16 research outputs found
Development of stimuli-responsive degradable block copolymer micelles as smart drug delivery nanocarriers
Polymer-based drug delivery systems offer the potential to increase the bioavailability of drug molecules without leaving toxic byproducts in the body. In particular, micellar aggregates based on amphiphilic block copolymers (ABPs) consisting of a hydrophobic core and a hydrophilic corona can enable the physical encapsulation of poorly water-soluble drugs. These micelles possess several advantages as drug delivery carriers due to their colloidal stability and tunable sizes with narrow size distribution. In addition, their physicochemical properties and small size enable passive tumor targeting through the enhanced permeability and retention effect. Also their chemical flexibility allows them to be tailored for active targeting. One additional benefit of using ABP-based micelles is that they can be engineered to incorporate stimuli-responsive moieties to control release of encapsulated drugs as a result of micellar degradation in response to external triggers such as pH, thiols and temperature. With this knowledge, ABP micelles can be designed with the ability to respond to stimuli that are inherently present in living systems and release their payload before being evacuated from the body. Presence of pH and redox gradients within the body makes them ideal stimuli in the design and development of stimuli-responsive degradable micelles for controlled release of therapeutics.
For better understanding of the structure-property relationship between morphological variance and stimuli-responsive degradation, we have developed new pH-sensitive degradable micelles having pendant t-butyl groups, as well as reductively degradable ABP micelles with single disulfide linkages positioned in the center of triblock copolymers, or with pendant disulfides positioned on the hydrophobic block. They were synthesized by atom transfer radical polymerization, a dynamic controlled radical polymerization method enabling the synthesis of copolymers with narrow molecular weight distributions and pre-determined molecular weights. Aqueous self-assembly of ABPs resulted in colloidally stable spherical micelles capable of encapsulating hydrophobic model drugs at above critical micellar concentration. Various analytical methods were used to characterize ABPs and their micelles. The resulting micelles in aqueous solutions were destabilized in response to acidic conditions or reductive conditions, which suggests the possibility of enhanced release of encapsulated compounds. Results show that degradable ABPs of varying architectures and designs, upon the proper stimuli, will be dissociated at different rates, leading to a wide range of morphologies and sustained release rates of the encapsulated molecules
Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis
We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA
Rapidly thiol-responsive degradable block copolymer nanocarriers with facile bioconjugation
Degradation of amphiphilic block copolymer (ABP) micelles in response to external stimuli (stimuli-responsive degradation) is a desired property in the design of controlled delivery vehicles. Here, a versatile methodology that combines facile carbodiimide coupling polycondensation with controlled radical polymerization to synthesize thiol-responsive degradable ABP micelles is described. These smart micelles consist of a hydrophobic degradable polyester block with disulfide linkages labeled repeatedly along the main chain; more importantly, in response to thiols they exhibit rapid and controlled degradation, thereby leading to enhanced release of encapsulated model drugs. Moreover, the proposed method allows for a facile bioconjugation of hydrophilic coronas using cell-targeting biomolecules during polymerization
Intracellular Drug Delivery Nanocarriers of Glutathione-Responsive Degradable Block Copolymers Having Pendant Disulfide Linkages
Self-assembled
micelles of amphiphilic block copolymers (ABPs)
with stimuli-responsive degradation (SRD) properties have a great
promise as nanotherapeutics exhibiting enhanced release of encapsulated
therapeutics into targeted cells. Here, thiol-responsive degradable
micelles based on a new ABP consisting of a pendant disulfide-labeled
methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene
oxide) (PEO) block were investigated as effective intracellular nanocarriers
of anticancer drugs. In response to glutathione (GSH) as a cellular
trigger, the cleavage of pendant disulfide linkages in hydrophobic
PHMssEt blocks of micellar cores caused the destabilization of self-assembled
micelles due to change in hydrophobic/hydrophilic balance. Such GSH-triggered
micellar destabilization changed their size distribution with an appearance
of large aggregates and led to enhanced release of encapsulated anticancer
drugs. Cell culture results from flow cytometry and confocal laser
scanning microscopy for cellular uptake as well as cell viability
measurements for high anticancer efficacy suggest that new GSH-responsive
degradable PEO-b-PHMssEt micelles offer versatility in multifunctional
drug delivery applications
Correction: MicroRNA-200c Represses IL-6, IL-8, and CCL-5 Expression and Enhances Osteogenic Differentiation.
[This corrects the article DOI: 10.1371/journal.pone.0160915.]
Correction: MicroRNA-200c Represses IL-6, IL-8, and CCL-5 Expression and Enhances Osteogenic Differentiation
<i>miR-200c</i> modulates proinflammatory mediators in human preosteoblasts.
<p><b>A</b> and <b>B:</b> the transcripts of IL-6 <b>(A)</b> and IL-8 (<b>B</b>) in non-treated HEPM cells and the cells with <i>miR-200c</i> or scrambled <i>miRs</i> cultured in DMEM supplemented with LPS at 0, 1, 5 and 10 μg/mL after 24 hours; *:p<0.05 vs non-treated; <b>C:</b> the amounts of IL-8 secreted by HEPM cells with <i>miR-200c</i> or scrambled <i>miRs</i> cultured in DMEM supplemented with or without LPS at different time points; *: p<0.05 vs cells with scrambled miRs; <b>D</b> and <b>E:</b> the amounts of IL-6 (<b>D</b>) and CCL-5 (<b>E</b>) secreted by HEPM cells with <i>miR-200c</i> or <i>scrambled miRs</i> cultured in DMEM supplemented with or without LPS after 24 hrs; <b>F:</b> the amounts of OPG secreted by HEPM cells with different <i>miRs</i> cultured in DMEM supplemented with or without LPS after 32 hours. *: p<0.05.</p
<i>miR-200c</i> delivered using PEI nanoparticles inhibits IL-6, IL-8, and CCL-5 in primary human periodontal ligament fibroblasts.
<p><b>A-C</b>: The transcripts of IL-6 (<b>A</b>), IL-8 (<b>B</b>), and CCL-5 (<b>C</b>) in the cells with <i>miR-200c</i> or empty vector cultured in DMEM supplemented with LPS after 24 hours; <b>D</b> and <b>E</b>: the amounts of IL-6 (<b>D</b>), IL-8 (<b>E</b>), and CCL-5 (<b>F</b>) secreted by the cells with miR-200c or empty vector cultured in DMEM supplemented with LPS after 12 and 32 hrs, respectively. *: p<0.05 vs empty vector with the same amount.</p
Intracellular delivery of <i>miR-200c</i> using PEI nanoparticles to human primary periodontal ligament fibroblasts and bone marrow MSCs.
<p><b>A</b>: TEM image of PEI-<i>miR-200c</i> nanoplexes. <b>B</b> and <b>C:</b> Fold change of the transcript of <i>miR-200c</i> in non-treated human periodontal ligament fibroblasts (<b>B</b>) and bone marrow MSCs (<b>C</b>) and the cells transfected with empty vector (EV) (10μg/per well) and <i>miR-200c</i> (1, 5, 10μg/per well).</p