- September 13, 2022
- By admin
Dose Monitoring device for delivery of thermosensitive dose
TSLs (thermosensitive liposomes) are an important research area in tumour targeted chemotherapy. Many studies have been conducted using this type of liposome since the first TSLs appeared, which used 1,2-dipalmitoyl-sn-glyce-ro-3-phosphocholine (DPPC) as the primary liposomal lipid. While TSLs made of DPPC improve cargo release near the phase transition temperature, many factors influence their temperature sensitivity. As a result, numerous attempts have been made to develop new TSLs in order to improve their thermal response performance.
The primary goal of this review is to introduce the development and recent updates of novel TSL formulations, which include a combination of radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), magnetic resonance imaging (MRI), and alternating magnetic field (AMF) (AMF). Furthermore, various factors influencing TSL design, such as lipid composition, surfactant, size, and serum components, are discussed.
Nanotechnology has emerged as a promising tool for improving drug pharmacokinetic behaviour and enabling passive or active targeting to some extent. Liposomes are currently one of the most thoroughly researched nanoparticle-based drug delivery systems for treating cancer and other diseases. Liposomes have a number of advantages over traditional drug administration methods, including treatment monitoring, diagnosis, and drug delivery. Furthermore, the increased permeability and retention (EPR) effect can increase the accumulation of these drug-loaded liposomes at the tumour site, improving their antitumor activity. Because of these benefits, liposomal encapsulation has significantly reduced the toxicity of various chemotherapeutic drugs to normal tissue, and several liposomes have been approved by the FDA for cancer treatment. The enhanced protective effect of liposomal encapsulation, on the other hand, limits the timely release and uptake of drugs at the tumour site.
The following are the components of thermosensitive liposomes:
Needham et al. created the first TSLs formulation with a Tm just above physiological temperature, resulting in significant drug release caused by phase transitions. The original TSLs were made up of DPPC (Tm= 41.4 °C) alone or in combination with DSPC (Tm range: 42.5-44.5 °C). At high temperatures, the chemotherapeutic drugs encapsulated in TSLs can be released. As a result, TSLs are primarily determined by thermosensitive materials.
3.1 Lysolipids:
The main molecular components used in the development of TSLs are lysolipids. It is hypothesised that adding small amounts of lyso-lipids (such as 10% 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSCP)) to DPPC liposomes helps to stabilise pores in the lipid bilayer as it transitions from gel to liquid and increases the drug release rate of DPPC liposomes at 39-42 °C. The incorporation of lysolipids such as monopalmitoylphosphatidylcholine (MPPC) into TSL formulations speeds up the drug cargo’s release under mild hyperthermia (40-42 °C).
Arsenic release from pure DPPC liposomes is comparable at 37 °C and 42 °C, indicating that the presence of lysolipid is required for a significant increase in release rate. After rapidly heating the liposomes to 42 °C, both the TSLs containing 5 mol% and 10 mol% MPPC released a large amount of arsenic within the first hour. The drug release rate of pure DPPC TSLs, on the other hand, remained nearly unchanged, indicating that the presence of lysolipids is required to significantly increase the drug release rate. Hexadecylphosphocholine (HePC) has a similar structure to lysolipid, which has a slower metabolism and a high accumulation in tumours and other tissues. Lindner et al. investigated whether HePC was as effective as lysolipids in speeding up the content release rate of TSLs based on dipalmitoyl-sn-glycero-3-phospho-glyceroglycerol (DPPGOG). HePC, like lysolipids, increases the rate of TSL release as expected. TSLs based on HePC incorporation also demonstrated cytotoxicity in a thermally induced manner. The phase transition temperature of the liposome can be controlled by adjusting the ratio of the compound phospholipid, which can improve liposome stability at 37 °C and reduce drug loaded liposome leakage before reaching the target organ.
3.2. Elastin-like polypeptides:
Aside from elastin-like recombinamers, several classes of recombinant polymers, such as collagen-like peptide, are used as responsive components in the thermo-responsive self-assembly of well-defined nanovesicles. Park et al. optimised the composition of elastin-like polypeptide (ELP)-TSLs, in which cholesterol serves as a membrane stabiliser and ELP serves as a heat-activated moiety to the liposome. The optimal formulation for stable blood circulation and effective drug release under mild hyperthermia was a liposome composed of DPPC/DSPE-PEG/cholesterol/ELP (55/2/15/0.41, molar ratio) for stable blood circulation and effective drug release under mild hyperthermia.
