46 research outputs found
Hyaluronidase Coated Molecular Envelope Technology Nanoparticles Enhance Drug Absorption via the Subcutaneous Route
Parenteral chemotherapy is usually administered intravenously, although patient preference and health economics suggest the subcutaneous (sc) route could be an attractive alternative. However, due to the low aqueous solubility of hydrophobic drugs and injection volume limitations, the total amount of drug that can be administered in a single sc injection is frequently insufficient. We have developed hyaluronidase coated nanoparticles (NPs) that efficiently encapsulate such drugs, thus addressing both issues and allowing sufficient amounts of hydrophobic drug to be administered and absorbed effectively. CUDC-101, a poorly water-soluble multitargeted anticancer drug that simultaneously inhibits the receptor tyrosine kinases (RTKs) EGFR and HER2, as well as histone deacetylase (HDAC), was encapsulated in polymeric Molecular Envelope Technology (MET) NPs. The role of polymer chemistry, formulation parameters, and coating with hyaluronidase (HYD) on MET-CUDC-101 NP formulations was examined and optimized to yield high drug loading and colloidal stability, and, after freeze-drying, stable storage at room temperature for up to 90 days. The pharmacokinetic studies in healthy rats showed that plasma AUC0-24h after sc administration correlates tightly with formulation physical chemistry, specifically in vitro colloidal stability. Compared to uncoated NPs, the HYD-coating doubled the drug plasma exposure. In a murine A431 xenograft model, the coated HYD-MET-CUDC-101 NPs at a dose equivalent to 90 mg kg-1 CUDC-101 increased the survival time from 15 days (control animals treated with hyaluronidase alone) to 43 days. Polymer MET nanoparticles coated with hyaluronidase enabled the subcutaneous delivery of a hydrophobic drug with favorable therapeutic outcomes
The Topical Ocular Delivery of Rapamycin to Posterior Eye Tissues and the Suppression of Retinal Inflammatory Disease
Treatment of posterior eye diseases with intravitreal injections of drugs, while effective, is invasive and associated with side effects such as retinal detachment and endophthalmitis. In this work, we have formulated a model compound, rapamycin (RAP), in nanoparticle-based eye drops and evaluated the delivery of RAP to the posterior eye tissues in a healthy rabbit. We have also studied the formulation in experimental autoimmune uveitis (EAU) mouse model with retinal inflammation. Aqueous RAP eye drops were prepared using N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (Molecular Envelope Technology - MET) containing 0.23 ± 0.001% w/v RAP with viscosity, osmolarity, and pH within the ocular comfort range, and the formulation (MET-RAP) was stable in terms of drug content at both refrigeration and room temperature for one month. The MET-RAP eye drops delivered RAP to the choroid-retina with a Cmax of 145 ± 49 ng/g (tmax = 1 hour). The topical application of the MET-RAP eye drops to the EAU mouse model resulted in significant disease suppression compared to controls, with activity similar to dexamethasone eye drops. The MET-RAP eye drops also resulted in a reduction of RORγt and an increase in both Foxp3 expression and IL-10 secretion, indicating a mechanism involving the inhibition of Th17 cells and the up-regulation of T-reg cells. The MET-RAP formulation delivers RAP to the posterior eye segments, and the formulation is active in EAU
Design, development and deployment of a hand/wrist exoskeleton for home-based rehabilitation after stroke - SCRIPT project
YesChanges in world-wide population trends have provided new demands for new technologies in areas
such as care and rehabilitation. Recent developments in the the field of robotics for neurorehabilitation
have shown a range of evidence regarding usefulness of these technologies as a tool to augment
traditional physiotherapy. Part of the appeal for these technologies is the possibility to place a
rehabilitative tool in one’s home, providing a chance for more frequent and accessible technologies
for empowering individuals to be in charge of their therapy.
Objective: this manuscript introduces the Supervised Care and Rehabilitation Involving Personal
Tele-robotics (SCRIPT) project. The main goal is to demonstrate design and development steps
involved in a complex intervention, while examining feasibility of using an instrumented orthotic
device for home-based rehabilitation after stroke.
