Thus, in recent years we have seen an explosion in the field of new micro- and nano-fabricated devices for drug delivery. Finally, magnetically responsive nanoparticles for drug delivery are expertly presented by Ting-Yu Liu of National Taiwan University and co-workers.
Evolution of Drug Dosage Forms
The first generation of controlled release systems (programmed drug release) appeared in the 1970s with the aim of prolonging the release of the drug as much as possible, so that this process is the limiting step in the access of the drug to the systemic system. circulation.3,5 Therefore, these drug dosage forms must release the drug according to the rate determined by the design, in a predictable manner and regardless of the patient's condition, in order to achieve constant levels of the drug for a period of time, which reduces the number of administrations. . This causes the concentration of the trigger to decrease and eventually the release of the drug stops.
Advanced Excipients
Later, the integration of biology and biomedical sciences improved the performance of biomaterials, equipping them with the ability to interact effectively with body components, to perceive their changes and to respond in an appropriate way. Furthermore, the use of Figure 1.3 Features to be considered when a polymer is intended to be used in.
Stimuli-responsive Components
Phase Transitions
Transitions can be classified as a function of the number of macromolecules involved in the process, as follows:73. In the isotropic phase, the center of mass is liquid and the rods can take any orientation.
Memorization of the Conformation. Molecular Imprinting and Recognition
In addition to the ten classes of transitions described above, it can happen that a material suddenly changes its chemical nature (eg breaking certain bonds by hydrolysis or oxidation/reduction) and transforms into another material with different groups. "Memorizing" this conformation after swelling the network and washing the template will only be possible if the network will always be able to change to a conformation that can perform its specific function during synthesis ( Fig. This revolutionary idea is the basis of new approaches to the design of imprinted hydrogels and was developed at different levels as discussed in Chapters 21 and 22.
Intelligent Drug-delivery Systems
- pH- and/or Ion-responsive DDSs
- Enzyme-responsive DDSs
- Biochemical-responsive DDSs
- Glutathione-responsive DDSs
- Temperature-responsive DDSs
- Ultrasound-responsive DDSs
- Light-responsive DDSs
- Magnetic-responsive DDSs
- Electric Field-responsive DDSs
The pH gradient that exists in the body under healthy and pathological conditions is one of the more studied internal variables as a stimulus to trigger drug release. Thus, an enzyme-responsive DDS requires at least an enzyme-sensitive component that is a substrate of the enzyme, and the drug may be chemically or physically entrapped in the system.
Conclusions and Future Aspects
The electrical conductivity of the ICPs is due to the uninterrupted and ordered p-conjugated backbone. 183 The ICPs are usually formed on an electrode and can be used in such a way after being loaded with the drug. Materials science and engineering of the low-temperature-sensitive liposome (LTSL): Composition-structure-property relationships underlying its design and.
Introduction
Lipids as ‘‘Smart Materials’’
While we will deal later with the properties of its bilayer assembly, this molecule also has its own properties, such as its water solubility, consisting of the two amphipathic parts. Thermodynamically, then, it is this high head group solubility and extremely low hydrocarbon chain solubility that largely controls the self-assembly of the bilayer in water, i.e.
Micelles, Bilayers and Inverted Micelles
Reverse Engineering the LTSL
- Define the Function
- LTSL Component Design
- Materials Choice and CSP Relationships
- Composition-Structure-Properties of Each Component
- The Solid Phase Encapsulating Membrane
- The Permeabilizing Component
- The Drug
- The Protective Layer
Moreover, because the acyl chains are similar (di C16, mono C18, di C18), they are ideally miscible in the solid phase and do not really extend the phase transition of the bilayer. Each component will now be discussed in the context of the CSP relationships that are part of the LTSL design.
