The bacterial cell envelope as delimiter of anti-infective bioavailability - An in vitro permeation model of the Gram-negative bacterial inner membrane.
J Control Release. 2016 Oct 18;243:214-224
Authors: Graef F, Vukosavljevic B, Michel JP, Wirth M, Ries O, De Rossi C, Windbergs M, Rosilio V, Ducho C, Gordon S, Lehr CM
Gram-negative bacteria possess a unique and complex cell envelope, composed of an inner and outer membrane separated by an intermediate cell wall-containing periplasm. This tripartite structure acts intrinsically as a significant biological barrier, often limiting the permeation of anti-infectives, and so preventing such drugs from reaching their target. Furthermore, identification of the specific permeation-limiting envelope component proves difficult in the case of many anti-infectives, due to the challenges associated with isolation of individual cell envelope structures in bacterial culture. The development of an in vitro permeation model of the Gram-negative inner membrane, prepared by repeated coating of physiologically-relevant phospholipids on Transwell(®) filter inserts, is therefore reported, as a first step in the development of an overall cell envelope model. Characterization and permeability investigations of model compounds as well as anti-infectives confirmed the suitability of the model for quantitative and kinetically-resolved permeability assessment, and additionally confirmed the importance of employing bacteria-specific base materials for more accurate mimicking of the inner membrane lipid composition - both advantages compared to the majority of existing in vitro approaches. Additional incorporation of further elements of the Gram-negative bacterial cell envelope could ultimately facilitate model application as a screening tool in anti-infective drug discovery or formulation development.
PMID: 27769806 [PubMed - as supplied by publisher]
Simultaneous regulation of apoptotic gene silencing and angiogenic gene expression for myocardial infarction therapy: Single-carrier delivery of SHP-1 siRNA and VEGF-expressing pDNA.
J Control Release. 2016 Oct 18;243:182-194
Authors: Kim D, Ku SH, Kim H, Jeong JH, Lee M, Kwon IC, Choi D, Kim SH
Gene therapy is aimed at selectively knocking up or knocking down the target genes involved in the development of diseases. In many human diseases, dysregulation of disease-associated genes is occurred concurrently: some genes are abnormally turned up and some are turned down. In the field of non-viral gene therapy, plasmid DNA (pDNA) and small interfering RNA (siRNA) are suggested as representative regulation tools for activating and silencing the expression of genes of interest, representatively. Herein, we simultaneously loaded both siRNA (Src homology region 2 domain-containing tyrosine phosphatase-1 siRNA, siSHP-1) for anti-apoptosis and pDNA (hypoxia-inducible vascular endothelial growth factor expression vector, pHI-VEGF) for angiogenesis in a single polymeric nanocarrier and used to synergistically attenuate ischemia-reperfusion (IR)-induced myocardial infarction, which is mainly caused by dysregulating of cardiac apoptosis and angiogenesis. For dual-modality cardiac gene delivery, siSHP-1 and pHI-VEGF were sequentially incorporated into a stable nanocomplex by using deoxycholic acid-modified polyethylenimine (DA-PEI). The resulting DA-PEI/siSHP-1/pHI-VEGF complexes exhibited the high structural stability against polyanion competition and the improved resistance to digestion by nucleases. The cardiac administration of DA-PEI/siSHP-1/pHI-VEGF reduced cardiomyocyte apoptosis and enhanced cardiac microvessel formation, thereby reducing infarct size in rat ischemia-reperfusion model. The simultaneous anti-apoptotic and angiogenic gene therapies synergized the cardioprotective effects of each strategy; thus our dual-modal single-carrier gene delivery system can be considered as a promising candidate for treating ischemic heart diseases.
PMID: 27765623 [PubMed - as supplied by publisher]
Self-assembled mirror DNA nanostructures for tumor-specific delivery of anticancer drugs.
