Novel Eudragit® -based polymeric nanoparticles for sustained release of simvastatin
This paper reports on the development of nanoparticles aiming at the in vitro controlled release of simvastatin (SVT). The nanoparticles were prepared by the nanoprecipitation method with polymers Eudragit® FS30D (EDGFS) or Eudragit® NE30D (EDGNE). EDGFS+SVT nanoparticles showed mean size of 148.8 nm and entrapment efficiency of 76.4%, whereas EDGNE+SVT nanoparticles showed mean size of 105.0 nm and entrapment efficiency of 103.2%. Infrared absorption spectra demonstrated that SVT incorporated into the polymer matrix, especially EDGNE. Similarly, the differential scanning calorimeter (DSC) curve presented no endothermic peak of fusion, indicating that the system is amorphous and the drug is not in the crystalline state. The maintenance of SVT in the amorphous state may favors its solubilization in the target release sites. In the in vitro dissolution assay, the SVT incorporated into the EDGFS+SVT nanoparticles showed a rapid initial release, which may be related to the pH of the dissolution medium used. Regarding the EDGNE+SVT nanoparticles, the in vitro release occurred in a bimodal behavior, i.e., an initial “burst” followed by a sustained delivery, with the kinetics of drug release following Baker-Lonsdale’s mathematical model. All these features suggest the nanoparticulate system’s potential to modulate SVT delivery and enhance its bioavailability.
RODRIGUES, Deborah Fernandes et al. Novel Eudragit®-based polymeric nanoparticles for sustained release of simvastatin. Brazilian Journal of Pharmaceutical Sciences, v. 56, 2020.
Oral Treatment of spontaneously hypertensive rats with captopril-surface funcionalized furosemid-loaded multi-well lipid-core nanocapsules
Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and dynamic light scattering). Zeta potential was inverted from -14.3 mV [LNC-Fur(0,5)] to +18.3 mV after chitosan coating. Transmission electron microscopy and atomic force microscopy showed spherical structures corroborating the nanometric diameter of the nanocapsules. Regarding the systolic pressure, on the first day, the formulations showed antihypertensive effect and a longer effect than the respective drug solutions. When both drugs were associated, the anti-hypertensive effect was prolonged. On the fifth day, a time effect reduction was observed for all treatments, except for the nanocapsule formulation containing both drugs [Capt(0.5)-Zn(25)-MLNC-Fur(0.45)]. For diastolic pressure, only Capt(0.5)-Zn(25)-MLNC-Fur(0.45) presented a significant difference (p < 0.05) on the first day. On the fifth day, both Capt(0.5)-MLNC-Fur(0.45) and Capt(0.5)-Zn(25)-MLNC-Fur(0.45) had an effect lasting up to 24 h. The analysis of early kidney damage marker showed a potential protection in renal function by Capt(0.5)-Zn(25)-MLNC-Fur(0.45). In conclusion, the formulation Capt(0.5)-Zn(25)-MLNC-Fur(0.45) proved to be suitable for hypertension treatment envisaging an important innovation.
MICHALOWSKI, Cecilia B. et al. Oral Treatment of Spontaneously Hypertensive Rats with Captopril-Surface Functionalized Furosemide-Loaded Multi-Wall Lipid-Core Nanocapsules. Pharmaceutics, v. 12, n. 1, p. 80, 2020.
Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche
Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
KROHN-GRIMBERGHE, Marvin et al. Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. Nature Biomedical Engineering, p. 1-14, 2020.
Design of chitosan-based particle system: A review the physicochemical foundations for tailored properties
Chitosan-based particles are widely proposed as biocompatible drug delivery systems with mucoadhesive and permeation enhancing properties. However, strategies on how to modulate the intended biological responses are still scarce. Considering that particle properties affect the biological outcome, the rational design of the synthesis variables should be proposed to engineer drug delivery systems with improved biological performance. The purpose of this review is to establish a deeper understanding of possible correlations between these variables and the particle properties from theoretical and experimental perspectives. The fundamental physicochemical knowledge of chitosan-based polyelectrolyte complexation and surface modification is discussed focusing on chitosan-TPP, polyelectrolyte complexes, and chitosan-surface modified PLGA or lipid particles. A set of design considerations is proposed to enable future investigation in the development of chitosan particles with modulated properties. The approach presented here contributes to the rational design of chitosan-based particles that meet different requirements for biological activities.
