This document summarizes research on using ultrasound-triggered release of anticancer agents from alginate-chitosen hydrogels. Hydrogel beads were developed that could encapsulate multiple drugs, including doxorubicin and temozolomide. Application of ultrasound caused pulsatile, on-demand release of the drugs. In vitro tests showed the ultrasound-triggered release resulted in decreased cell viability compared to no ultrasound treatment. Further work will focus on controlling sequential release of multiple drugs and tuning the hydrogel degradation rate.
Genipin cross-linked electrospun chitosan-based nanofibrous mat as tissue eng...Nanomedicine Journal (NMJ)
Objective(s):
To improve water stability of electrospun chitosan/ Polyethylene oxide (PEO) nanofibers, genipin, a biocompatible and nontoxic agent, was used to crosslink chitosan based nanofibers.
Materials and Methods:
Different amounts of genipin were added to the chitosan/PEO solutions, chitosan/PEO weight ratio 90/10 in 80 % acetic acid, and the solutions were then electrospun to form nanofibers. The spun nanofibers were exposed to water vapor to complete crosslinking. The nanofibrous membranes were subjected to detailed analysis by scanning electron microscopy (SEM), Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectroscopy, swelling test, MTT cytotoxicity, and cell attachment.
Results:
SEM images of electrospun mats showed that genipin-crosslinked nanofibers retained their fibrous structure after immerging in PBS (pH=7.4) for 24 hours, while the uncrosslinked samples lost their fibrous structure, indicating the water stability of genipin-crosslinked nanofibers. The genipin-crosslinked mats also showed no significant change in swelling ratio in comparison with uncrosslinked ones. FTIR-ATR spectrum of uncrosslinked and genipin-crosslinked chitosan nanofibers revealed the reaction between genipin and amino groups of chitosan. Cytotoxicity of genipin-crosslinked nanofibers was examined by MTT assay on human fibroblast cells in the presence of nanofibers extraction media. The genipin-crosslinked nanofibers did not show any toxic effects on fibroblast cells at the lowest and moderate amount of genipin. The fibroblast cells also showed a good adhesion on genipin-crosslinked nanofibers.
Conclusion:
This electrospun matrix would be used for biomedical applications such as wound dressing and scaffold for tissue engineering without the concern of toxicity.
Genipin cross-linked electrospun chitosan-based nanofibrous mat as tissue eng...Nanomedicine Journal (NMJ)
Objective(s):
To improve water stability of electrospun chitosan/ Polyethylene oxide (PEO) nanofibers, genipin, a biocompatible and nontoxic agent, was used to crosslink chitosan based nanofibers.
Materials and Methods:
Different amounts of genipin were added to the chitosan/PEO solutions, chitosan/PEO weight ratio 90/10 in 80 % acetic acid, and the solutions were then electrospun to form nanofibers. The spun nanofibers were exposed to water vapor to complete crosslinking. The nanofibrous membranes were subjected to detailed analysis by scanning electron microscopy (SEM), Fourier transform infrared-attenuated total reflection (FTIR-ATR) spectroscopy, swelling test, MTT cytotoxicity, and cell attachment.
Results:
SEM images of electrospun mats showed that genipin-crosslinked nanofibers retained their fibrous structure after immerging in PBS (pH=7.4) for 24 hours, while the uncrosslinked samples lost their fibrous structure, indicating the water stability of genipin-crosslinked nanofibers. The genipin-crosslinked mats also showed no significant change in swelling ratio in comparison with uncrosslinked ones. FTIR-ATR spectrum of uncrosslinked and genipin-crosslinked chitosan nanofibers revealed the reaction between genipin and amino groups of chitosan. Cytotoxicity of genipin-crosslinked nanofibers was examined by MTT assay on human fibroblast cells in the presence of nanofibers extraction media. The genipin-crosslinked nanofibers did not show any toxic effects on fibroblast cells at the lowest and moderate amount of genipin. The fibroblast cells also showed a good adhesion on genipin-crosslinked nanofibers.
Conclusion:
This electrospun matrix would be used for biomedical applications such as wound dressing and scaffold for tissue engineering without the concern of toxicity.