J Control Release. 2016 Oct 14;243:121-131
Authors: Kim KR, Kim HY, Lee YD, Ha JS, Kang JH, Jeong H, Bang D, Ko YT, Kim S, Lee H, Ahn DR
Nanoparticle delivery systems have been extensively investigated for targeted delivery of anticancer drugs over the past decades. However, it is still a great challenge to overcome the drawbacks of conventional nanoparticle systems such as liposomes and micelles. Various novel nanomaterials consist of natural polymers are proposed to enhance the therapeutic efficacy of anticancer drugs. Among them, deoxyribonucleic acid (DNA) has received much attention as an emerging material for preparation of self-assembled nanostructures with precise control of size and shape for tailored uses. In this study, self-assembled mirror DNA tetrahedron nanostructures is developed for tumor-specific delivery of anticancer drugs. l-DNA, a mirror form of natural d-DNA, is utilized for resolving a poor serum stability of natural d-DNA. The mirror DNA nanostructures show identical thermodynamic properties to that of natural d-DNA, while possessing far enhanced serum stability. This unique characteristic results in a significant effect on the pharmacokinetics and biodistribution of DNA nanostructures. It is demonstrated that the mirror DNA nanostructures can deliver anticancer drugs selectively to tumors with enhanced cellular and tissue penetration. Furthermore, the mirror DNA nanostructures show greater anticancer effects as compared to that of conventional PEGylated liposomes. Our new approach provides an alternative strategy for tumor-specific delivery of anticancer drugs and highlights the promising potential of the mirror DNA nanostructures as a novel drug delivery platform.
PMID: 27746274 [PubMed - as supplied by publisher]
Characterization of needle-assisted jet injections.
J Control Release. 2016 Oct 13;243:195-203
Authors: Li X, Ruddy B, Taberner A
Hypodermic injections have been the standard for transcutaneous drug delivery for many years. However, needle phobia, pain, and risks of needle-stick injuries have manifested in poor patient compliance. Needle-free jet injections (NFJI) have been developed to address these drawbacks but the reliability of dose and depth of delivery have been limited by a lack of control over jet parameters, and by variability in the skin's mechanical properties among individuals. Moreover, the device size and cost have been restrained by the high pressure (>20MPa) required to penetrate the skin. Needle-assisted jet injections have been proposed to improve delivery reliability of conventional jet injectors by penetrating the skin with a short needle (<5mm) and thereby allowing jet delivery to a desired injection depth at a reduced pressure. This study characterized needle-assisted jet injections performed after first penetrating the skin with a 1.5mm needle, examining the effect of needle size on jet parameters, and evaluating injection performance in porcine skin. A voice-coil actuated jet injector was modified to incorporate needles of 30G, 31G and 32G. A series of pulse tests was performed to compare jet velocity and injection volume across the needle sizes, where it was found that the jet velocity and injection volume achieved with 32G needles were 13% and 16% lower, respectively, than with 30G. In contrast, there was no significant difference in jet velocity and injection volume between 30G and 31G needles, suggesting that a reduction of 10μm in the mean inner diameter of the 31G needle has minimal impact on jet velocity and injection volume. Injection studies performed in porcine skin revealed that injections driven by fluid pressures ranging between 0.8MPa and 1.4MPa were able to achieve substantial injectate penetration (~10mm) and delivery (~100μL) into subcutaneous fat regardless of needle size, in a period of 40ms. The required pressures are an order of magnitude lower than those used in NFJI, yet still maintain the high-speed nature of jet injection by achieving a delivery rate of 2.25mL/s. The lower pressures required in needle-assisted drug delivery can lead to reduced device size and cost, as well as reduced shear stresses during jet injection and can therefore minimise the potentially adverse effect of shear on the structural integrity of proteins, vaccines and DNA.
PMID: 27746273 [PubMed - as supplied by publisher]
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A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer.
J Control Release. 2016 Oct 12;243:172-181
Authors: Dimcevski G, Kotopoulis S, Bjånes T, Hoem D, Schjøtt J, Gjertsen BT, Biermann M, Molven A, Sorbye H, McCormack E, Postema M, Gilja OH
BACKGROUND: The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival.
METHODS: Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5min. SonoVue® was injected intravenously (0.5ml followed by 5ml saline every 3.5min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy.
RESULTS: The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n=10) tolerated an increased number of gemcitabine cycles compared with historical controls (n=63 patients; average of 8.3±6.0cycles, versus 13.8±5.6cycles, p=0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n=10) was also increased from 8.9months to 17.6months (p=0.011).