FERREIRA, Leonardo MB et al. Design of chitosan-based particle systems: a review of the physicochemical foundations for tailored properties. Carbohydrate Polymers, p. 116968, 2020.
Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays
Solanum lycocarpum fruits contain two major glycoalkaloids (GAs), solamargine (SM) and solasonine (SS). These compounds are reported as cytotoxic. However, they have poor water solubility and low bioavailability. To overcome these disadvantages and getting an efficient formulation the current study aimed to develop, characterize, and test the effectiveness of a nanotechnology-based strategy using poly(D,L-lactide) (PLA) nanoparticles functionalized with folate as delivery system of glycoalkaloidic extract (AE) for bladder cancer therapy. The strategic of adding folic acid into nanoformulations can increase the selectivity of the compounds to the cancer cells reducing the side effects. Our results revealed the successful preparation of AE-loaded folate-targeted nanoparticles (NP-F-AE) with particle size around 177 nm, negative zeta potential, polydispersity index <0.20, and higher efficiency of encapsulation for both GAs present in the extract (>85 %). To investigate the cellular uptake, the ﬂuorescent dye coumarin-6 was encapsulated into the nanoparticle (NP-F-C6). The cell studies showed high uptake of nanoparticles by breast (MDA-MB-231) and bladder (RT4) cancer cells, but not for normal keratinocytes cells (HaCaT) indicating the target uptake to cancer cells. The cytotoxicity of nanoparticles was evaluated on RT4 2D culture model showing 2.16-fold lower IC50 than the free AE. Furthermore, the IC50 increased on the RT4 spheroids compared to 2D model. The nanoparticles penetrated homogeneously into the urotheliumof porcine bladder. These results showed that folate-conjugated polymeric nanoparticles are potential carriers for targeted glycoalkaloidic extract delivery to bladder cancer cells.
MIRANDA, M. A. et al. Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays. Colloids and Surfaces B: Biointerfaces, p. 111106, 2020.
Nanoestructured lipid carrier co-delivering tacrolimus and TNF-alfa siRNA as na innovate approach to psioriasis
Since psoriasis is an immuno-mediated skin disease, long-term therapies are necessary for its treatment. In clinical investigations, tacrolimus (TAC), a macrolide immunosuppressive inhibitor of calcineurin, arises as an alternative for the treatment of psoriasis, acting in some cytokines involved in the pathogenesis of the disease. Here, we aim to study the psoriasis treatment with TAC and siRNA for one of most cytokines expressed in psoriasis, the TNF-α. A multifunctional nanostructure lipid carrier (NLC) was developed to co-delivery TAC and siRNA. Results showed that the particle size and zeta potential were around 230 nm and + 10 mV, respectively. The release study demonstrated a controlled release of TAC, and the permeation and retention profile in the skin tissue show to be promising for topical application. The cell viability and uptake in murine fibroblast presented low toxicity associated to uptake of NLC in 4 h, and finally, the in vivo animal model demonstrates the efficiency of the NLC multifunctional, exhibiting a reduction of the cytokine TNF-α expression about 7-fold and presenting a synergic effect between the TAC and TNF-α siRNA. The developed system was successfully to treat in vivo psoriatic animal model induced by imiquimod and the synergic combination was reported here for the first time.
VIEGAS, Juliana Santos Rosa et al. Nanostructured lipid carrier co-delivering tacrolimus and TNF-α siRNA as an innovate approach to psoriasis. Drug Delivery and Translational Research, p. 1-15, 2020.