Production
As is now well established, the presence of just a few mol% PEG lipid in a bilayer provides a steric repulsion due to the extension of PEG from the bilayer surface. The structure of the PEG molecule at the interface depends on its surface density, as is well described by several theoretical and experimental studies53,90,91 Basically, the surface density of DSPE-PEG2000 in a lipid bilayer should be B5 mol% relative to to the host lipid to form a complete coverage of touching ``sponges''.
Performance-in-Service
Performance-in-Service: in vitro
- Carboxyfluoroscene Release
- Dithionite Permeability
- Doxorubicin Release
- Drug Release Mechanism
In the absence of MSPC, a DPPC: DSPE-PEG2000 (in which DSPE-PEG2000 was increased from 2 mol% to 20 mol%) released only 20% doxorubicin at the lipid phase transition, which was probably due to membrane-bound doxorubicin (Figure 2.16) . A). With MSPC and DSPE-PEG2000 in the bilayer, as shown in Figure 2.17B, the bilayer in the phase transition region gains enhanced permeability through a putative MSPC pore.
Performance-in-Service: in vivo (Preclinical)
- First Preclinical Data
- MRI Contrast Data
- Effect of Drug Release on Tumor Vasculature
- Other Tumors
- Triggered, Intravascular Release to Improve Drug Penetration into Tumors
During this time, the plasma concentration of Dox-LTSL decreases somewhat before the transition temperature in the tumor is reached. As shown in Figure 2.18, real-time confocal imaging of doxorubicin delivery to the FaDu xenograft in window chambers and histological analysis of flank tumors illustrate that intravascular drug release increases the amount of free drug in the interstitial space.
Performance-in-Service: in vivo (Canine and Human Clinical Trials)
- Phase I Studies: Canine
- Phase I Studies: Human
- Phase III Studies: HepatoCellular Carcinoma (HEAT)
- Phase I/II Trial Breast Cancer Recurrence at the Chest Wall (RCW) (DIGNITY Study)
- Phase II Colorectal Liver Metastases ABLATE
Primary liver cancer is one of the deadliest forms of cancer and is the fifth most common solid tumor. The objective of the phase I study was to determine the maximum tolerated dose (MTD) of ThermoDoxs when used in combination with radiofrequency ablation (RFA) in the treatment of primary and metastatic liver tumors.111,112 As reported by Poonet al.113a a total of 24 patients (9 with HCC and 15 with metastatic liver cancer (MLC)) were treated with a dose of 60 mg/m2 and 60 mg/m2, respectively).
Future Prospects
New ThermoDox s Trials and Preclinical Studies
In addition to the trials reviewed above, HCC (HEAT), RCW (DIGNITY), and CRLM (ABLATE), new research and preclinical development has begun in bone metastases, pancreatic cancer, and metastatic liver cancer. This is a joint development program for Celsion's ThermoDoxs combined with Philips' Sonalleve MR-HIFU (MR-guided high intensity focused ultrasound) technology for the relief of painful bone metastases caused by lung, prostate or breast cancer.
Other Drugs
As always, controlling the triggered release of the encapsulated drug to increase the bioavailability of the drug exclusively at the diseased site has always been one of the biggest challenges.123 In the Stealths liposomal formulation (SPI-077), minimal clinical efficacy despite sufficient tumor accumulation was observed.124–126 This means , that measures to establish adequate drug loading, circulating half-life, drug retention in the bloodstream, and passive tumor accumulation resulted in excessive retention of cisplatin in the liposome so that it was not significantly released to the tumor site. Again, both sides of the same coin trade off each other - good retention to reduce toxicity vs. not using the drug, leading to reduced efficacy.
Other New Thermal-sensitive Formulations (Lipids and Polymers)
It is expected that such membrane-impermeable drugs, if well maintained, in an LTSL formulation will prove to be an advantage, as drugs such as cisplatin, when entrapped in secreted liposomes, proved to be less effective than the free drug. In other studies, temperature-sensitive liposomes have been designed using temperature-sensitive polymers: Hayashi et al.130 studied temperature-sensitive liposomes composed of different phospholipids and coated with poly(N-isopropylacrylamide) showing a transition temperature near 321C;.