CONCLUSIONS: It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.
PMID: 27744037 [PubMed - as supplied by publisher]
Macroporous acrylamide phantoms improve prediction of in vivo performance of in situ forming implants.
J Control Release. 2016 Oct 11;243:225-231
Authors: Hernandez C, Gawlik N, Goss M, Zhou H, Jeganathan S, Gilbert D, Exner AA
In situ forming implants (ISFIs) have shown promise as a sustained, local drug delivery system for therapeutics in a variety of applications. However, development of ISFIs has been hindered by poor correlation between in vitro study results and in vivo performance. In contrast to oral dosage forms, there is currently no clear consensus on a standard for in vitro drug dissolution studies for parenteral formulations. Recent studies have suggested that the disparity between in vivo and in vitro behavior of phase-inverting ISFIs may be, in part, due to differences in injection site stiffness. Accordingly, this study aimed to create acrylamide-based hydrogel phantoms of varying porosity and stiffness, which we hypothesized would better predict in vivo performance. Implant microstructure and shape were found to be dependent on the stiffness of the phantoms, while drug release was found to be dependent on both phantom porosity and stiffness. Specifically, SEM analysis revealed that implant porosity and interconnectivity decreased with increasing phantom stiffness and better mimicked the microstructure seen in vivo. Burst release of drug increased from 31% to 43% when in standard acrylamide phantoms vs macroporous phantoms (10kPa), improving the correlation to the burst release seen in vivo. Implants in 30kPa macroporous phantoms had the best correlation with in vivo burst release, significantly improving (p<0.05) the burst release relative to in vivo from 64%, using a standard PBS dissolution method, to 92%. These findings confirm that implant behavior is affected by injection site stiffness. Importantly, with appropriate optimization and validation, hydrogel phantoms such as the one investigated here could be used to improve the in vitro-in vivo correlation of in situ forming implant formulations and potentially augment their advancement to clinical use.
PMID: 27742445 [PubMed - as supplied by publisher]
Functional exosome-mimic for delivery of siRNA to cancer: in vitro and in vivo evaluation.
J Control Release. 2016 Oct 11;243:160-171
Authors: Yang Z, Xie J, Zhu J, Kang C, Chiang C, Wang X, Wang X, Kuang T, Chen F, Chen Z, Zhang A, Yu B, Lee RJ, Teng L, Lee LJ
Exosomes, the smallest subgroup of extracellular vesicles, have been recognized as extracellular organelles that contain genetic and proteomic information for long distance intercellular communication. Exosome-based drug delivery is currently a subject of intensive research. Here, we report a novel strategy to produce nanoscale exosome-mimics (EMs) in sufficient quantity for gene delivery in cancer both in vitro and in vivo. Size-controllable EMs were generated at a high yield by serial extrusion of non-tumorigenic epithelial MCF-10A cells through filters with different pore sizes. siRNA was then encapsulated into the EMs by electroporation. Biosafety and uptake efficiency of the EMs were evaluated both in vitro and in vivo. The mechanism underlying their cellular endocytosis was also studied.
PMID: 27742443 [PubMed - as supplied by publisher]
Tacrolimus and curcumin co-loaded liposphere gel: Synergistic combination towards management of psoriasis.
J Control Release. 2016 Oct 8;243:132-145
Authors: Jain A, Doppalapudi S, Domb AJ, Khan W
Psoriasis is an autoimmune skin disorder characterized by hyper proliferation and poor differentiation of keratinocytes. It significantly affects patient's quality of life. This study reports the anti-psoriatic efficacy of tacrolimus and curcumin loaded liposphere gel formulation. Poor solubility, poor skin penetration and erratic absorption are some problems associated with the topical delivery of these drugs. To overcome these problems, lipospheres containing combination of tacrolimus and curcumin was prepared with a particle size of nearly 50nm and incorporated into a gel for topical application. Liposphere gel showed slow release of both the drugs and shear thinning behaviour that is desirable property of topical formulation. Further, dermal distribution study using dye loaded formulation suggested penetration of dye into skin layers. The therapeutic efficacy of tacrolimus and curcumin loaded liposphere gel was assessed on imiquimod induced psoriatic plaque model, and the level of expression of psoriatic biochemical markers was evaluated using enzyme-linked immunosorbent assay. Results indicated improvement in the phenotypic and histopathological features of psoriatic skin treated with tacrolimus and curcumin loaded liposphere gel. There was reduction in the level of TNF-α, IL-17 and IL-22 compared to imiquimod group. These results corroborate the premise that liposphere gel containing combination of tacrolimus and curcumin can be an effective strategy for the treatment of psoriasis.