N,N,N-trimethylchitosan-poly (n-butylcyanoacrylate) core-shell nanoparticles as a potential oral delivery system for acyclovir
This study investigated the feasibility of polysaccharide-coated poly(n-butyl cyanoacrylate) (PBCA) nanoparticles for oral delivery of acyclovir (ACV). PBCA nanoparticles were obtained by the emulsion polymerization method. Chitosan was chemically modified to obtain N,N,N-trimethylchitosan (TMC), which was used to coat the nanoparticles (PBCA-TMC). Nanoparticles were characterized by dynamic light scattering, zeta potential, differential scanning calorimetry (DSC), atomic force microscopy (AFM), cytotoxicity, and the effect on the transepithelial electrical resistance (TEER) of the Caco-2 cells. The size of the coated nanoparticles (296.2 nm) was significantly larger than uncoated (175.0 nm). Furthermore, PBCA nanoparticles had a negative charge (-11.7 mV), which was inverted to highly positive values (+36.5 mV) after coating. DSC analysis suggested the occurrence of the coating, which was confirmed by AFM images. The MTT assay revealed concentration-dependent cytotoxicity for the core-shell nanoparticles. Additionally, PBCA-TMC caused a significant but reversible decrease in the Caco-2 cell monolayer TEER. Entrapped ACV (PBCA-ACV-TMC), a Biopharmaceutical Classification System class III drug substance, increased approximately 3.25 times the Papp of ACV in the Caco-2 permeability assay. The nanoparticles were also able to provide in vitro ACV controlled release using media with different pH values (1.2; 6.8; 7.4). Accordingly, this new core-shell nanoparticle showed the potential to improve the oral delivery of ACV.
TAVARES, Guilherme Diniz et al. N, N, N-trimethylchitosan-poly (n-butylcyanoacrylate) core-shell nanoparticles as a potential oral delivery system for acyclovir. Colloids and Surfaces B: Biointerfaces, v. 196, p. 111336, 2020.
Role of the complement cascade in the biological fate of liposomes in rodents
Nanomedicines, including liposomes, have been used to improve the clinical efficacy and safety of drugs. In some liposomal formulations, a hydrophilic polymer coating of poly(ethylene glycol) (PEG) is used to increase the circulation time. Understanding the biological mechanisms responsible for the clearance of PEGylated and non-PEGylated nanomedicines is necessary to develop better-performing materials. The purpose of this work is to explore the role of complement in the elimination of intravenously administered liposomes (PEGylated and non-PEGylated) in mice and rats. Here, the complement cascade was depleted by intraperitoneal injections of cobra venom factor (CVF) 12 and 24 hours before the intravenous injection of radiolabeled liposomes. In both mice and rats, non-PEGylated liposomes showed faster elimination than PEGylated liposomes. At a lipid dose of 20 mg kg−1, the abrogation of the complement cascade (in CVF group) did not alter the circulation time of either PEGylated or non-PEGylated liposomes. In contrast, at lower doses (2 mg kg−1), animals treated with CVF had slightly higher levels of circulating liposomes, especially during the 24 hours pharmacokinetic studies. The complement cascade seems to govern the uptake of non-PEGylated liposomes by splenic B cells. Altogether, these results suggest that although PEGylated and non-PEGylated liposomes can activate complement, the impact of this cascade on their circulation time is minor and mostly perceivable at later phases of distribution. This work enlightens biological pathways responsible for in vivo clearance of liposomes and will help in orienting future research in elucidating the nano-bio interface.
DE OLIVEIRA VIANA, Iara Maíra et al. Role of the complement cascade in the biological fate of liposomes in rodents. Nanoscale, v. 12, n. 36, p. 18875-18884, 2020.
Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization
D Xylan extracted from corn cobs was used to produce mesalamine-loaded xylan microparticles (XMP5-ASA) by cross-linking polymerization using a non-hazardous cross-linking agent. The microparticles were characterized by thermal analysis (DSC/TG), X-ray diffraction (XRD), Infrared spectroscopy (FTIR-ATR) and scanning electron microscopy (SEM). A comparative study of the in vitro drug release from XMP5-ASA and from gastro-resistant capsules filled with XMP5-ASA (XMPCAP5-ASA) or 5-ASA was also performed. NMR, FTIR-ATR, XRD and DSC/TG studies indicated molecularly dispersed drug in the microparticles with increment on drug stability. The release studies showed that XMPCAP5-ASA allowed more efficient drug retention in the simulated gastric fluid and a prolonged drug release lasting up to 24 h. XMPCAP5-ASA retained approximately 48 % of its drug content after 6 h on the drug release assay. Thus, the encapsulation of 5-ASA into xylan microparticles together with gastro-resistant capsules allowed a better release control of the drug during different simulated gastrointestinal medium.
DA COSTA URTIGA, Silvana Cartaxo et al. Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization. Carbohydrate Polymers, v. 250, p. 116929, 2020.
ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer's disease
Despite the various mechanisms that involved in the pathogenesis of Alzheimer's disease (AD), neuronal damage and synaptic dysfunction are the key events leading to cognition impairment. Therefore, neuroprotection and neurogenesis would provide essential alternatives to the rescue of AD cognitive function. Here we demonstrated that extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs derived EVs, abbreviated as EVs) entered the brain quickly and efficiently following intranasal administration, and majorly accumulated in neurons within the central nervous system (CNS). Proteomics analysis showed that EVs contained multiple proteins possessing neuroprotective and neurogenesis activities, and neuronal RNA sequencing showed genes enrichment in neuroprotection and neurogenesis following the treatment with EVs. As a result, EVs exerted powerful neuroprotective effect on Aβ1–42 oligomer or glutamate acid-induced neuronal toxicity, effectively ameliorated neurologic damage in the whole brain areas, remarkably increased newborn neurons and powerfully rescued memory deficits in APP/PS1 transgenic mice. EVs also reduced Aβ deposition and decreased microglia activation although in a less extent. Collectively, here we provide direct evidence that ADSCs-derived EVs may potentially serve as an alternative for AD therapy through alleviating neuronal damage and promoting neurogenesis.
MA, Xinyi et al. ADSCs-derived extracellular vesicles alleviate neuronal damage, promote neurogenesis and rescue memory loss in mice with Alzheimer's disease. Journal of Controlled Release, 2020.
Biofilm microenvironment activated supramolecular nanoparticles for enhanced photodynamic therapy of bacterial keratitis
Infectious keratitis caused by bacterial biofilms is one of the main causes of corneal blindness, presenting a serious threat to public health. In this study, matrix metalloproteinase (MMP)-sensitive supramolecular nanoparticles (denoted as MMP-S NPs) were constructed for enhancing photodynamic antibacterial effect against biofilm-associated bacterial keratitis. MMP-S NPs were prepared by host-guest self-assembly of chlorin e6 (Ce6) conjugated β-cyclodextrin (β-CD) prodrug (β-CD-Ce6) and MMP-9-sensitive peptides (YGRKKKRRQRRR-GPLGVRG-EEEEEE) terminated with adamantane (ad) (ad-MMP-S PEPs). MMP-S NPs with EEEEEE peptide shell had a negatively charged surface, preventing adhesion to the normal ocular surface or healthy corneal cells, thus enhancing tear retention time. After arriving at the infected lesions, the protective EEEEEE peptide shell of MMP-S NPs was removed, triggered by overexpressed MMP-9 in the keratitis microenvironment. The subsequently exposed cationic peptides helped the nanoparticles penetrate and accumulate in biofilms as well as bind to gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa), which eventually improved the photodynamic antibacterial effect. Furthermore, the P. aeruginosa keratitis model verified the high effectiveness of a topical eye drop formulation of MMP-S NPs in killing bacteria by destroying the bacterial membrane as a result of in situ photodynamic activation of reactive oxygen species (ROS) formation under light irradiation. Moreover, the inflammatory response in the cornea was inhibited to a great extent. As a result, further damage to the corneal tissue was completely suppressed. This research provides a viable antibacterial alternative to fight against bacterial keratitis through effective elimination of infectious bacteria and eradication of bacterial biofilms in the cornea
HAN, Haijie et al. Biofilm microenvironment activated supramolecular nanoparticles for enhanced photodynamic therapy of bacterial keratitis. Journal of Controlled Release, 2020.
Tannic acid-functionalized boron nitride nanosheets for theranostics
Here, we report a tannic acid-Fe3+ coordination complex coating that confers magnetic resonance imaging (MRI) theranostic properties to inert nanomaterials. Boron nitride nanosheets (BNS), which lack magnetic field and light responsiveness, were used as a model nonfunctional nanomaterial. Among various catechol derivatives tested (i.e., dopamine, 3,4-dihydroxyphenylacetic acid, gallic acid, and tannic acid), a coating of tannic acid-Fe3+ coordination complex provided the highest magnetic field relaxivity and near infrared (NIR) laser light responsiveness. An in vitro study showed that KB tumor cells treated with tannic acid-Fe3+ coordination complex adsorbed on BNS (TA-Fe/BNS) exhibited higher T1-weighted magnetic resonance contrast compared with plain BNS, and BNS coated with tannic acid or Fe alone. NIR irradiation at 808 nm caused a significant increase in KB tumor cell death after treatment with TA-Fe/BNS compared with other treatments. In vivo MRI imaging revealed tumor accumulation of intravenously administered TA-Fe/BNS. Guided by MRI information, application of focused laser irradiation onto tumor tissues resulted in complete tumor ablation. These results support the potential of TA-Fe/BNS for MRI theranostics. Moreover, this study suggests the wide applicability of TA-Fe noncovalent coating as biocompatible and facile tool for converting nonfunctional early-generation nanomaterials into functional new nanomaterials, opening new opportunities for their use in translational biomedical applications such as MRI theranostics.