ST8 micellar/niosomal vesicular nanoformulation for delivery of naproxen in c...Vahid Erfani-Moghadam
Naproxen (NPX) is a non-steroidal anti-inflammatory drug (NSAID) used against a variety of diseases, including autoimmune disorders and chronic inflammations. However, low water solubility limits its therapeutic efficacy and novel nanoformulations are required to bypass its poor bioavailability to reach its therapeutic effect. The purpose of the study was to investigate the role of the nanoformulation of biocompatible molecules; Squalene (S) and Tween 80 (T8) Micellar/Niosomal Vesicles (ST8MNV) prepared, by thin-film hydration method and their potential as a drug delivery system for NPX. The percentage of encapsulation efficiency was calculated to be 99.5 ± 0.2% for 5% of NPX weight in total ingredients of micellar/niosomal vesicles (w/w). The ST8MNV nanoformulation exhibited a slower rate of NPX release from the drug encapsulated over seven days, suggesting a stable complex of NPX. Finally, cell toxicity assay demonstrated that the half-maximal inhibitory concentrations (IC50) of NPX were drastically reduced by ST8MNV nanoformulation in MCF-7, A549, HeLa, and MDA-MB-231 cancer cell lines. Our data show this micellar/niosomal naproxen nanoformulation is a great candidate for the future in vitro and in vivo studies for potential clinical anti-inflammatory and anticancer applications.
Effective in vitro gene delivery to murine cancerous brain cells using carbon...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Carbon nanotube (CNT) has been widely applied at molecular and cellular levels due to its exceptional properties. Studies based on conjugation of CNTs with biological molecules indicated that biological activity is preserved. Polyethylenimine (PEI) is explored in designing novel gene delivery vectors due to its ability to condense plasmid DNA through electrostatic attraction. In this study functionalization and grafting polyethylenimine onto the surface of carbon nanotube was used to improve the solubility and biocompatibility.
Materials and Methods:
The effect of molecular weight of polymer on final efficacy of vectors has been investigated using three different molecular weights of polymer. In this study no linker was used and both segments (PEI and CNT) were directly attached resulted in the synthesis of three different vectors. Synthesized vectors were tested for their ability to condense plasmid DNA and cellular toxicity using ethidium bromide and MTT assays. Size and Zeta potential of nanoparticles was determined using Malvern zeta sizer. Evaluation of transfection efficiency of vectors was carried out on N2A cell line by different methods including qualitative fluorescence imaging, flow cytometry and luciferase assay.
Results:
All three synthesized vectors bear positive surface charges with sizes in the range of 85-190 nm. More than 80 percent of treated cells were viable and in the case of V25 significant improvement in reducing cytotoxicity compared to unmodified polymer was observed. Obtained results indicated that vector containing PEI 1.8 kDa has the greatest improvement in terms of its transfection efficiency compared to unmodified polymer.
Conclusion:
Conjugation of PEI with carbon nanotube les to new vectors with lowered cytotoxicity and higher transfection efficiency. The highest transfection efficiency was obtained with the lowest molecular weight PEI.
Science and technology of manipulating and improving microbial strains, in order to enhance their metabolic capacities for biotechnological applications, are referred to as strain improvement.
Phytochemicals are considered as natural bio-active compounds with extraordinary bio-activities like free radical scavenging, enhancing mitochondrial integrity. preventing severe inflammation, regulating apoptosis and inhibiting toxic protein aggregations. This presentation deals with how phytochemicals are promoting brain health against various molecular assaults and wide range of diseases and disorders.
This is a lecture by Dr. Jerry McLaughlin about his research into extracts of pawpaw plants, annonaceous acetogenins, in vitro, in vivo, mechanism of action, and toxicity in mice.
Mutagenesis; A conventional tool for strain improvement in industry Zohaib HUSSAIN
The strain improvement is the process of improvement and manipulation of microbial strains for the icreasment of metabolic level for industrial applications. The yield of microbial enzymes can be increased by using microbe specific medium for fermentation, improving the fermentation process and strain improvement for higher yield of product.
All these things lead to decrease in cost production. Microbe produce product according to its need therefore there is great need for overproduction. There is tremendous contribution of conventional Mutagenesis for strain improvement. Mutagenesis is important tool for the production of mutants which are capable to produce large product i.e. hyperactive.
