
metronidazole-conjugated polyÂ(ethylene glycol)-<i>b</i>-polyÂ(Îł-propargyl-l-glutamate) (PEG-<i>b</i>-PÂ(PLG-<i>g</i>-MN)), which can be self-assembled into coreâshell micelles
(MN-Micelle) with an optimal size of âź60 nm in aqueous solution.
In vitro cytotoxicity evaluation indicated that MN-Micelle sensitized
the hypoxic cancer cells more efficiently under radiation with the
sensitization enhancement ratio (SER) of 1.62 as compared with that
of commercially available sodium glycididazole (GS; SER = 1.17) at
the metronidazole-equivalent concentration of 180 Îźg/mL. Upon
intravenous injection of MN-Micelle into the tumor-bearing mice, high
tumor deposition was achieved, which finally suppressed tumor growth
completely after electron beam radiation at a low radiation dose of
4 Gy. MN-Micelle with outstanding performance as an in vivo radiosensitizer
holds great potentials for translation into radiotherapy application
Multifunctional Polymeric Micelles with Amplified Fenton Reaction for Tumor Ablation
Relative
to normal cells, tumor cells lack adequate capability
of reactive oxygen scavenging. Thus, tumor cells can be selectively
killed by increasing the concentration of reactive oxygen species
in tumor tissue. In this report, we construct an integrated multifunctional
polymeric nanoparticle which can selectively improve hydrogen peroxide
(H<sub>2</sub>O<sub>2</sub>) levels in tumor tissue and convert them
into more active hydroxyl radicals by Fenton reaction. First, the
diblock copolymers containing polyethylene glycol (PEG) and polyÂ(glutamic
acid) modified by <i>β-</i>cyclodextrin (β-CD)
were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl
ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous
solution to obtain stable coreâshell micelles through the inclusion
complexation between β-CD moieties in the block copolymer and
ferrocene (Fc) groups from DFc. After intravenous injection, the particles
achieved significant accumulation in tumor tissue where ascorbic acid
at the pharmacological concentration promotes the production of H<sub>2</sub>O<sub>2</sub>, and subsequently Fenton reaction was catalyzed
by Fc groups to produce hydroxyl radicals to efficiently kill cancer
cells and suppress tumor growth. The micellar systems possess great
potentials toward cancer therapy through synergistic H<sub>2</sub>O<sub>2</sub> production and conversion into hydroxyl radicals specifically
in tumor tissue
Mitochondria-Targeting Polyprodrugs to Overcome the Drug Resistance of Cancer Cells by Self-Amplified Oxidation-Triggered Drug Release
The
multi-drug resistance (MDR) of cancers is one of the main barriers
for the success of diverse chemotherapeutic methods and is responsible
for most cancer deaths. Developing efficient approaches to overcome
MDR is still highly desirable for efficient chemotherapy of cancers.
The delivery of targeted anticancer drugs that can interact with mitochondrial
DNA is recognized as an effective strategy to reverse the MDR of cancers
due to the relatively weak DNA-repairing capability in the mitochondria.
Herein, we report on a polyprodrug that can sequentially target cancer
cells and mitochondria using folic acid (FA) and tetraphenylphosphonium
(TPP) targeting moieties, respectively. They were conjugated to the
terminal groups of the amphiphilic block copolymer prodrugs composed
of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA)
and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin
(DOX). After self-assembly into micelles with the suitable size (âź30
nm), which were termed as TF@CNM + DOX, and upon intravenous administration,
the micelles can accumulate in tumor tissues. After FA-mediated endocytosis,
the endosomal acidity (âźpH 5) can trigger the release of CNM
from TF@CNM + DOX micelles, followed by enhanced accumulation into
the mitochondria via the TPP target. This promotes the overproduction
of reactive oxygen species (ROS), which can subsequently enhance the
intracellular oxidative stress and trigger ROS-responsive release
of DOX into the mitochondria. TF@CNM + DOX shows great potential to
inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable
side effects. Therefore, the tumor and mitochondria dual-targeting
polyprodrug design represents an ideal strategy to treat MDR tumors
through improvement of the intracellular oxidative level and ROS-responsive
drug release
Polyplex Micelles with Thermoresponsive Heterogeneous Coronas for Prolonged Blood Retention and Promoted Gene Transfection
Adequate
retention in blood circulation is a prerequisite for construction
of gene delivery carriers for systemic applications. The stability
of gene carriers in the bloodstream requires them to effectively resist
protein adsorption and maintain small size in the bloodstream avoiding
dissociation, aggregation, and nuclease digestion under salty and
proteinous medium. Herein, a mixture of two block catiomers consisting
of the same cationic block, polyÂ{<i>N</i>-[<i>N</i>-(2-aminoethyl)-2-aminoethyl]Âaspartamide} (PAspÂ(DET)), but varying
shell-forming blocks, polyÂ[2-(2-methoxyethoxy) ethyl methacrylate]
(PMEO<sub>2</sub>MA), and polyÂ[oligoÂ(ethylene glycol) methyl ether
methacrylate] (POEGMA), was used to complex with plasmid DNA (pDNA)
to fabricate polyplex micelles with mixed shells (MPMs) at 20 °C.
The thermoresponsive property of PMEO<sub>2</sub>MA allows distinct
phase transition from hydrophilic to hydrophobic by increasing incubation
temperature from 20 to 37 °C, which results in a distinct heterogeneous
corona containing hydrophilic and hydrophobic regions at the surface
of the MPMs. Subsequent study verified that this transition promoted
further condensation of pDNA, thereby giving rise to improved complex
and colloidal stability. The proposed system has shown remarkable
stability in salty and proteinous solution and superior tolerance
to nuclease degradation. As compared with polyplex micelles formed
from single POEGMA-<i>b</i>-PAspÂ(DET) block copolymer, in
vivo circulation experiments in the bloodstream further confirmed
that the retention time of MPMs was prolonged significantly. Moreover,
the proposed system exhibited remarkably high cell transfection activity
especially at low N/P ratios and negligible cytotoxicity and thus
portends promising utility for systemic gene therapy applications