GAYONG, Shim et al. Tannic acid-functionalized boron nitride nanosheets for theranostics. Journal of Controlled Release, 2020.
Implant-based direction of magnetic nanoporous silica nanoparticles - influence of macrophage depletion and infection
Implant associated infections are still key problem in surgery. In the present study, the combination of a magnetic implant with administered magnetic nanoporous silica nanoparticles as potential drug carriers was examined in mice in dependence of local infection and macrophages as influencing factors. Four groups of mice (with and without implant infection and with and without macrophage depletion) received a magnet on the left and a titanium control on the right hind leg. Then, fluorescent nanoparticles were administered and particle accumulations at implant surfaces and in inner organs as well as local tissue reactions were analyzed. Magnetic nanoparticles could be found at the surfaces of magnetic implants in different amounts depending on the treatment groups and only rarely at titanium surfaces. Different interactions of magnetic implants, particles, infection and surrounding tissues occurred. The general principle of targeted accumulation of magnetic nanoparticles could be proven.
REIFENRATH, Janin et al. Implant-based direction of magnetic nanoporous silica nanoparticles-influence of macrophage depletion and infection. Nanomedicine: Nanotechnology, Biology and Medicine, p. 102289, 2020.
Cloxacillin nanostructured formulation for the treatment of bovine keratoconjunctivitis
Infectious bovine keratoconjunctivitis (IBK) is a widespread, contagious ocular disease that affects cattle, especially dairy breeds. The disease is caused by Gram-negative bacteria mainly Moraxella bovis, and its treatment consists of parenteral or topic antibiotic therapy. The topic treatment approach is used more commonly in lactating cows, to avoid milk disposal. However, treatment failures are common, because the antibiotic is removed during lacrimation. This study aimed to evaluate the susceptibility of commercial cloxacillin and evaluate the efficacy of nanostructured cloxacillin in clinical cases of IBK by Moraxella. The minimum inhibitory concentration (MIC) of nanoparticle cloxacillin nanocoated, the nanoparticle without the antibiotic and the commercial cloxacillin were determined in vitro with field samples of Moraxella ovis (5) and Moraxella bovis (5). The efficiency of nanoparticles was tested in three cows naturally infected that were treated with 1.0 mL (with 0.32 mg of nanostructured cloxacillin) for the ocular route. Moraxella bovis was isolated and identified by biochemical and molecular methods before the treatment. The animals were treated every 12 h for six days. The cure was considered by the absence of clinical symptoms and bacteria after treatment. The mucoadhesive nanoparticle-based formulation promoted clinical cure with a low number of doses of antibiotics, probably due to the maintenance of the MIC in the ocular mucosa for longer due to the mucoadhesive characteristics of the nanoparticle. The results indicate that the use of nanocoated cloxacillin is possible to control infectious bovine keratoconjunctivitis.
FONSECA, Miriam das Dores Mendes et al. Cloxacillin nanostructured formulation for the treatment of bovine keratoconjunctivitis. Veterinary and Animal Science, v. 9, p. 100089, 2020.