Plant phenolics in animal health and methane mitigation. avijit deyAvijit Dey
Phenolics are ubiquitous in all plant organs and integral part of animal and human foods. Phenolic acids, flavanoids and tannins are the most common phenolic compounds. Fruits and vegetables are rich source of polyphenols for humans. Whereas, tree leaves in tropical countries are potential sources phenolic compounds for animals. Researchers have become more interested in polyphenols due to their potent antioxidant properties and credible effects in the prevention of cardiovascular, neurodegenerative diseases and cancer. Condensed tannins (CT) and flavanoids have the ability to modify the rumen fermentation towards reduced methanogenesis by altering rumen microbial community and their supplementation reduces nitrogen excretion in ruminants by improving its utilization efficiency. Improvement in feed intake, growth rate, wool production, reproduction and milk production in ruminants fed CT containing diets were observed in a dose dependent manner. In ruminants, most proteins are rapidly solubilised and release 56- 65% N in the rumen during mastication; consequently large losses of N (25-35%) occur as ammonia absorbed from rumen. CT from tree leaves could be used as organic protectant of proteins to improve protein utilization by ruminants and reduce environmental pollution by minimising N losses through urine. Supplementation of CT through leaves of Artocarpus heterophyllus, Ficus infectoria, Ficus bengalensis and Ficus glomerata at 1.5- 2.0% levels was observed to reduce the rumen degradability of groundnut cake to 60-75 per cent from the normal value of 92 per cent. Controlling gastro-intestinal parasites by supplementation of CT through F. infectoria, Psidium guajava and Ficus bengalensis was effective to ameliorate drug resistance. Feeding study to lambs and crossbred cows with supplementation of CT (1.5%) either through F. Infectoria and F. bengalensis leaves was found to increase feed efficiency, growth rate, milk yield, fat yield, antioxidant status and immunity of animals. Flavanoids and tannin-rich feeds could reduce or inhibit rumen biohydrogenation of vaccenic acid to stearic acid, resulting in the accumulation of conjugated linoleic acids (CLA) in milk and meat which has hypolipidaemic and anti carcinogenic effects in humans. Judicious application of plant phenolics could improve overall health and production performance of animals.
ST8 micellar/niosomal vesicular nanoformulation for delivery of naproxen in c...Vahid Erfani-Moghadam
Naproxen (NPX) is a non-steroidal anti-inflammatory drug (NSAID) used against a variety of diseases, including autoimmune disorders and chronic inflammations. However, low water solubility limits its therapeutic efficacy and novel nanoformulations are required to bypass its poor bioavailability to reach its therapeutic effect. The purpose of the study was to investigate the role of the nanoformulation of biocompatible molecules; Squalene (S) and Tween 80 (T8) Micellar/Niosomal Vesicles (ST8MNV) prepared, by thin-film hydration method and their potential as a drug delivery system for NPX. The percentage of encapsulation efficiency was calculated to be 99.5 ± 0.2% for 5% of NPX weight in total ingredients of micellar/niosomal vesicles (w/w). The ST8MNV nanoformulation exhibited a slower rate of NPX release from the drug encapsulated over seven days, suggesting a stable complex of NPX. Finally, cell toxicity assay demonstrated that the half-maximal inhibitory concentrations (IC50) of NPX were drastically reduced by ST8MNV nanoformulation in MCF-7, A549, HeLa, and MDA-MB-231 cancer cell lines. Our data show this micellar/niosomal naproxen nanoformulation is a great candidate for the future in vitro and in vivo studies for potential clinical anti-inflammatory and anticancer applications.
Effective in vitro gene delivery to murine cancerous brain cells using carbon...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Carbon nanotube (CNT) has been widely applied at molecular and cellular levels due to its exceptional properties. Studies based on conjugation of CNTs with biological molecules indicated that biological activity is preserved. Polyethylenimine (PEI) is explored in designing novel gene delivery vectors due to its ability to condense plasmid DNA through electrostatic attraction. In this study functionalization and grafting polyethylenimine onto the surface of carbon nanotube was used to improve the solubility and biocompatibility.
