Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these ‘hit’ materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions.
Cell-biomaterial interactions can be controlled by modifying the surface chemistry or nanotopography of the material, to induce cell proliferation and differentiation if desired. Here we combine both approaches in forming silk nanofibers (SNFs) containing gold nanoparticles (AuNPs) and subsequently chemically modifying the fibers. Silk fibroin mixed with gold seed nanoparticles was electrospun to form SNFs doped with gold seed nanoparticles (SNFseed). Following gold reduction, there was a two-fold increase in particle diameter confirmed by the appearance of a strong absorption peak at 525 nm. AuNPs were dispersed throughout the AuNP-doped silk nanofibers (SNFsAu). The Young’s modulus of the SNFsAu was almost 70% higher than that of SNFs. SNFsAu were modified with the arginine-glycine-aspartic acid (RGD) peptide. Human mesenchymal stem cells that were cultured on RGD-modified SNFAu had a more than two-fold larger cell area compared to the cells cultured on bare SNFs; SNFAu also increase cell size. We suggest that this approach can be used to alter the cell-material interface in tissue engineering and other applications.
silk; nanofibers; gold nanoparticles; cellular adhesion; tissue engineering; mesenchymal stem cells
3D microfluidic networks are fabricated in a gelatin hydrogel using sacrificial melt-spun microfibers made from a material with pH-dependent solubility. The fibers, after being embedded within the gel, can be removed by changing the gel pH to induce dissolution. This process is performed in an entirely aqueous environment, avoiding extreme temperatures, low pressures, and toxic organic solvents.
vascular; hydrogel; gelatin; shellac; microfiber
Designing materials to control biology is an intense focus of biomaterials and regenerative medicine research. Discovering and designing materials with appropriate biological compatibility or active control of cells and tissues is being increasingly undertaken using high throughput synthesis and assessment methods. We report a relatively simple but powerful machine-learning method of generating models that link microscopic or molecular properties of polymers or other materials to their biological effects. We illustrate the potential of these methods by developing the first robust, predictive, quantitative, and purely computational models of adhesion of human embryonic stem cell embryoid bodies (hEB) to the surfaces of a 496-member polymer micro array library.
Bacteria have shown a remarkable ability to overcome drug therapy if there is a failure to achieve sustained bactericidal concentration or if there is a reduction in activity in situ. The latter can be caused by localized acidity, a phenomenon that can occur as a result of the combined actions of bacterial metabolism and the host immune response. Nanoparticles (NP) have shown promise in treating bacterial infections, but a significant challenge has been to develop antibacterial NPs that may be suitable for systemic administration. Herein we develop drug-encapsulated, pH-responsive, surface charge-switching poly(D, L-lactic-co-glycolic acid)-b-poly(L-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for treating bacterial infections. These NP drug carriers are designed to shield nontarget interactions at pH 7.4 but bind avidly to bacteria in acidity, delivering drugs and mitigating in part the loss of drug activity with declining pH. The mechanism involves pH-sensitive NP surface charge-switching, which is achieved by selective protonation of the imidazole groups of PLH at low pH. NP binding studies demonstrate pH-sensitive NP binding to bacteria with a 3.5±0.2 to 5.8±0.1 fold increase in binding to bacteria at pH 6.0 compared to 7.4. Further, PLGA-PLH-PEG-encapsulated vancomycin demonstrates reduced loss of efficacy at low pH, with an increase in minimum inhibitory concentration of 1.3-fold as compared to 2.0-fold and 2.3-fold for free- and PLGA-PEG-encapsulated vancomycin, respectively. The PLGA-PLH-PEG NPs described herein are a first step towards developing systemically administered drug carriers that can target and potentially treat Gram-positive, Gram-negative, or polymicrobial infections associated with acidity.
nanoparticles; S. aureus; pH-sensitive; vancomycin; cystic fibrosis
There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany.
Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine.
The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin–kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine.
Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.
The assembly, stability and timely disassembly of short interfering RNA (siRNA) nanocomplexes all have the potential to affect the efficiency of siRNA delivery and gene silencing. As such, the design of new probes that can measure these properties without significantly perturbing the nanocomplexes or their environment may facilitate the study and further development of new siRNA nanocomplexes. Herein, we study Förster resonance energy transfer (FRET)-labeled siRNA probes that can track the assembly, stability and disassembly of siRNA nanocomplexes in different environments. The probe is composed of two identical siRNAs, each labeled with a fluorophore. Upon nanocomplex formation, the siRNA-bound fluorophores become locally aggregated within the nanocomplex and undergo FRET. A key advantage of this technique is that the delivery vehicle (DV) need not be labeled, thus enabling the characterization of a large variety of nanocarriers, some of which maybe difficult or even impossible to label. We demonstrate proof-of-concept by measuring the assembly of various DVs with siRNAs and show good agreement with gel electrophoresis experiments. As a consequence of not having to label the DV, we are able to determine nanocomplex biophysical parameters such as the extracellular apparent dissociation constants (KD) and intracellular disassembly half-life for several in-house and proprietary commercial DV’s. Furthermore, the lack of DV modification allows for a true direct comparison between DVs as well as correlation between their biophysical properties and gene silencing.