Methods: the project uses a user-centred design methodology to develop a hand/wrist
rehabilitation device for home-based therapy after stroke. The patient benefits from a dedicated
user interface that allows them to receive feedback on exercise as well as communicating with
the health-care professional. The health-care professional is able to use a dedicated interface
to send/receive communications and remote-manage patient’s exercise routine using provided
performance benchmarks. Patients were involved in a feasibility study (n=23) and were instructed to
use the device and its interactive games for 180 min per week, around 30 min per day, for a period of
6 weeks, with a 2-months follow up. At the time of this study, only 12 of these patients have finished
their 6 weeks trial plus 2 months follow up evaluation.
Results: with the “use feasibility” as objective, our results indicate 2 patients dropping out due
to technical difficulty or lack of personal interests to continue. Our frequency of use results indicate
that on average, patients used the SCRIPT1 device around 14 min of self-administered therapy a day.
The group average for the system usability scale was around 69% supporting system usability.
Conclusions: based on the preliminary results, it is evident that stroke patients were able to use the
system in their homes. An average of 14 min a day engagement mediated via three interactive games
is promising, given the chronic stage of stroke. During the 2nd year of the project, 6 additional games
with more functional relevance in their interaction have been designed to allow for a more variant context for interaction with the system, thus hoping to positively influence the exercise duration.
The system usability was tested and provided supporting evidence for this parameter. Additional
improvements to the system are planned based on formative feedback throughout the project and
during the evaluations. These include a new orthosis that allows a more active control of the amount
of assistance and resistance provided, thus aiming to provide a more challenging interaction.This work has been partially funded under Grant FP7-ICT-288698(SCRIPT) of the European Community Seventh Framework Programme
Platinum(IV)-Loaded Degraded Glycol Chitosan as Efficient Platinum(IV) Drug Delivery Platform
A new class of anticancer prodrugs was designed by combining the cytotoxicity of platinum(IV) complexes and the drug carrier properties of glycol chitosan polymers: Unsymmetrically carboxylated platinum(IV) analogues of cisplatin, carboplatin and oxaliplatin, namely (OC-6-44)-acetatodiammine(3-carboxypropanoato)dichloridoplatinum(IV), (OC-6-44)-acetaodiammine(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) and (OC-6-44)-acetato(3-carboxypropanoato)(1R,2R-cyclohexane-1,2-diamine)oxalatoplatinum(IV) were synthesised and conjugated via amide bonding to degraded glycol chitosan (dGC) polymers with different chain lengths (5, 10, 18 kDa). The 15 conjugates were investigated with 1H and 195Pt NMR spectroscopy, and average amounts of platinum(IV) units per dGC polymer molecule with ICP-MS, revealing a range of 1.3–22.8 platinum(IV) units per dGC molecule. Cytotoxicity was tested with MTT assays in the cancer cell lines A549, CH1/PA-1, SW480 (human) and 4T1 (murine). IC50 values in the low micromolar to nanomolar range were obtained, and higher antiproliferative activity (up to 72 times) was detected with dGC-platinum(IV) conjugates in comparison to platinum(IV) counterparts. The highest cytotoxicity (IC50 of 0.036 ± 0.005 µM) was determined in CH1/PA-1 ovarian teratocarcinoma cells with a cisplatin(IV)–dGC conjugate, which is hence 33 times more potent than the corresponding platinum(IV) complex and twice more potent than cisplatin. Biodistribution studies of an oxaliplatin(IV)–dGC conjugate in non-tumour-bearing Balb/C mice showed an increased accumulation in the lung compared to the unloaded oxaliplatin(IV) analogue, arguing for further activity studies
Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) Loaded with Platinum-Based Anticancer Agents—A Novel Polymer Formulation for Anticancer Therapy
Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by 1H and 195Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue
Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration
The clinical development of neuropeptides has been limited by a combination of the short plasma half-life of these drugs and their ultimate failure to permeate the blood brain barrier. Peptide nanofibres have been used to deliver peptides across the blood brain barrier and in this work we demonstrate that the polymer coating of peptide nanofibres further enhances peptide delivery to the brain via the intravenous route. Leucine5-enkephalin (LENK) nanofibres formed from the LENK ester prodrug - tyrosinyl1palmitate-leucine5-enkephalin (TPLENK) were coated with the polymer - N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) and injected intravenously. Peptide brain delivery was enhanced because the GCPQ coating on the peptide prodrug nanofibres, specifically enables the peptide prodrug to escape liver uptake, avoid enzymatic degradation to non-active sequences and thus enjoy a longer plasma half life. Plasma half-life is increased 520%, liver AUC0-4 decreased by 54% and brain AUC0-4 increased by 47% as a result of the GCPQ coating. The increased brain levels of the GCPQ coated peptide prodrug nanofibres result in the pharmacological activity of the parent drug (LENK) being significantly increased. LENK itself is inactive on intravenous injection
Oral particle uptake and organ targeting drives the activity of amphotericin B nanoparticles
There are very few drug delivery
systems that target key organs
via the oral route, as oral delivery advances normally address gastrointestinal
drug dissolution, permeation, and stability. Here we introduce a nanomedicine
in which nanoparticles, while also protecting the drug from gastric
degradation, are taken up by the gastrointestinal epithelia and transported
to the lung, liver, and spleen, thus selectively enhancing drug bioavailability
in these target organs and diminishing kidney exposure (relevant to
nephrotoxic drugs). Our work demonstrates, for the first time, that
oral particle uptake and translocation to specific organs may be used
to achieve a beneficial therapeutic response. We have illustrated
this using amphotericin B, a nephrotoxic drug encapsulated within <i>N</i>-palmitoyl-<i>N</i>-methyl-<i>N</i>,<i>N</i>-dimethyl-<i>N</i>,<i>N</i>,<i>N</i>-trimethyl-6-<i>O</i>-glycol chitosan
(GCPQ) nanoparticles, and have evidenced our approach in three separate
disease states (visceral leishmaniasis, candidiasis, and aspergillosis)
using industry standard models of the disease in small animals. The
oral bioavailability of AmB-GCPQ nanoparticles is 24%. In all disease
models, AmB-GCPQ nanoparticles show comparable efficacy to parenteral
liposomal AmB (AmBisome). Our work thus paves the way for others to
use nanoparticles to achieve a specific targeted delivery of drug
to key organs via the oral route. This is especially important for
drugs with a narrow therapeutic index
Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes
Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. 4APPA complexes anti- itchy E3 ubiquitin protein ligase (anti-ITCH) siRNA to form positively charged (zeta potential +15 ± 5 mV) 150 nm nanoparticles. The siRNA-4APPA polyplexes demonstrated low cellular toxicity (IC50 = 13.92 ± 6 mg mL−1) in the A431 cell line and were three orders of magnitude less toxic than Lipofectamine 2000 (IC50 = 0.033 ± 0.04 mg mL−1) in this cell line. Cell association and uptake of fluorescently labelled siRNA bound to siRNA-4APPA nanoparticles was demonstrated using fluorescent activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), respectively. Gene silencing of the ITCH gene was observed in vitro in the A431 cell line (65% down regulation when compared to the use of anti-ITCH siRNA alone). On intranasal dosing with fluorescently labelled siRNA-4APPA polyplexes, fluorescence was seen in the cells of the olfactory bulb, cerebral cortex and mid-brain regions. Finally, down regulation of ITCH was seen in the brain cells (54 ± 13% ITCH remaining compared to untreated controls) in a healthy rat model, following intranasal dosing of siRNA-4APPA nanoparticles (0.15 mg kg−1 siRNA twice daily for 3 days). Gene silencing in the brain may be achieved by intranasal administration of siRNA- poly(ethylene glycol) based polyplexes