Materials and Methods:
The effect of molecular weight of polymer on final efficacy of vectors has been investigated using three different molecular weights of polymer. In this study no linker was used and both segments (PEI and CNT) were directly attached resulted in the synthesis of three different vectors. Synthesized vectors were tested for their ability to condense plasmid DNA and cellular toxicity using ethidium bromide and MTT assays. Size and Zeta potential of nanoparticles was determined using Malvern zeta sizer. Evaluation of transfection efficiency of vectors was carried out on N2A cell line by different methods including qualitative fluorescence imaging, flow cytometry and luciferase assay.
Results:
All three synthesized vectors bear positive surface charges with sizes in the range of 85-190 nm. More than 80 percent of treated cells were viable and in the case of V25 significant improvement in reducing cytotoxicity compared to unmodified polymer was observed. Obtained results indicated that vector containing PEI 1.8 kDa has the greatest improvement in terms of its transfection efficiency compared to unmodified polymer.
Conclusion:
Conjugation of PEI with carbon nanotube les to new vectors with lowered cytotoxicity and higher transfection efficiency. The highest transfection efficiency was obtained with the lowest molecular weight PEI.
Science and technology of manipulating and improving microbial strains, in order to enhance their metabolic capacities for biotechnological applications, are referred to as strain improvement.
Phytochemicals are considered as natural bio-active compounds with extraordinary bio-activities like free radical scavenging, enhancing mitochondrial integrity. preventing severe inflammation, regulating apoptosis and inhibiting toxic protein aggregations. This presentation deals with how phytochemicals are promoting brain health against various molecular assaults and wide range of diseases and disorders.
This is a lecture by Dr. Jerry McLaughlin about his research into extracts of pawpaw plants, annonaceous acetogenins, in vitro, in vivo, mechanism of action, and toxicity in mice.
Mutagenesis; A conventional tool for strain improvement in industry Zohaib HUSSAIN
The strain improvement is the process of improvement and manipulation of microbial strains for the icreasment of metabolic level for industrial applications. The yield of microbial enzymes can be increased by using microbe specific medium for fermentation, improving the fermentation process and strain improvement for higher yield of product.
All these things lead to decrease in cost production. Microbe produce product according to its need therefore there is great need for overproduction. There is tremendous contribution of conventional Mutagenesis for strain improvement. Mutagenesis is important tool for the production of mutants which are capable to produce large product i.e. hyperactive.
Plant phenolics in animal health and methane mitigation. avijit deyAvijit Dey
Phenolics are ubiquitous in all plant organs and integral part of animal and human foods. Phenolic acids, flavanoids and tannins are the most common phenolic compounds. Fruits and vegetables are rich source of polyphenols for humans. Whereas, tree leaves in tropical countries are potential sources phenolic compounds for animals. Researchers have become more interested in polyphenols due to their potent antioxidant properties and credible effects in the prevention of cardiovascular, neurodegenerative diseases and cancer. Condensed tannins (CT) and flavanoids have the ability to modify the rumen fermentation towards reduced methanogenesis by altering rumen microbial community and their supplementation reduces nitrogen excretion in ruminants by improving its utilization efficiency. Improvement in feed intake, growth rate, wool production, reproduction and milk production in ruminants fed CT containing diets were observed in a dose dependent manner. In ruminants, most proteins are rapidly solubilised and release 56- 65% N in the rumen during mastication; consequently large losses of N (25-35%) occur as ammonia absorbed from rumen. CT from tree leaves could be used as organic protectant of proteins to improve protein utilization by ruminants and reduce environmental pollution by minimising N losses through urine. Supplementation of CT through leaves of Artocarpus heterophyllus, Ficus infectoria, Ficus bengalensis and Ficus glomerata at 1.5- 2.0% levels was observed to reduce the rumen degradability of groundnut cake to 60-75 per cent from the normal value of 92 per cent. Controlling gastro-intestinal parasites by supplementation of CT through F. infectoria, Psidium guajava and Ficus bengalensis was effective to ameliorate drug resistance. Feeding study to lambs and crossbred cows with supplementation of CT (1.5%) either through F. Infectoria and F. bengalensis leaves was found to increase feed efficiency, growth rate, milk yield, fat yield, antioxidant status and immunity of animals. Flavanoids and tannin-rich feeds could reduce or inhibit rumen biohydrogenation of vaccenic acid to stearic acid, resulting in the accumulation of conjugated linoleic acids (CLA) in milk and meat which has hypolipidaemic and anti carcinogenic effects in humans. Judicious application of plant phenolics could improve overall health and production performance of animals.