PMID: 27725194 [PubMed - as supplied by publisher]
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Non-invasive epicutaneous vaccine against Respiratory Syncytial Virus: Preclinical proof of concept.
J Control Release. 2016 Oct 6;243:146-159
Authors: Hervé PL, Descamps D, Deloizy C, Dhelft V, Laubreton D, Bouguyon E, Boukadiri A, Dubuquoy C, Larcher T, Benhamou PH, Eléouët JF, Bertho N, Mondoulet L, Riffault S
To put a Respiratory Syncytial Virus (RSV) vaccine onto the market, new vaccination strategies combining scientific and technical innovations need to be explored. Such a vaccine would also need to be adapted to the vaccination of young children that are the principal victims of acute RSV infection. In the present project, we describe the development and the preclinical evaluation of an original epicutaneous RSV vaccine that combines two technologies: Viaskin® epicutaneous patches as a delivery platform and RSV N-nanorings (N) as a subunit antigen. Such a needle-free vaccine may have a better acceptability for the vaccination of sensible population such as infants since it does not require any skin preparation. Moreover, this self-applicative vaccine would overcome some issues associated to injectable vaccines such as the requirement of sterile medical devices, the need of skilled health-care professionals and the necessity of stringent store conditions. Here, we demonstrate that Viaskin® patches loaded with a formulation containing N-nanorings (Viaskin®-N) are highly immunogenic in mice and promotes a Th1/Th17 oriented immune response. More importantly, Viaskin®-N epicutaneous vaccine confers a high level of protection against viral replication upon RSV challenge in mice, without exacerbating clinical symptoms. In swine, which provides the best experimental model for the transcutaneous passage of drug/antigen in human skin, we have shown that GFP fluorescent N-nanorings, delivered epicutaneously with Viaskin® patches, are taken up by epidermal Langerhans cells. We have also demonstrated that Viaskin®-N induced a significant RSV N-specific T-cell response in pig. In conclusion, Viaskin®-N epicutaneous vaccine seems efficient to protect against RSV infection in animal model.
PMID: 27720994 [PubMed - as supplied by publisher]
The interaction of protamine nanocapsules with the intestinal epithelium: A mechanistic approach.
J Control Release. 2016 Oct 6;243:109-120
Authors: Thwala LN, Beloqui A, Csaba NS, González-Touceda D, Tovar S, Dieguez C, Alonso MJ, Préat V
Single-layer protamine and double layer polysialic acid (PSA)/protamine nanocapsules (NCs) were designed in order to be used as carriers to facilitate the transport of macromolecules across the intestinal epithelium. The rational for the design of these NCs was based on that protamine is a non-toxic yet potent cell-penetrating peptide, capable of translocating protein cargos through cell membranes, while PSA is a low molecular weight polysaccharide used to enhance the stability of macromolecules and nanocarriers. The aim of this work was to study in vitro the mechanism of interaction of these NCs with different intestinal cell models (Caco-2, Caco-2/Raji mimicking follicle associated epithelium and Caco-2/HT29-MTX to study the effect of mucus). For this, a fluorescent marker, TAMRA was covalently linked to protamine. The interaction and transport of the NCs with the Caco-2 cells was found to be concentration, temperature and size dependent. In all cases, the double layer PSA-protamine NCs exhibited a significantly higher transport compared to protamine NCs. On the other hand, the transport of the NCs was significantly higher in the co-culture (Caco-2/Raji monolayer) compared to the monoculture model (Caco-2 monolayer), implying that M cells are involved in the transport of these nanosystems. The formulations, administered intra-jejunally to healthy rats (4h fasting) resulted in a moderate reduction of the glucose levels (20% reduction), which lasted for up to 4h. This work raises prospects that protamine-based nanocapsules may have the potential as oral peptide delivery nanocarriers.