Concluding Remarks
The Drug-delivery Problem
Kono et al.131 also used polymers consisting of dioleoylphosphatidylethanolamine modified with copolymers of N-isopropylacrylamide and N-acryloylpyrrolidine; and Paasonen et al.132 reported polymer-coated liposomes with thermosensitive poly[N-(2-hydroxypropyl) methacrylamide mono/dilactate] (pHPMA mono/dilactate) having a Tm at 421C. Thus, several new studies have introduced the idea of modifications of the liposome bilayer composition or surface with temperature-sensitive polymers that retain the temperature-triggered release from the liposome.
A New Paradigm for Local Drug Delivery: Drug Release in the Bloodstream
What the LTSL formulation has shown is that compared to either free drug delivery or the EPR effect required by the more traditional non-thermally sensitive liposomes (Doxilt), intravascular drug release improves drug penetration and accumulation levels that not only reach more tumor cells, but also stroma, endothelial cells and pericytes. Thus, our studies so far have introduced and characterized the liposomal system and have established the fundamental relationships between compositions, structure, properties, processing and performance of the three main components. In preclinical studies, we have found that this unique formulation offers a more effective way to achieve targeted, local release of drugs for cancer chemotherapy than more traditional and even stealth liposomes.16,45 Indeed, it offers a new paradigm for drug delivery, drug release into the bloodstream and an antivascular as well as antineoplastic mechanism of tumor killing. 17.
New Horizons
Celsion Corporation, Dose escalation, pharmacokinetics and safety study of doxorubicin encapsulated in temperature-sensitive liposomes released via microwave therapy in the treatment of prostate cancer, NCT. Celsion Corporation, Phase 1/2 Study of ThermoDox with Hyperthermia Approved in the Treatment of Chest Wall Recurrence of Breast Cancer (DIGNITY), NCT.
Introduction
These lipids have negatively charged groups, which become neutral in the acidic environment of the endosome, leading to destabilization, fusion with the endosomal membrane, and release of contents. 12. Although stable in plasma, the application of pH-sensitive liposomes is limited by recognition and sequestration by reticulo-endothelial system (RES) phagocytes, leading to very short circulation half-lives.
pH-sensitive liposomes are stable at physiological pH (pH 7.4), but undergo destabilization and acquire fusogenic properties under acidic conditions, thus leading to the release of their water content. Further, antibodies or ligands for cell surface receptors can be conjugated to pH-sensitive or sterically stabilized pH-sensitive liposomes for active targeting.
Uptake and Intra-cellular Delivery of Therapeutic Agents from pH-sensitive Liposomes
Studies performed with high molecular weight proteins (eg, DTA and BSA) indicated that only 0.01–10% of the molecules are released into the cytoplasm, in contrast to nearly 100% release observed with the low molecular weight fluorescent probe calcein.27,28.
Therapeutic Applications of pH-sensitive Liposomes
Cancer Chemotherapy
PE was PEGylated using a degradable pH-sensitive hydrazone bond between PE and long protecting PEG chains (PEG(2k)-Hz-PE). Estrone, a bioligand, was anchored on the surface of pH-sensitive liposomes (ES-pH-sensitive-SL) for drug targeting to ERs overexpressed by breast cancer cells.
Gene Delivery
Other reports have also confirmed the importance of fusogenic properties of pH-sensitive liposomal membranes for intracellular gene transfection.43–45. Using pH-sensitive masked liposomes, the peptide was able to reach the nucleus of tumorigenic and non-tumorigenic breast cancer cells.46 In summary, available information demonstrates the utility of pH-sensitive liposomes as an intracellular carrier for bioactive substances.