Local drug delivery is simple to use and may conceivably in the future be delivered by the patients themselves, hence can be used as an adjunct to mechanical plaque removal.
This topic include all the drugs that are locally applied in periodontal pocket so that their levels in GCF should be more than blood.
Advantages:
Can attain higher concentrations at base of pocket
Can use drugs that are not suitable for systemic administration
Patient compliance is not required
Alternative for patients predisposed to adverse drug reactions from systemic administration.
Reduced risk for drug resistant microbe development
Lower total drug dose
INDICATIONS:
As an adjunct to mechanical therapy in pockets of 5 mm or greater depth
In patients who are systemically compromised & cannot undergo periodontal flap surgery
Localized recurrent pockets with supportive periodontal therapy
In refractory periodontitis (that is resistant to treatment)
In Vitro Cell Tests for Functional FoodInstitut Kurz
The relationship between the food we eat and our health is
clear. In the constant search for healthier foods rich in
bioactive compounds that promote health and healthy
ageing, a wide variety of functional foods have appeared on
the market.
To know the real function of these functional foods
in our body, it is necessary to carry out different types of in
vitro cell tests.
Institut Kurz specializes in conducting in vitro cell tests for functional foods.
Contact us for more information:
info@institut-kurz.com
https://www.institut-kurz.com/
Evidence-Based Treatments of AddictionAuthor(s) Charles P. .docxgitagrimston
Evidence-Based Treatments of Addiction
Author(s): Charles P. O'Brien
Source: Philosophical Transactions: Biological Sciences, Vol. 363, No. 1507, The Neurobiology of
Addiction: New Vistas (Oct. 12, 2008), pp. 3277-3286
Published by: The Royal Society
Stable URL: http://www.jstor.org/stable/20208741 .
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PHILOSOPHICAL
TRANSACTIONS
_of-?TT^
PhiL Trans' R' Soc' B (2008) 363' 3277~3286
THE ROYAL 4\ doi:10.1098/rstb.2008.0105
SOCIETY JAJJ Published online 18 July 2008
Review
Evidence-based treatments of addiction
Charles P. O'Brien*
Department of Psychiatry, University of Pennsylvania, 3900 Chestnut Street,
Philadelphia, PA 19104-6178, USA
Both pharmacotherapy and behavioural treatment are required to relieve the symptoms of addictive
disorders. This paper reviews the evidence for the benefits of pharmacotherapy and discusses
mechanisms where possible. Animal models of addiction have led to some medications that are effective
in reducing symptoms and improving function but they do not produce a cure. Addiction is a chronic
disease that tends to recur when treatment is stopped; thus, long-term treatment is recommended.
Keywords: addiction; relapse; withdrawal; endophenotype
1. INTRODUCTION
Most theories of drug-addiction mechanisms have been
based on animal models and, until recently, these
theories have made the assumption that all subjects are
alike in their responses to drugs (Deroche-Gamonet
et ah 2004). In reality, human subjects are quite
variable in how they respond to drugs. Moreover,
data from the studies of non-human primates indicate
that genetic variation is also important in other higher
species. Drugs that demonstrate rewarding properties
in animals also tend to be abused by humans, but only
by a relatively small percentage of those humans
exposed (table 1). The most obvious effects of chronic
drug use are tolerance and physiological dependence
and these phenomena trans ...
El 12 de mayo de 2017 celebramos en la Fundación Ramó Areces una jornada con IS Global y Unitaid sobre enfermedades transmitidas por vectores, como la malaria, entre otras.