Using chitosan microparticles to treat metritis in lactating dairy cows
The main objective of this study was to evaluate the efficacy of intrauterine administration of chitosan microparticles (CM) in curing metritis in dairy cows. A secondary objective was to evaluate the effects of metritis treatments on milk yield, survival, and reproductive performance. Cows with a fetid, watery, red-brownish vaginal discharge were diagnosed with metritis. Holstein cows (n = 826) with metritis from 3 dairies located in northern Florida were blocked by parity (primiparous or multiparous) and, within each block, randomly assigned to one of 3 treatments: CM (n = 276) = intrauterine infusion of 24 g of CM dissolved in 40 mL of sterile distilled water at the time of metritis diagnosis (d 0), 2 (d 2), and 4 (d 4) d later; ceftiofur (CEF; n = 275) = subcutaneous injection of 6.6 mg/kg ceftiofur crystalline-free acid in the base of the ear at d 0 and d 3; Control (CON; n = 275) = no treatment applied at metritis diagnosis. All groups could receive escape therapy if condition worsened. Cure was considered when vaginal discharge became mucoid and not fetid. A group of nonmetritic (NMET; n = 2,436) cows was used for comparison. Data were analyzed by generalized linear mixed and Cox's proportional hazard models. Cows in CM and CON had lesser risk of metritis cure on d 12 than cows in CEF (58.6 ± 5.0 vs. 61.9 ± 4.9% vs. 77.9 ± 3.9, respectively). The proportion of cows culled within 60 days in milk (DIM) was greater for cows in CM than for cows in CEF and CON (21.5 ± 2.7 vs. 9.7 ± 1.9 vs. 11.3 ± 2.0%, respectively). Treatment did not affect rectal temperature or plasma nonesterified fatty acids, β-hydroxybutyrate, and haptoglobin concentrations. Milk yield in the first 60 DIM differed for all treatments, and it was lowest for CM (35.8 ± 0.3 kg/d), followed by CON (36.8 ± 0.3 kg/d) and CEF (37.9 ± 0.3 kg/d). The hazard of pregnancy up to 300 DIM was lesser for CM than CEF (hazard ratio = 0.62; 95% CI: 0.50–0.76), for CM than CON (hazard ratio = 0.77; 95% CI: 0.62–0.95) and for CON than CEF (hazard ratio = 0.80; 95% CI: 0.65–0.99). Culling was greater, and milk yield and fertility were lesser for CEF than NMET. In summary, CM did not improve the cure of metritis, and was detrimental to milk yield, survival, and fertility compared with CON. In contrast, CEF increased the cure of metritis, milk yield, and fertility compared with CM and CON. Finally, the negative effects of metritis on milk yield culling and fertility could not be completely reversed by CEF.
DE OLIVEIRA, E. B. et al. Using chitosan microparticles to treat metritis in lactating dairy cows. Journal of Dairy Science, 2020.
Topical siRNA delivery to anterior eye using novel hybrid silicon-lipid nanoparticle delivery system
The major unmet need and crucial challenge hampering the exciting potential of RNAi therapeutics in ophthalmology is to find an effective, safe and non-invasive means of delivering siRNA to the cornea. Although all tissues of the eye are accessible by injection, topical application is preferable for the frequent treatment regimen that would be necessary for siRNA-induced gene silencing. However, the ocular surface is one of the more complex biological barriers for drug delivery due to the combined effect of short contact time, tear dilution and poor corneal cell penetration. Using nanotechnology to overcome the challenges, we developed a unique silicon-based delivery platform for ocular delivery of siRNA. This biocompatible hybrid of porous silicon nanoparticles and lipids has demonstrated an ability to bind nucleic acid and deliver functional siRNA to corneal cells both in vitro and in vivo. Potent transfection of human corneal epithelial cells with siRNA-ProSilic® formulation was followed by a successful downregulation of reporter protein expression. Moreover, siRNA complexed with this silicon-based hybrid and applied in vivo topically to mice eyes penetrated across all cornea layers and resulted in a significant reduction of the targeted protein expression in corneal epithelium. In terms of siRNA loading capacity, system versatility, and potency of action, ProSilic provides unique attributes as a biodegradable delivery platform for therapeutic oligonucleotides.
BARAN-RACHWALSKA, Paulina et al. Topical siRNA delivery to anterior eye using novel hybrid silicon-lipid nanoparticle delivery system. Journal of Controlled Release, 2020.
Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines
Cancer vaccines targeting patient-specific neoantigens have emerged as a promising strategy for improving responses to immune checkpoint blockade. However, neoantigenic peptides are poorly immunogenic and inept at stimulating CD8+ T cell responses, motivating a need for new vaccine technologies that enhance their immunogenicity. The stimulator of interferon genes (STING) pathway is an endogenous mechanism by which the innate immune system generates an immunological context for priming and mobilizing neoantigen-specific T cells. Owing to this critical role in tumor immune surveillance, a synthetic cancer nanovaccine platform (nanoSTING-vax) was developed that mimics immunogenic cancer cells in its capacity to efficiently promote co-delivery of peptide antigens and the STING agonist, cGAMP. The co-loading of cGAMP and peptides into pH-responsive, endosomolytic polymersomes promoted the coordinated delivery of both cGAMP and peptide antigens to the cytosol, thereby eliciting inflammatory cytokine production, co-stimulatory marker expression, and antigen cross-presentation. Consequently, nanoSTING-vax significantly enhanced CD8+ T cell responses to a range of peptide antigens. Therapeutic immunization with nanoSTING-vax, in combination with immune checkpoint blockade, inhibited tumor growth in multiple murine tumor models, even leading to complete tumor rejection and generation of durable antitumor immune memory. Collectively, this work establishes nanoSTING-vax as a versatile platform for enhancing immune responses to neoantigen-targeted cancer vaccines.