PMID: 27720993 [PubMed - as supplied by publisher]
Effect of intraocular pressure (IOP) and choroidal circulation on controlled episcleral drug delivery to retina/vitreous.
J Control Release. 2016 Oct 4;243:78-85
Authors: Li J, Lan B, Li X, Sun S, Lu P, Cheng L
Transscleral drug delivery may become a safe alternative to the intravitreal injection for chronic retinal diseases such as age-related macular degeneration or diabetic macular edema. However, the drug delivered onto the sclera subjects to vigorous clearance by episcleral and choroidal circulation; in addition, the penetration from episclera to retina needs to overcome counter-directional ocular fluid current driven by intraocular pressure (IOP) as well as unfavorable drug disposition exerted by drug transporters before the drug reach retina. It is imperative to understand these processes and quantitate their influence for efficient designing of a sustained formulation or device to achieve efficient transscleral drug delivery. The current study was focused on the effects of intraocular pressure (IOP) and choroidal circulation on transscleral drug delivery using triamcinolone acetonide (TA) as a model drug. Rabbit eye IOP was modulated through cannulation in ex vivo study or through cryopexy of ciliary body in vivo studies before subtenon TA injection or episcleral TA-film implantation. In a subgroup of the rabbit eyes, localized choroid atrophy was induced by cryopexy before TA-film implantation. Each condition had a concurrent control group. The vitreous TA concentration was quantitated by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC/MS/MS). The vitreous TA concentration was compared between the study and control groups for effect of IOP or choroid circulation. For ex vivo studies, higher IOP was a significant effect against TA penetration from episclera towards vitreous. TA was 8.5±5ng/mL in receptor chamber with a cross pressure of 50mmHg versus 15.9±10ng/mL with the cross pressure of 5mmHg; p=0.001, t-test. A multivariate regression demonstrated each mmHg of IOP increase would result in 3ng/mL lower concentration in the receptor chamber. Similar IOP effect was also identified in a 3-hour study using euthanized rabbit eyes whose IOP was controlled at 10 or 40mmHg by cannulation (3261±1821ng/mL vs. 755±763ng/mL; p=0.013, Wilcoxon test). However, the effect of IOP was not significant in alive animal with the same IOP setting. In vivo chronic study using low IOP (7.7mmHg) versus normal IOP (14.4mmHg), vitreous TA was not statistically significant (154±200ng/mL vs. 80±130ng/mL, p=0.17, Wilcoxon test). However, removing of choroidal circulation by local cryopexy significantly enhanced the TA penetration from episclera to vitreous (mean 163±129.8ng/mL for choroidal cryopexy vs. 81.8±37.2ng/mL for ciliary cryopexy or 75.5±36ng/mL for control group, p=0.007, regression analysis). In conclusion, the effect of IOP on transscleral drug delivery was not a significant effect in alive rabbit eyes; however, choroidal circulation seems to be a significant effect to affect TA penetration from episclera towards retina and vitreous.
PMID: 27717742 [PubMed - as supplied by publisher]
Smart nanoparticles with a detachable outer shell for maximized synergistic antitumor efficacy of therapeutics with varying physicochemical properties.
J Control Release. 2016 Oct 1;243:54-68
Authors: Yin T, Liu J, Zhao Z, Dong L, Cai H, Yin L, Zhou J, Huo M
Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA de-protected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy.
PMID: 27702595 [PubMed - as supplied by publisher]
A stabilized peptide ligand for multifunctional glioma targeted drug delivery.