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Richard's entangled aventures in wonderlandRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Ultrasound triggered release of anticancer agents from alginate chitosan hydrogels
1. ULTRASOUND TRIGGERED RELEASE OF
ANTICANCER AGENTS FROM ALGINATE-CHITOSAN
HYDROGELS
MSc. Antonio Di Martino, Ph.D.
dimartino@utb.cz / dimartino@tpu.ru
MSDT 2017, 1-3 November 2017, Tomsk
2. Triggered Drug Delivery
Advanced drug delivery systems (DDS) enhance efficacy of different therapeutics in a dosage, spatial, and/or
temporal way
Numerous chemical, physical and biological-based stimuli-responsive formulations or devices for
controlled drug release have been developed
Theranostics 2013; 3(3):141-151
3. Physical stimuli for local drug delivery
X-Rays
Good penetration
Precise
Easily tuned
High cost
Ionizing radiation
Magnetic field
Localized accumulation
Energy modulation
Accumulation – embolism, increased cytotoxicity
Light
Precise
Low cost
Easily tuned
Limited tissue penetration (can be enhanced
with NIR light) Invasive for deep zone
Ultrasound
Good penetration (Dependent on frequency)
Easily tuned
Low cost
Difficulty to target moving organs
Not homogeneous exposure of large zones
Radiofrequency Invasive, temperature gradient from the heated zone Easily tuned
4. Ultrasounds –general definition
-Ultrasounds are mechanical longitudinal waves propagating in a medium through changes in pressure-
Ultrasound technology is already well implanted in the medical field
Frequency modulation of the depth of penetration and spatial resolution
Intensity amount of energy delivered at the target site
Focused
Not focused
diagnosis (ultrasound imaging)
therapeutic
More interesting in drug delivery – large amount of energy in a small area
Physical therapy
6. US-therapeutic
“any type of procedure that uses ultrasound for therapeutic benefit”
Applied Physics Letters 106(2):021902 · January 2015
http://www.trust-biosonics.com/technology/1
Ultrasound probe
Blood vessel
4. Local nanoparticle
delivery
3. Targeted sonoporation at
the region of interest
2. Microbubbles and nanoparticles reach
target tissue
1. IV injection of microbubbles
and nanoparticles
Microbubble Nanoparticle
Microbubble
undergoing inertial
cavitation
Therapeutic
ultrasound
7. c
US in Drug Delivery
US-induced effects
Thermal
Mechanical
Acoustic radiation
forces
Journal of Controlled Release 241 (2016) 144-163
Theranostics 2014; 4(4):432-444.
8. Drug Delivery Carriers designed for use with US
Using carriers prevents premature and extraneous delivery of the drug
Control the release, reduction of burst
Targeting
Nano or Micro-carrier in solid or liquid form
Combination of gas-liquid form ( lipospheres = hybrid between liposomes and microbubbles)
Low sensibility to US
http://www.dataphysics.de
Liposomes
Micelles
http://www.fbs.leeds.ac.uk
Solid Lipid Nanoparticles
Di Martino et al, International Journal of Pharmaceutics, 526,2017,380-390
Hybrid-NPs
9. Highly adsorbent, are able to swell in water or in a biological fluid while conserving their shape
Swelling behavior is related to the Mw and nature of the polymer(s) used
Unique properties such as flexibility, low interfacial energy with water,
highly charged structure in water
Biocompatible materials, because of their high water content, their composition
and their mechanical behaviour which is close to that for an extracellular matrix
of natural origin
Conventional hydrogels are not sensitive to changes in the environment, as opposed to stimuli-responsive
hydrogels which can sense an external stimulus
Hydrogels
http://dev.nsta.org
10. Stimuli responsive hydrogels
Stimuli-responsive hydrogels are based on smart polymers
Ability to respond to small changes in the surrounding environment by changes in volume, swelling or
shrinking
Slight variations in parameters (pressure, temperature, concentration, solvent, etc...) induce considerable
modifications of the physical and chemical properties of the macromolecules (solubility, structure, shape,
size)
Soft Matter, 2011,7, 4414-4424
11. Development of biopolymer hydrogel beads for multidrug encapsulation
Control the release of the drugs, individually
Deliver drugs at the right place and the right time
Trigger the release by application of US = pulsatile release
No constant release over time = more effective
Control the biodegradation rate
Self-healing
Aims
12. Hydrogel-mbead : preparation
Alginic acid
Chitosan
Doxorubicin Temozolomide
+
• 100 mm average diameter
• Drug loading does not affect dimension
13. Multiple Drug Loading
0
20
40
60
80
100
0.25 0.5 1 1.5 2 2.5 3 5 10
Drug conc. mg/ml
EncapsulationEfficiency(%)
Individual
0
20
40
60
80
100
0.25 0.5 1 1.5 2 2.5 3 5 10
Drug conc. mg/ml
EncapsulationEfficiency(%)
Encapsulation
Holding
Weight ratio between drugs
Multiple
Chitosan to Alginic acid weight ratio : 2
pH 5
Temp : 22-25ﹾC
14. Release investigation
Simulated body fluids
pH 2-7.4 T 37ﹾC
US transducer
ON/OFF
Stirrer
IN
OUT
Temp. contr.