siRNA; FRET; Nanocomplex; Fluorescent Probe; polycation; lipid; lipidoid
Surface modification is one of the most important techniques in modern science and engineering. The facile introduction of a wide variety of desired properties onto virtually any material surface is an ultimate goal in surface chemistry. To achieve this goal, the incorporation of structurally diverse molecules onto any material surface is an essential capability for ideal surface modification. Here, we present a general strategy of surface modification, in which many diverse surfaces can be functionalized by immobilizing a wide variety of molecules. This strategy functionalizes surfaces by a one-step immersion of substrates in a one-pot mixture of a molecule and a catecholamine surface modification agent. This one-step procedure for surface modification represents a standard protocol to control interfacial properties.
Surface modification; Bio-inspired coating; ATRP; Mineralization; Polydopamine
Lipid-polymer hybrid (LPH) nanoparticles can deliver a wide range of therapeutic compounds in a controlled manner. LPH nanoparticle syntheses using microfluidics improve the mixing process, but are restricted by a low throughput. In this study we present a pattern-tunable microvortex platform that allows mass production and size control of LPH nanoparticles with superior reproducibility and homogeneity. We demonstrate that by varying flow rates (i.e. Reynolds number (30∼150)) we can control the nanoparticle size (30∼170nm) with high productivity (∼3g/hour) and low polydispersity (∼0.1). Our approach may contribute to efficient development and optimization of a wide range of multicomponent nanoparticles for medical imaging and drug delivery.
nanoparticle; microvortex; synthesis; control; polymer; microfluidics
Dynamic cell-microenvironment interactions regulate many biological events and play a critical role in tissue regeneration. Cell homing to targeted tissues requires well balanced interactions between cells and adhesion molecules on blood vessel walls. However, many stem cells lack affinity with adhesion molecules. It is challenging and clinically important to engineer these stem cells to modulate their dynamic interactions with blood vessels. In this study, a new chemical strategy was developed to engineer cell-microenvironment interactions. This method allowed the conjugation of peptides onto stem cell membranes without affecting cell viability, proliferation or multipotency. Mesenchymal stem cells (MSCs) engineered in this manner showed controlled firm adhesion and rolling on E-selectin under physiological shear stresses. For the first time, these biomechanical responses were achieved by tuning the binding kinetics of the peptide-selectin interaction. Rolling of engineered MSCs on E-selectin is mediated by a Ca2+ independent interaction, a mechanism that differs from the Ca2+ dependent physiological process. This further illustrates the ability of this approach to manipulate cell-microenvironment interactions, in particular for the application of delivering cells to targeted tissues. It also provides a new platform to engineer cells with multiple functionalities.
Cell therapy holds promise as a method for the treatment of ischemic disease. However, one significant challenge to the efficacy of cell therapy is poor cell survival in vivo. Here we describe a non-viral, gene therapy approach to improve the survival and engraftment of cells transplanted into ischemic tissue. We have developed biodegradable poly(β-amino esters) (PBAE) nanoparticles as vehicles to genetically modify human umbilical vein endothelial cells (HUVECs) with vascular endothelial growth factor (VEGF). VEGF transfection using these nanoparticles significantly enhanced VEGF expression in HUVECs, compared with a commercially-available transfection reagent. Transfection resulted in the upregulation of survival factors, and improved viability under simulated ischemic conditions. In a mouse model of hindlimb ischemia, VEGF nanoparticle transfection promoted engraftment of HUVECs into mouse vasculature as well as survival of transplanted HUVECs in ischemic tissues, leading to improved angiogenesis and ischemic limb salvage. This study demonstrates that biodegradable polymer nanoparticles may provide a safe and effective method for genetic engineering of endothelial cells to enhance therapeutic angiogenesis.