J Control Release. 2016 Sep 29;243:86-98
Authors: Ying M, Shen Q, Zhan C, Wei X, Gao J, Xie C, Yao B, Lu W
Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of (L)A7R to receptors. It is very interesting that cA7R adopting a different structure from (L)A7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or (L)A7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or (L)A7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to (L)A7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did (L)A7R conjugation, which in turn, cA7R-LS/DOX could substantially suppress subcutaneous tumor growth when compared with other DOX formulations (free DOX, LS/DOX and (L)A7R-LS/DOX). The designed cyclic A7R exhibited the capability of targeting glioma cells, neovasculature and VM simultaneously in vivo. Considering the ease of synthesis, high binding affinity to receptors and increased stability of cA7R peptide in the present study, the design of head-to-tail cyclized peptides by the formation of amide bond based on computer-aided peptide design presents an alternative method to identify proteolytically stable peptide ligands.
PMID: 27693752 [PubMed - as supplied by publisher]
A New Method for Evaluating Actual Drug Release Kinetics of Nanoparticles inside Dialysis Devices via Numerical Deconvolution.
J Control Release. 2016 Sep 29;243:11-20
Authors: Zhou Y, He C, Chen K, Ni J, Cai Y, Guo X, Wu XY
Nanoparticle formulations have found increasing applications in modern therapies. To achieve desired treatment efficacy and safety profiles, drug release kinetics of nanoparticles must be controlled tightly. However, actual drug release kinetics of nanoparticles cannot be readily measured due to technique difficulties, although various methods have been attempted. Among existing experimental approaches, dialysis method is the most widely applied one due to its simplicity and avoidance of separating released drug from the nanoparticles. Yet this method only measures the released drug in the medium outside a dialysis device (the receiver), instead of actual drug release from the nanoparticles inside the dialysis device (the donor). Thus we proposed a new method using numerical deconvolution to evaluate actual drug release kinetics of nanoparticles inside the donor based on experimental release profiles of nanoparticles and free drug solution in the receptor determined by existing dialysis tests. Two computer programs were developed based on two different numerical methods, namely least square criteria with prescribed Weibull function or orthogonal polynomials as input function. The former was used for all analyses in this work while the latter for verifying the reliability of the predictions. Experimental data of drug release from various nanoparticle formulations obtained from different dialysis settings and membrane pore sizes were used to substantiate this approach. The results demonstrated that this method is applicable to a broad range of nanoparticle and microparticle formulations requiring no additional experiments. It is independent of particle formulations, drug release mechanisms, and testing conditions. This new method may also be used, in combination with existing dialysis devices, to develop a standardized method for quality control, in vitro-in vivo correlation, and for development of nanoparticles and other types of dispersion formulations.
PMID: 27693750 [PubMed - as supplied by publisher]
Controlled bone formation using ultrasound-triggered release of BMP-2 from liposomes.
J Control Release. 2016 Sep 28;243:99-108
Authors: Crasto GJ, Kartner N, Reznik N, Spatafora MV, Chen H, Williams R, Burns PN, Clokie C, Manolson MF, Peel SA
Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used clinically to enhance implant-mediated bone regeneration. However, there are risks associated with the high rhBMP-2 dose that is required in the implant to mitigate diffusional loss over the therapeutic timespan. On-demand, localized control over delivery of rhBMP-2, days after implantation, would therefore be an attractive solution in the area of bone repair and reconstruction, yet this has posed a significant challenge, with little data to support in vivo efficacy to date. To address this, we have developed novel liposome-rhBMP-2 nanocomplexes that release rhBMP-2 in response to non-thermogenic, clinical diagnostic ultrasound exposure. In vitro validation shows that rhBMP-2 release is in proportion to applied ultrasound pressure and duration of exposure. Moreover, here we show in vivo validation of this ultrasound-triggered rhBMP-2 delivery system in a standard mouse bone regeneration model. Implanted into hindleg muscles, the liposome-rhBMP-2 nanocomplexes induced local bone formation only after ultrasound exposure. Such post-implantation control of delivery has potential to improve the safety, efficacy and cost of rhBMP-2 use in bone reconstruction. Furthermore, this first proof-of-concept demonstration of in vivo efficacy for ultrasound-triggered liposomal delivery of rhBMP-2 has broader implications for tunable delivery of a variety of drugs and biologics in medicine and tissue engineering.
PMID: 27693545 [PubMed - as supplied by publisher]
Anticancer drug-loaded hydrogels as drug delivery systems for the local treatment of glioblastoma.
