18 research outputs found
Can pulsed electromagnetic fields trigger on-demand drug release from high-tm magnetoliposomes?
Recently, magnetic nanoparticles (MNPs) have been used to trigger drug release from magnetoliposomes through a magneto-nanomechanical approach, where the mechanical actuation of the MNPs is used to enhance the membrane permeability. This result can be effectively achieved with low intensity non-thermal alternating magnetic field (AMF), which, however, found rare clinic application. Therefore, a different modality of generating non-thermal magnetic fields has now been investigated. Specifically, the ability of the intermittent signals generated by non-thermal pulsed electromagnetic fields (PEMFS) were used to verify if, once applied to high-transition temperature magnetoliposomes (high-Tm MLs), they could be able to efficiently trigger the release of a hydrophilic model drug. To this end, hydrophilic MNPs were combined with hydrogenated soybean phosphatidylcholine and cholesterol to design high-Tm MLs. The release of a dye was evaluated under the effect of PEMFs for different times. The MNPs motions produced by PEMF could effectively increase the bilayer permeability, without affecting the liposomes integrity and resulted in nearly 20% of release after 3 h exposure. Therefore, the current contribution provides an exciting proof-of-concept for the ability of PEMFS to trigger drug release, considering that PEMFS find already application in therapy due to their anti-inflammatory effects
Magnetoliposomes: envisioning new strategies for water decontamination
In this work, the inclusion of magnetic nanoparticles (MNPs) within phospholipid vesicles has been
investigated as novel strategy for improving stability and reactivity of these nanoparticles and extending their
potential use in the environmental field. Two phospholipids able to form liposomes characterized by different
rigidity and stiffness, were used as potential carriers of MNPs. The magneto-responsive liposomes were
investigated for their physicochemical and stability properties. In particular, the stability of the two systems
was indirectly investigated evaluating the ability of the hybrid constructs to retain a fluorescent marker in their
structure. Alterations in the permeability of the membranes were determined by the rate of the marker release
from the liposomes, under both mechanical and thermal stress conditions
Investigation on smart triggers and smart lipid vesicles as new tools for drug delivery applications
The rational design of systems for controlled drug delivery is an important area of research
for advancing new therapies for many diseases. Nanomaterial based controllable drug
delivery platforms would overcome many of the major drawbacks in pharmacological
therapy, because they would store the therapeutic molecules during transportation within
the body and provide triggered and finely controlled release of the agent at the target site.
In this context, lipid vesicles as liposomes attracted, since their discovery, growing interest
for their potential applications as drug delivery vectors. They are now considered clinically
established nanometer-scaled systems for the delivery of cytotoxic drugs or agents for
biomedical applications. However, liposomes can be further engineered to improve their
performance in terms of stability and controlled delivery, since the rapid degradation, due
to the reticuloendothelial system (RES), and inability to achieve sustained drug delivery,
over a prolonged period, limit their biological efficacy and use in pharmaceutics.
Interesting results were obtained in terms of physical stability through the approach that
provides the combination of different biomaterials within the same delivery lipid system.
Following this concept, it was possibile to change the surface properties of the bilayer, by
coating it with water-soluble polymers, like polyethylene glycol, leading to “stealth
liposomes”. More recently, satisfying achievements resulted from the modification of the
internal structure of liposomes, with the aim to convert the aqueous inner core into a soft
and elastic hydrogel, obtaining structures able to retain the cargo for longer time, without
unwanted burst release of the delivered compound.
An ideal drug delivery platform should encompass not only the carrier stability, but also
controllable timing, dosage and site specificity of drug release, and permit remote, noninvasive
and reliable switching of the therapeutic agent, in order to prevent deleterious side
effects of cytotoxic drugs toward normal and healthy tissue. Much of innovations in
materials design, for drug delivery, manifest in producing “smart liposomes” that are able to respond to “smart triggers”, in order to realize on-demand processes, allowing for
tailored release profiles with excellent temporal and dosage control. In principle, the ondemand
drug delivery is becoming feasible through the design of stimuli-responsive
systems that recognize their microenvironment and react in a dynamic way. Specifically, it
is possible to engineere the liposomal structure making it capable of responding to physical,
chemical or biological triggers.