Tumor Diagnosis
pH-sensitive masked liposomes have been reported to be suitable vectors for targeting therapeutic peptides to the nucleus. 46 Cellular uptake of peptide-loaded liposomes was investigated in human breast carcinoma epithelial cells Hs578t, MDA-MB-231 breast carcinoma cells, and WI -26 human diploid lung fibroblast cells. The difference between the two formulations in terms of peptide delivery from the endosome to the cytoplasm and even to the nucleus was observed as a function of time.
Conclusion
In vitro test with isolated tumor (HepG2) cells and in vivo evaluation in tumor bearing mice confirmed the transfection efficiency. Furthermore, most of the components used for their design have been proven to be safe, which could pave the way for the approval and commercialization of pH-sensitive liposomes.
CHIE KOJIMA
Introduction
Differences in pH and redox state between different tissues and/or subcellular compartments can occur physiologically or pathologically and can be used as self-regulated internal body stimuli. To design stimuli-responsive dendritic polymers, tunable moieties can be incorporated at the terminal groups and/or the core.
Temperature-responsive Dendrimers
- Dendrimers Containing Thermo-sensitive Polymers
- Dendrimers Containing Thermo-sensitive Moieties
- Collagen-mimic Dendrimers
Temperature-sensitive polymers can be attached to the core or terminal groups of dendrimers (Figures 4.2A and 4.2B). The temperature-dependent behavior of collagen is different from that of temperature-sensitive synthetic polymers that have an LCST.
Photoresponsive Dendrimers
- Dendrimers for Photochemical Internalization
- Dendrimers with Photodegradable Moieties
Although DPc showed PDT effects, the cytotoxicity and tumor growth inhibition caused by the combination of DPc and Dox after photoirradiation were higher than those observed for the same system without Dox. In addition, multi-drug resistance (MDR) could be overcome through DPC nanoparticles and photoirradiation.
- Dendrimers Containing pH-responsive Moieties
- Dendrimer Assembly with pH-sensing Moieties
- Drug-dendrimer Conjugates with pH-responsive Linkages
In contrast, at low pH the micelles degraded by cleavage of the acetal group and separation of the hydrophobic phenyl groups from the dendron; as a result, the drug was released.88,89 Recently, Liu et al.90 prepared a complex of cationic PAMAM dendrimer with PEG polyanionic block polymer containing lactic acid by electrostatic interaction. A polylysine dendrimer was modified with a PEG on the alpha-amino group and HSBA-linked Dox on the side chain. In vitro and in vivo tests indicated that the drug action of the dendrimer was similar to that of the PEGylated liposomes containing Dox, but the side effects of the dendrimer were less significant.98 pH-sensitive Dox-dendrimer conjugates were modified with ligands such as biotin and galactose .99,100 Ligand conjugation is useful for active targeting of the pH-sensitive dendrimers.
Redox-responsive Dendritic Polymers
The length of PEG was found to be very important for release profiles and in vitro and in vivo drug action.101,102 These studies illustrate how important the release of drug molecules from a dendrimer is for efficient drug action.
Enzyme-responsive Dendritic Polymers
Consequently, a two-armed dendrimer was the most effective for drug release.112 When heterogeneous enzymatic substrates were attached to dendrimer termini, a molecular. As a result, the encapsulated model drug, pyrene, was released from the dendritic micelles by enzyme activity.114 Thayumanavan's group also reported protein-protein interaction-dependent drug release using dendritic micelles.
Theragnostic Dendrimers
Upon addition of avidin, the dendritic micelles dissociated and the encapsulated model drugs were released.115 These papers indicate that the association-dissociation transition of these micelles is sensitive to enzyme activity and protein absorption.114,115 It is likely that the temperature sensitivity of these dendritic micelles contributed to the controlled release. Kaminskas et al.116 reported drug-conjugated dendrimers via a matrix metalloproteinase (MMP)-degradable bond for MMP-dependent drug release (Figure 4.6B).