Polymer nanoparticles; Genetic engineering; Endothelial cells; Angiogenesis; Ischemia
While there are data supporting the use of light in clinical populations, there has been less investigation of relationships among light and psychological variables in non-clinical samples. Subjects were 459 ethnically diverse women (mean age 67.68) recruited as part of the Women's Health Initiative. Light exposure and sleep were measured with an Actillume wrist actigraph. Subjects completed questionnaires, investigating Social Support, Social Functioning, Social Strain, Quality of Life, Satisfaction with Life, Emotional Well-being, Optimism, Negative Emotional Expressiveness, and Role Limitation Due to Emotional Problems. Significant partial correlations (controlling for age, education and ethnicity) were found between mesor light exposure and Social Functioning, Quality of Life, Satisfaction with Life, and Emotional Well-Being. Quality of Life and Satisfaction with Life were also found to be significantly correlated with morning light. The most parsimonious model to account for the variance shared between mesor light and the predictors included only Quality of Life. The variance shared between mesor light exposure and social and emotional functioning could be subsumed under the variance shared between mesor light exposure and Quality of Life. Increased light exposure is related to improved quality of life and social and emotional functioning. Increased light exposure is related to improved quality of life and social and emotional functioning.
Phototherapy; Circadian rhythm; Interpersonal relations; Emotional disturbances; Sleep
The development of responsive nanomaterials—nanoscale systems that actively respond to stimuli—is one general goal of nanotechnology. Here we develop nanoparticles that can be controllably triggered to synthesize proteins. The nanoparticles consist of lipid vesicles filled with the cellular machinery responsible for transcription and translation, including amino acids, ribosomes, and DNA caged with a photo-labile protecting group. These particles served as nanofactories capable of producing proteins including green fluorescent protein (GFP) and enzymatically-active luciferase. In vitro and in vivo, protein synthesis was spatially and temporally controllable, and could be initiated by irradiating micron-scale regions on the timescale of milliseconds. The ability to control protein synthesis inside nanomaterials may enable new strategies to facilitate the study of orthogonal proteins in a confined environment and for remotely-activated drug delivery.
protein; nanoparticle; molecular nanotechnology; drug delivery
The use of estrogen plus progestin therapy increases both breast cancer incidence and breast tenderness. Whether breast tenderness during estrogen plus progestin therapy is associated with breast cancer risk is uncertain.
We analyzed data from the Women’s Health Initiative Estrogen plus Progestin Clinical Trial, which randomized postmenopausal women with an intact uterus to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily (CEE + MPA, N=8506) or placebo (N=8102). At baseline and annually, participants underwent mammography and clinical breast exam. Self-report of breast tenderness was assessed at baseline and 12 months. Invasive breast cancer incidence was confirmed by medical record review (mean 5.6 years of follow-up).
Among women without baseline breast tenderness (N=14538), significantly more women assigned to CEE + MPA than placebo experienced new-onset breast tenderness after 12 months (36.1% vs. 11.8%, P<0.001). Among women in the CEE + MPA group, breast cancer risk was significantly higher in those with new-onset breast tenderness compared to those without new-onset breast tenderness (Hazard Ratio 1.48, 95% confidence interval 1.08–2.03, P=0.02). Among women in the placebo group, breast cancer risk was not significantly associated with new-onset breast tenderness.
New-onset breast tenderness during use of CEE + MPA was associated with increased breast cancer risk. The sensitivity and specificity for the association between breast tenderness and breast cancer were similar in magnitude to those of the Gail model.
Using nanoparticles for therapy and imaging holds tremendous promise for the treatment of major diseases such as cancer. However, their translation into the clinic has been slow because it remains difficult to produce nanoparticles that are consistent ‘batch-to-batch’, and in sufficient quantities for clinical research. Moreover, platforms for rapid screening of nanoparticles are still lacking. Recent microfluidic technologies can tackle some of these issues, and offer a way to accelerate the clinical translation of nanoparticles. In this Progress Article, we highlight the advances in microfluidic systems that can synthesize libraries of nanoparticles in a well-controlled, reproducible and high-throughput manner. We also discuss the use of microfluidics for rapidly evaluating nanoparticles in vitro under microenvironments that mimic the in vivo conditions. Furthermore, we highlight some systems that can manipulate small organisms, which could be used for evaluating the in vivo toxicity of nanoparticles or for drug screening. We conclude with a critical assessment of the near- and long-term impact of microfluidics in the field of nanomedicine.
Diet is the first line of treatment for elevated cholesterol. High-intensity dietary counseling (≥360 minutes/year of contact with providers) improves blood lipids, but is expensive and unsustainable in the current healthcare settings. Low-intensity counseling trials (≤ 30 minutes/year) have demonstrated modest diet changes, but no improvement in lipids. This pilot study evaluated the feasibility and the effects on lipids and diet of a low-intensity dietary counseling intervention provided by the primary care physician (PCP), in patients at risk for cardiovascular diseases.