Solution
Ultrasonics Sonochemistry 16 (2009) 41–49
15. Improve TMZ stability
Control
6h
24h
Di Martino et al.Journal of Nanoparticle Research 19(2) ·2017
TMZ undergoes pH dependent ring-opening under both
acidic and alkaline conditions
Free drug
Drug loaded
Methylating agent
TMZ half life : 1.8h
MTIC half life : slight longer than TMZ
16. Individual Release
70kHz, 2W/cm2
REF
US 5x10s
US 5x30s
US every 20 minutes (ON/OFF)
Temperature is stable
pH 3
pH 5
pH 7.4
T = 37ﹾC ± 1
120 rpm oscillatory shaker
Pulsatile Release
More effective than constant release rate
17. T im e ( m in )
mgReleased
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0
0
2 5
5 0
7 5
1 0 0
1 2 5
1 5 0
1 7 5
2 0 0
T im e ( m in )
mgReleased
1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1 1 0
0
2 5
5 0
7 5
1 0 0
1 2 5
1 5 0
1 7 5
2 0 0
U S 5 x 1 0 s
U S 5 x 3 0 s
U S 5 x 1 0 s
U S 5 x 3 0 s
pH 3
pH 7.4
Ref : 128 mg/mg
Tot : 233 mg/mg 5x10s
Tot : 461 mg/mg 5x30s
Ref : 211 mg/mg
Tot : 400 mg/mg 5x10s
Tot : 669 mg/mg 5x30s
650 mg/mg 720 mg/mg
Ref : 276 mg/mg
Tot : 385mg/mg 5x10s
Tot : 611 mg/mg 5x30s
Ref :338 mg/mg
Tot : 460 mg/mg 5x10s
Tot : 704 mg/mg 5x30s
Individual Release
18. Simultaneous release
mgReleased
D O X T M Z
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
8 0 0
R E F
U S 5 x 1 0 s
U S 5 x 3 0 s
mgReleased
D O X T M Z
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
8 0 0
R E F
U S 5 x1 0s
U S 5 x3 0s
mgReleased
D O X T M Z
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
8 0 0
R E F
U S 5 x1 0s
U S 5 x3 0s
19. In vitro degradation rate
PBS (pH 7.4)
Lysozyme human
(0.5 mg/ml)
Evaluation of the Content of reducing sugar (GPC)
Pectinase from A.Niger
(0.5 mg/ml)
Cellulase from A.Niger
(0.5 mg/ml)
T im e (d a y s )
%Degradation
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0
0
2 0
4 0
6 0
8 0
1 0 0
E n z y m e fre e
L y s o z y m e
P e c tin a se
C ellu lase
Release time ( 2h )
Up to 80% of the loaded drugs are released
20. In vitro studies
No US treatment
No Drugs
5x10s treatment
DOX
5x10s treatment
DOX+TMZ
5x10s treatment
TMZ
MCF7NIH/3T3
Viability(%)
M C F 7 N IH 3 T 3 H E K 2 9 3
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
Flow cytometry demonstrate that US cycles does
not affect cells viability
5x10s treatment has been chose
Drug free mbead
Cells respond in a different way when short burst occurs
21. In vitro studies
The decrease in cell viability is greater when combination of US + drug is used
Three possible mechanisms
I)The release after US events create a concentration gradient across the cell membrane
promoting the transport by diffusion
II)Upregulation of endocytosys --- cells respond differently to US
III)US cause a perturbation in the cell membrane leading to the passive transport
23. • Functionalization of the carrier to control the release selectively – in
serie release
• Derivatives to tune the biodegradation rate according with the
needed
• US-hydrogel relation
Perspectives