Conclusion
ALEJANDRO SOSNIK
Polymeric Micelles
- Micellar Encapsulation
- Preparation Methods
- Physical Stability
The molecular properties of polymeric micelles can be modified to tailor the size of the core and the nature and strength of core-drug interactions. Other procedures may be used to determine the properties of the copolymer and drug.
Temperature-sensitive Polymeric Micelles
- Poly(ethylene Oxide)-Poly(propylene Oxide) and Other Polyether Amphiphiles
- Poly(ethylene Oxide)-Polyester Block Copolymers
- Poly(N-isopropylacrylamide)
- Substitutes of PEG as Hydrophilic Building Block
Depending on the functionality of the initiator (mono-, di- or multifunctional), biomaterials with different architectures have been adapted. Modification of precursors and synthetic routes results in copolymers with different block organization along the backbone.
These systems were further modified by the incorporation of biotin, a ligand exposed on the micellar surface after the acidification of the system and the ionization of the polyamino acid, resulting in the interaction with the correct receptor. In addition, the ionization of poly(histidine) in the nucleus promoted the disassembly of the micellar cells and the disruption of the endosome, enhancing the cytosolic delivery of the drug's payload after uptake.260 Poly(hydroxyethylaspartamide) was another building block used to synthesize pH-responsive amphiphiles. with PEG.261,262 These micelles were found to encapsulate amphotericin B.
Translation into Clinics and Perspectives
A similar carrier was explored to solubilize and stabilize zinc porphyrin for photodynamic therapy.265 Cavallaro et al.266 developed derivatives modified with PEG and hexadecylalkylamine as hydrophilic and hydrophobic pendant moieties for the encapsulation of paclitaxel and amphotericin B. Iberoamerican Network of New Materials for the design of advanced drug delivery systems in diseases with high socio-economic impact".
Introduction
In addition to ultrasound, there are other types of external trigger mechanisms mentioned above 1–3 and several types of passive internal trigger mechanisms such as local pH, 4,5 heat6 or local biochemistry.7 The interested reader is invited to consider these stimuli (discussed in other chapters of this book), especially when comparing the advantages and disadvantages of ultrasound-triggered drug release from micelles. This chapter begins with a description of ultrasound and micelles, then continues with a brief overview of conventional micellar drug delivery and ends with a thorough review of ultrasound-triggered delivery from micelles and a discussion of the physical mechanisms involved.
Ultrasound
- Physics of Ultrasound
- Wave Nature of Ultrasound
- Ultrasonic Heating
- Mechanical Cavitation
- Acoustic Streaming
- Safety
Collapse cavitation occurs at relatively large pressure amplitudes or when the resonance frequency of the bubble is close to the ultrasonic frequency. Needless to say, collapse cavitation is a very violent event, especially in the close vicinity of the collapse event.
Micelles
- Drug Delivery from Micelles
- Traditional Surfactant Micelles
- Polymeric Micelles
- Drug–Polymer Conjugates
- Targeting
- Passive Targeting
- Active Targeting
- Ultrasound-triggered Release from Micelles
- Triggered Release from Micelles in vitro
- Triggered Release to Cells in vitro
- Triggered Release in Animal Models
- Mechanisms of Ultrasonic-Activated Delivery from Micelles
These amphiphilic drugs partition at the interface between the hydrophobic core and the hydrophilic crown of the micelle. It was also found that drug release increases at lower concentrations of Pluronic and decreases as the drug is inserted deeper into the micelle core.
The Future of Ultrasound-triggered Drug Delivery from Micelles
As mentioned, the great advantage of the micellar systems is that they are self-assembling, which makes them inherently stable and does not disintegrate upon long-term storage. Even better, the micelles could be attached directly to the surface of the microbubbles using the same conjugation chemistry used to attach liposomes to microbubbles.179,180 The size of the gas bubbles limits delivery to the lumen of the vascular system, but these assemblages could be targeted to collect on diseased tissues of the circulatory system.