J Control Release. 2016 Sep 28;243:29-42
Authors: Bastiancich C, Danhier P, Préat V, Danhier F
Among central nervous system tumors, Glioblastoma (GBM) is the most common, aggressive and neurological destructive primary brain tumor in adults. Standard care therapy for GBM consists in surgical resection of the accessible tumor (without causing neurological damage) followed by chemoradiation. However, several obstacles limit the assessment of tumor response and the delivery of cytotoxic agents at the tumor site, leading to a lack of effectiveness of conventional treatments against GBM and fatal outcome. Despite the efforts of the scientific community to increase the long-term benefits of GBM therapy, at the moment GBM remains incurable. Among the strategies that have been adopted in the last two decades to find new and efficacious therapies for the treatment of GBM, the local delivery of chemotherapeutic drugs in the tumor resection cavity emerged. In this review, our aim is to provide an overview on hydrogels loaded with anticancer drugs for the treatment of GBM recently used in preclinical and clinical studies, their advantages and major limitations for clinical translation. This review is divided in three parts: the first one describes the context of GBM and its current treatments, with a highlight on the role of local delivery in GBM treatment and the development of GBM resection murine models. Then, recent developments in the use of anticancer drug-loaded hydrogels for the treatment of GBM will be detailed. The final section will be focused on the limitations for in vivo studies, clinical translation and the clinical perspectives to the development of hydrogels.
PMID: 27693428 [PubMed - as supplied by publisher]
Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro.
J Control Release. 2016 Sep 26;243:69-77
Authors: Marshalek JP, Sheeran PS, Ingram P, Dayton PA, Witte RS, Matsunaga TO
Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6μm (IQR=800nm-1.5μm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.
PMID: 27686582 [PubMed - as supplied by publisher]
Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets.
J Control Release. 2016 Oct 5;243:1-10
Authors: Li T, Vandesquille M, Koukouli F, Dudeffant C, Youssef I, Lenormand P, Ganneau C, Maskos U, Czech C, Grueninger F, Duyckaerts C, Dhenain M, Bay S, Delatour B, Lafaye P
Detection of intracerebral targets with imaging probes is challenging due to the non-permissive nature of blood-brain barrier (BBB). The present work describes two novel single-domain antibodies (VHHs or nanobodies) that specifically recognize extracellular amyloid deposits and intracellular tau neurofibrillary tangles, the two core lesions of Alzheimer's disease (AD). Following intravenous administration in transgenic mouse models of AD, in vivo real-time two-photon microscopy showed gradual extravasation of the VHHs across the BBB, diffusion in the parenchyma and labeling of amyloid deposits and neurofibrillary tangles. Our results demonstrate that VHHs can be used as specific BBB-permeable probes for both extracellular and intracellular brain targets and suggest new avenues for therapeutic and diagnostic applications in neurology.
PMID: 27671875 [PubMed - as supplied by publisher]
Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs.
J Control Release. 2016 Sep 21;243:43-53
Authors: Cunha-Reis C, Machado A, Barreiros L, Araújo F, Nunes R, Seabra V, Ferreira D, Segundo MA, Sarmento B, das Neves J
Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base - NPs-in-film - and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice. NPs-in-film presented suitable technological, mechanical and cytotoxicity features for vaginal use. Retention of NPs in vivo was enhanced both in vaginal lavages and tissue when associated to film. PK data evidenced that vaginal drug levels rapidly decreased after administration but NPs-in-film were still able to enhance drug concentrations of EFV. Obtained values for area-under-the-curve for EFV were around one log10 higher than those for the free drugs in aqueous vehicle (phosphate buffered saline). Film alone also contributed to higher and more prolonged local drug levels as compared to the administration of TFV and EFV in aqueous vehicle. Systemic exposure to both drugs was low. NPs-in-film was found to be safe upon once daily vaginal administration to mice, with no significant genital histological changes or major alterations in cytokine/chemokine profiles being observed. Overall, the proposed NPs-in-film system seems to be an interesting delivery platform for developing combination vaginal anti-HIV microbicides.
PMID: 27664327 [PubMed - as supplied by publisher]