Among the endogenous or exsogenous stimuli that can be applied, magnetic stimulus
represents a potential trigger for the remotely-on demand release, evaluating that normal
biological tissues are essentially transparent to low-frequency magnetic fields. Through the
encapsulation of superparamagnetic nanoparticles, giving rise to the Magneto-Liposomes
(MLs), it is possibile to modulate the transmembranal drug diffusion by using an external
magnetic field with intensity significantly lower that no heat generation, harmful to healthy
tissues, is observed.
Another challenging way to activate release from liposomes is the use of pulsed electric
fields. In particular, since it was demonstrated that electric pulses of shorter duration
(nanosecond) and higher intensity (in the order of MV/m) directly interact not only with cell
membrane, but also with internal cell organelles of nanometer dimensions, nanosecond
electric pulses are proposed as sufficient signals to generate an alteration of the liposomal
transmembrane voltage, which is followed by the formation of temporary hydrophilic
pores. Without implying the phenomenon of irreversible poration, the nanosecond pulses
therefore can be considered useful external stimuli to trigger the simultaneous
permabilization of liposomes and cells membranes, in order to let that the chemical load
internalized in the vesicles to be released inside the cells.
In this scenario is placed the main activity of this Ph.D. thesis, whose aim is to provide a
multiscale and multidisciplinary approach to demonstrate the capability of liposomes to
prove effective smart systems for the on-demand and modified drug delivery, able to
minimize off-target effects and maximize programmability of therapy. Following a briefly overview of this Ph.D. thesis is given.
In Chapter 3 is reported the study which highlights the utility in trapping MNPs within
phospholipid vesicles, generating hybrid magneto-responsive constructs. Particularly, in
this work the inclusion of hydrophilic Fe3O4 nanoparticles (MNPs) within phospholipid
vesicles, characterized by different rigidity and stiffness, was investigated as novel strategy
for improving stability and reactivity of these MNPs, since the integration in liposomes may
prevent MNPs from aggregation and extend their potential use in the environmental
remediation. The stability of these hybrid systems was indirectly investigated evaluating
the ability of retaining a fluorescent marker in their structure, under both mechanical and
thermal stress conditions. In particular, for the mechanical stress test, a low intensity nonthermal
alternating magnetic field (AMF) was applyed to magnetic liposomes. The AMF
could, in fact, cause a mechanical destabilization of the vesicle membrane, due to MNPs
oscillation within the liposomes, which may induce the release of the dye.
In Chapter 4, according to the results obtained in the previous work, shown in Chapter 3,
is presented the research project which combines engineering skills, specifically focused on
electromagnetic fields, with competences in synthesis and characterization of hybrid
magnetic nanocarriers, to assess a remotely on-demand drug delivery. Specifically, here is
refiled the possibility to trigger drug release from high-transition temperature
magnetoliposomes (high-Tm MLs) entrapping MNPs, through a magneto-nanomechanical
approach, where the mechanical actuation of the MNPs is used to enhance the membrane
permeability, avoiding temperature rise. Since the AMF, as an external magnetic signal,
found rare application in clinic, in this case, the ability of the non-thermal pulsed
electromagnetic fields (PEMFs), that are already employed in theraphy, due to their antiinflammatory
effects, was tested, in order to verify if, once applied to high-Tm MLs, PEMFs
could be able to efficiently trigger the transmembranal drug diffusion. In the Chapter 5 and 6 is illustrated another sophisticated and innovative drug delivery
strategy to activate an efficient on-demand release. Specifically, in Chapter 5 is reported the
theoretical work and the experimental proof-of-concept of the possibility of applying ultrashort
(ns) and intense (MV/m) external pulsed electric fields (nsPEFs), to remotely trigger
the release from liposomes of nanometer-sizing. The nanoelectropermeabilization, that
probably occurs with the formation of transient pores in the bilayer, because of the external
pulsed electric field enforcement, was evaluated in relation to the diffusion across the
bilayer of a probe, previously trapped in the core of liposomes. To support the experimental
data, a numerical model of liposomes suspension, exposed to nsPEF by means a standard
electroporation cuvette, was carried out according with the experimental conditions. In
Chapter 6 was demonstrated, once again, the possibility of permeabilizing the liposomal
membrane, applying the same type of pulses, described in Chapter 5, but, in this case,
delivered to the nanometer-sized lipid vesicles by a coplanar exposure system. Furthermore,
the electropermeabilization mechanism in liposomes membrane was investigated through
the Raman Coherent anti-Stokes spectroscopy (CARS), highlighting, for the first time, the
experimental proof of the role of water molecules of the interstitial phase in the
electropermeabilization of vesicles bilayer.