Six month study with a three month randomized-controlled phase (group A received the intervention, group B served as controls) followed by three months of intervention in both groups.
Sixty-one adults age 21 to 75 years, with LDL-cholesterol ≥ 3.37 mmol/L, possessing Internet access and active email accounts were enrolled. Diet was evaluated using the Rate-Your-Plate questionnaire. Dietary counseling was provided by the PCP during routine office visits, three months apart, using printed educational materials and a minimally interactive counseling website. Weekly emails were sent reminding participants to use the dietary counseling resources. The outcomes were changes in LDL-cholesterol, other lipid subclasses, and diet quality.
At month 3, group A (counseling started at month 1) decreased their LDL-cholesterol by −0.23 mmol/L, (−0.04 to −0.42 mmol/L, P = 0.007) and total cholesterol by −0.26 mmol/L, (−0.05 to −0.47 mmol/L, P = 0.001). At month 6, total and LDL-cholesterol in group A remained better than in group B (counseling started at month 3). Diet score in group A improved by 50.3 points (38.4 to 62.2, P < 0.001) at month 3; and increased further by 11.8 (3.5 to 20.0, P = 0.007) at month 6. Group B made the largest improvement in diet at month 6, 55 points (40.0 to 70.1, P < 0.001), after having a small but significant improvement at month 3, 22.3 points (12.9 to 31.7, P < 0.001). No significant changes occurred in HDL-cholesterol in either group.
A low-intensity dietary counseling provided by the PCP in patients at risk for cardiovascular diseases produced clinically meaningful improvements in both diet and lipids of magnitude similar to changes reported with high intensity interventions.
Diet; Behavior change; Lipid management; Cardiovascular; Risk reduction; Primary care
Concerns over neurotoxicity have impeded the development of sustained release formulations providing prolonged duration local anesthesia (PDLA) from a single injection, for which there is an urgent clinical need. Here, we have used toxicogenomics to investigate whether nerve injury occurred during week-long continuous sciatic nerve blockade by microspheres containing bupivacaine, tetrodotoxin, and dexamethasone (TBD). Animals treated with amitriptyline solution (our positive control for local anesthetic-associated nerve injury) developed irreversible nerve blockade, had severely abnormal nerve histology, and the expression of hundreds of genes was altered in the dorsal root ganglia at 4 and 7 days after injection. In marked contrast, TBD-treated nerves reverted to normal function, were normal histologically and there were changes in the expression of a small number of genes. Toxicogenomic studies have great potential in delineating patterns of gene expression associated with specific patterns of tissue injury (e.g. amitriptyline neurotoxicity), and in identifying related changes in gene expression upon exposure to a drug, biomaterial, or drug delivery system.
Toxicogenomics; drug delivery; biocompatibility; prolonged duration local anesthesia; neurotoxicity; nerve injury
Amine end-modified poly(ß-amino ester)s (PBAEs) have generated interest as efficient, biodegradable polymeric carriers for plasmid DNA (pDNA). For cationic, non-degradable polymers, such as polyethylenimine (PEI), the polymer molecular weight (MW) and molecular weight distribution (MWD) significantly affect transfection activity and cytotoxicity. The effect of MW on DNA transfection activity for PBAEs has been less well studied. We applied two strategies to obtain amine end-modified PBAEs varying in MW. In one approach, we synthesized four amine end-modified PBAEs with each at 15 different monomer molar ratios, and observed that polymers of intermediate length mediated optimal DNA transfection in HeLa cells. Biophysical characterization of these feed ratio variants suggested that optimal performance was related to higher DNA complexation efficiency and smaller nanoparticle size, but not to nanoparticle charge. In a second approach, we used preparative size exclusion chromatography (SEC) to obtain well-defined, monodisperse polymer fractions. We observed that the transfection activities of size-fractionated PBAEs generally increased with MW, a trend that was weakly associated with an increase in DNA binding efficiency. Furthermore, this approach allowed for the isolation of polymer fractions with greater transfection potency than the starting material. For researchers working with gene delivery polymers synthesized by step-growth polymerization, our data highlight the potentially broad utility of preparative SEC to isolate monodisperse polymers with improved properties. Overall, these results help to elucidate the influence of polymer MWD on nucleic acid delivery and provide insight toward the rational design of next-generation materials for gene therapy.