SHAE, Daniel et al. Co-Delivery of Peptide Neoantigens and Stimulator of Interferon Genes (STING) Agonists Enhances Response to Cancer Vaccines. ACS nano, 2020.
Ionic liquid-mediated delivery of insulin to buccal mucosa
Buccal drug delivery offers a potential non-invasive means of delivering therapeutics to patients. Despite the promise, the feasibility of transporting proteins and peptides into systemic circulation from buccal administration remains a daunting challenge. Here, we report the fabrication of a biodegradable polymeric patch for buccal delivery of insulin using chitosan as the mucoadhesive matrix and ionic liquids (ILs)/deep eutectic solvent (DES) as the transport facilitator. Insulin is mixed with ILs/DES made from Choline and Geranic acid (CAGE) to form a viscoelastic CAGE gel and sandwiched between two layers of a biodegradable polymer. The rheological properties of the CAGE gel were dominated by the elastic modulus and suggested a solid-like viscoelastic behavior. CAGE induced a 7-fold increase in the cumulative insulin transport across the ex vivo porcine buccal tissue (~26% of loaded insulin) which was also confirmed by confocal microscopy. The CAGE/insulin patches placed in the rat buccal pouch in vivo lowered blood glucose levels in a dose-dependent manner (up to 50% drop recorded) with no obvious tissue damage at the application site. The pharmacokinetic performance of the delivered insulin indicated a sustained profile as serum insulin levels plateaued after 3 h for the duration of study. The safety and efficacy of the polymeric patch using insulin as a model drug holds significant promise as a platform technology to deliver injectables through the buccal route.
VAIDYA, A. and MITRAGOTRI, S. Ionic liquid-mediated delivery of insulin to buccal mucosa. Journal of Controlled Release, 2020.
Delivery of a model lipophilic membrane cargo to bone marrow via cell-derived microparticles
Bone marrow (BM) is the central immunological organ and the origin of hematological diseases. Efficient and specific drug delivery to the BM is an unmet need. We tested delivery of fluorescent indocarbocyanine lipids (ICLs, DiR, DiD, DiI) as a model lipophilic cargo. Systemically injected T-lymphocyte cell line Jurkat delivered ICLs to the BM more efficiently than erythrocytes, and more selectively than PEGylated liposomes. Near infrared imaging showed that the delivery was restricted to the BM, lungs, liver and spleen, with no accumulation in the kidneys, brain, heart, intestines, fat tissue and pancreas. Following systemic injection of ICL-labeled cells in immunodeficient or immunocompetent mice, few cells arrived in the BM intact. However, between 5 and 10% of BM cells were ICL-positive. Confocal microscopy of intact BM confirmed that ICLs are delivered independently of the injected cells. Flow cytometry analysis showed that the lipid accumulated in both CD11b + and CD11b- cells, and in hematopoietic progenitors. In a xenograft model of acute myeloid leukemia, a single injection of 10 million Jurkat cells delivered DiD to ~15% of the tumor cells. ICL-labeled cells disappeared from blood almost immediately post-intravenous injection, but numerous cell-derived microparticles continued to circulate in blood. The microparticle particle formation was not due to the ICL labeling or complement attack and was observed after injection of both syngeneic and xenogeneic cells. Injection of microparticles produced in vitro from Jurkat cells resulted in a similar ICL delivery as the injection of intact Jurkat cells. Our results demonstrate a novel delivery paradigm wherein systemically injected cells release microparticles that accumulate in the BM. In addition, the results have important implications for studies involving systemically administered cell therapies.
YANG, Chunyan et al. Delivery of a model lipophilic membrane cargo to bone marrow via cell-derived microparticles. Journal of Controlled Release, 2020.