Finally, in Chapter 7 is described the project who leaded to the development of a novel
hybrid lipid-polymer nanocostructs, designed to merge the beneficial properties of both
polymeric drug delivery systems and liposomes in a single nanocarrier and at the same time
take care of liposomes limitations, such as the physical and chemical stability issues. Starting
from previous studies on the use of liposomes as template to create nanohydrogel, this
research brought to the novel Gel-in-Liposome (GiL) systems, relying from the combination
of lipid vesicles and the polymer polyethylene glycol-dimethacrylate (PEG-DMA) at two
different molecular weight. These hybrid systems are characterized by the presence of a
chemically crosslinked polymeric network within the aqueous compartment of liposomes.
The effect of PEG-DMA, on the properties of the new lipid-polymer nanosystems and on the related changes of the membrane permeability and stability, against different stresses,
were evaluated to understand GiL potential use as drug carriers in clinics
Manufacturing and characterization of polymeric thin films for buccal delivery of drugs
This study aimed to explore film forming capacity of a natural
polysaccharide, gellan gum (GG), for fabrication of oral thin films
(OTFs) for the delivery of drugs [1]. For the development of
buccal film with ideal mechanical properties and adequate
amount of drug incorporated, concentration of polymer and
plasticizer were optimized to obtain films with the highest
standard in terms of flexibility and homogeneity [2]. Moreover,
attention was also paid to the exploration of opportune
dissolution tests able to discriminate the release profiles of drugs
from polymeric thin films
Planning sine waves electroporation on liposomes for drug delivery application
Radiofrequency (RF) signals as a way to remotely control smart drug delivery nanocarriers represent a promising tool to overcome traditional therapeutic issues, such as overdosing therapeutic agents with a reduced efficacy and related side effects on healthy tissues, in order to obtain a targeted release near diseased cells. Aim of this work is to provide a deep investigation on the possible effect of sine wave RF signals, of 100 kHz and 10 MHz, applied to a non-uniform random distribution of 142 liposomes, as a realistic model of a biocompatible drug delivery suspension, to study electroporation mechanisms occurring during exposure
Proof-of-concept of electrical activation of liposome nanocarriers: from dry to wet experiments
The increasing interest toward biocompatible nanotechnologies in medicine, combined with electric fields stimulation, is leading to the development of electro-sensitive smart systems for drug delivery applications. To this regard, recently the use of pulsed electric fields to trigger release across phospholipid membranes of liposomes has been numerically studied, for a deeper understanding of the phenomena at the molecular scale. Aim of this work is to give an experimental validation of the feasibility to control the release from liposome vesicles, using nanosecond pulsed electric fields characterized by a 10 ns duration and intensity in the order of MV/m. The results are supported by multiphysics simulations which consider the coupling of three physics (electromagnetics, thermal and pore kinetics) in order to explain the occurring physical interactions at the microscopic level and provide useful information on the characteristics of the train of pulses needed to obtain quantitative results in terms of liposome electropermeabilization. Finally, a complete characterization of the exposure system is also provided to support the reliability and validity of the study
Design and characterization of a biocompatible physical hydrogel based on scleroglucan for topical drug delivery
Physical hydrogels of a high-carboxymethylated derivative of scleroglucan (Scl-CM300) were investigated as potential systems for topical drug delivery using three different therapeutic molecules (fluconazole, diclofenac and betamethasone). Rheological tests were carried out on drug-loaded hydrogels along with in-vitro release studies in a vertical Franz cell, in order to investigate if and how different drugs may influence the rheological and release properties of Scl-CM300 hydrogels. Experimental results and theoretical modeling highlighted that, in the absence of drug/polymer interactions (as for fluconazole and betamethasone) Scl-CM300 matrices offer negligible resistance to drug diffusion and a Fickian transport model can be adopted to estimate the effective diffusion coefficient in the swollen hydrogel. The presence of weak drug/hydrogel chemical bonds (as for diclofenac), confirmed by frequency sweep tests, slow down the drug release kinetics and a non-Fickian two-phase transport model has to be adopted. In-vivo experiments on rabbits evidenced optimal skin tolerability of Scl-CM300 hydrogels after topical application. © 2017 Elsevier Lt