Here we describe the development of a water-responsive polymer film; combining both a rigid matrix (polypyrrole) and a dynamic network (polyol-borate), strong and flexible polymer films were developed that can exchange water with the environment to induce film expansion and contraction, resulting in rapid and continuous locomotion. The film actuator can generate contractile stress up to 27 MPa, lift objects 380 times heavier than itself, and transport cargo 10 times heavier than itself. We have assembled a generator by associating this actuator with a piezoelectric element. Driven by water gradients, this generator outputs alternating electricity at ∼0.3 Hz, with a peak voltage of ∼1.0 V. The electrical energy is stored in capacitors that could power micro- and nano-electronic devices.
Conventional synthesis of polymers by ATRP is relatively low throughput, involving iterative optimization of conditions in an inert atmosphere. Automated, high-throughput controlled radical polymerization was developed to accelerate catalyst optimization and production of disulfide-functionalized polymers without the need of an inert gas. Using ARGET ATRP, polymerization conditions were rapidly identified for eight different monomers, including the first ARGET ATRP of 2-(diethylamino)ethyl methacrylate and di(ethylene glycol) methyl ether methacrylate. In addition, butyl acrylate, oligo(ethylene glycol) methacrylate 300 and 475, 2-(dimethylamino)ethyl methacrylate, styrene, and methyl methacrylate were polymerized using bis(2-hydroxyethyl) disulfide bis(2-bromo-2-methylpropionate) as the initiator, tris(2-pyridylmethyl)amine as the ligand, and tin(II) 2-ethylhexanoate as the reducing agent. The catalyst and reducing agent concentration was optimized specifically for each monomer, and then a library of polymers was synthesized systematically using the optimized conditions. The disulfide-functionalized chains could be cleaved to two thiol-terminated chains upon exposure to dithiothreitol, which may have utility for the synthesis of polymer bioconjugates. Finally, we demonstrated that these new conditions translated perfectly to conventional batch polymerization. We believe the methods developed here may prove generally useful to accelerate the systematic optimization of a variety of chemical reactions and polymerizations.
The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological micro-environments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Additionally, we show the integrated sensory capability of the nanoES by real-time monitoring of (i) the local electrical activity within 3D nanoES/cardiomyocyte constructs, (ii) the response of 3D nanoES based neural and cardiac tissue models to drugs, and (iii) distinct pH changes inside and outside tubular vascular smooth muscle constructs.
Polylactic-co-glycolic acid (PLGA) based nanoparticles are biocompatible and biodegradable and therefore have been extensively investigated as therapeutic carriers. Here, we engineered diagnostically active PLGA nanoparticles that incorporate high payloads of nanocrystals into their core for tunable bioimaging features. We accomplished this through esterification reactions of PLGA to generate polymers modified with nanocrystals. The PLGA nanoparticles formed from modified PLGA polymers that were functionalized with either gold nanocrystals or quantum dots exhibited favorable features for computed tomography and optical imaging, respectively.
The synergism between low-frequency sonophoresis (LFS) and chemical penetration enhancers (CPEs), especially surfactants, in transdermal enhancement has been investigated extensively since this phenomenon was first observed over a decade ago. In spite of the identifying that the origin of this synergism is the increased penetration and subsequent dispersion of CPEs in the skin in response to LFS treatment, to date, no mechanism has been directly proposed to explain how LFS induces the observed increased transport of CPEs. In this study, we propose a plausible physical mechanism by which the transport of all CPEs is expected to have significantly increased flux into the localized-transport regions (LTRs) of LFS-treated skin. Specifically, the collapse of acoustic cavitation microjets within LTRs induces a convective flux. In addition, because amphiphilic molecules preferentially adsorb onto the gas/water interface of cavitation bubbles, amphiphiles have an additional adsorptive flux. In this sense, the cavitation bubbles effectively act as carriers for amphiphilic molecules, delivering surfactants directly into the skin when they collapse at the skin surface as cavitation microjets. The flux equations derived for CPE delivery into the LTRs and non-LTRs during LFS treatment, compared to that for untreated skin, explain why the transport of all CPEs, and to an even greater extent amphiphilic CPEs, is increased during LFS treatment. The flux model is tested with a non-amphiphilic CPE (propylene glycol) and both nonionic and ionic amphiphilic CPEs (octyl glucoside and sodium lauryl sulfate, respectively), by measuring the flux of each CPE into untreated skin and the LTRs and non-LTRs of LFS-treated skin. The resulting data shows very good agreement with the proposed flux model.
Chemical Penetration Enhancers; Diffusion; Sonophoresis; Synergism; Transdermal; Ultrasound
Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality.
Oxaliplatin; Intestinal tumorigenesis; Colon cancer; Oral delivery; Alginate
Microfluidics; vascular; 3D; resistance; microfiber