3.3. Surfactants:
Polyoxyethylene (20) stearyl ether (Brij78) is a non-ionic surfactant made up of PEGylated acyl chains that can be used to replace the functions of DSPE-mPEG2000 in PEGylated phospholipids, reducing opsonization and improving pharmacokinetics. Tatsuaki et al. created a TSLs formulation with DPPC and Brij78 in a 96:4 molar ratio and compared its drug release rate to TSLs containing lysolipids (DPPC: MSPC: DSPE-mPEG2000 = 86:10:4, molar ratio). The results revealed that, when compared to lysolipid-TSLs, the novel TSLs formulation had a higher drug release rate at 40-41 °C and comparable stability at 37-38 °C. Tagamii et al. inserted 16 mol% Brij78 to improve DOX release kinetics (100% drug release in 15-40 s at 40-42 °C), while maintaining stability at 37 °C with only 5% drug loss in 30 min. Brij78, on the other hand, could only be accommodated to a limited extent by the lipid membrane. Incubating preformed Cu-TSLs with 24 mol% Brij78, for example, reduced bilayer stability, caused significant drug loss (> 20%), and resulted in an unstable formulation. Tagami et al. found that calcein released faster at 42 °C than at 37 °C after incorporating Poloxamer 188 (P188) into DPPC liposomes.
The mechanism is that the critical micelle concentration (CMC) of P188 converted from monomers to micelles is extremely temperature sensitive, with small changes in temperature changing the CMC by several orders of magnitude. As a result, P188/DPPC may release calcein at 42 °C. P188 also protects injured cells and tissues and shows promise for medical applications. Zeng et al. used oxaliplatin (OXP) as a model drug and added poloxamer to the TSLs formulation. The results showed that OXP-TSLs had the best body temperature stability and the fastest release at the trigger temperature. In conclusion, DPPC/P188 liposomes show advantages both in vitro and in vivo, and hold great promise for future cancer treatment.
4. Influence of serum components on TSLs:
Plasma opsonin proteins, lipoproteins, and other proteins would like to interact with liposomes after parenteral administration. The mononuclear macrophage system would recognise liposomes with different serum components, causing the liposomes to be degraded. Hossann et al. investigated the effect of blood components and developed four different TSLs. They loaded calcein (CF) into the TSLs using a thin film dispersion method as a marker for fluorescence spectrum detection. The results demonstrated that the release of CF in normal saline or low molecular weight serum is low; however, the serum component of polymer can increase the membrane permeability of tumour cells, which is beneficial to increasing the rate of heat sensitive drug release.
Human serum protein (HSA) can significantly increase the rate of CF release at the Tm of lipid, while it can improve the stability of the membrane bilayer below Tm. Immunoglobulin G (IgG) can only increase the rate of CF release in anion sensitive liposomes, and the effect is negligible. Cholesterol is a necessary component of serum and can be exchanged from the vesicles to the liposome membrane, altering membrane permeability and improving CF release. Because serum proteins cannot bind to the water gathered on the surface of the liposomes, the PEG chains on the surface of the liposomes reduced the adsorption of opsonizing proteins as their water binding ability increased.
5. Influences of size on TSLs:
Tm determination alone is insufficient for predicting drug release from TSLs. It is well known that vesicle size can affect drug release rate, pharmacokinetic parameters, and therapeutic efficacy of liposomes by decreasing clearance by organs of the mononuclear phagocyte system. Because of the increased specific surface area, smaller particles have a higher rate of drug release. Hossann et al. investigated the effect of vesicle size (50-200 nm) on TSL intravenous application and discovered that the Tm of the lipid bilayer was unaffected by vesicle size within the test range. However, at temperatures ranging from 30 to 45 °C, vesicle size has a significant effect on the in vitro release characteristics of TSLs. In general, the vesicle size is inversely proportional to the release properties of the content. The rate of content release increases as the vesicle size decreases. The size dependence of the content release from TSLs containing 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG2) is generally less affected in the range of 100-150 nm when compared to TSLs containing lysolipids.
In addition to gadodiamide release, vesicle size influenced the signal intensity of DPPG2-containing TSLs at temperatures below Tm due to improved water exchange in smaller vesicles. Liposomes with diameters of 100 nm are routinely used in vivo, so TSL preparations must undergo quality control before use. Even minor changes in size or a wider size distribution may affect the stability and release properties of drug-loaded TSLs during in vivo applications, resulting in decreased efficacy or unwanted side effects. DOX-loaded liposomes with ammonium sulphate as the interior buffer did not release DOX at 42 °C, whereas citric acid-loaded liposomes released DOX as quickly as calcein-loaded liposomes. As a result, Tagami et al. hypothesised that gelation might inhibit drug release from DPPC/poloxamer 188 hybrid TSLs containing ammonium sulphate.
7. Final Thoughts:
Early TSLs are primarily composed of lipids capable of undergoing gel-liquid phase transitions at response temperatures, such as DPPC with a Tc of 41 °C. Because pure DPPC liposomes invariably result in incomplete drug release, other phospholipids such as DSPC and HSPC are typically added to increase the rate of drug release. However, the Tc of the liposome is also increased to 43-45 °C, necessitating higher thermal doses to trigger drug release, which may result in necrosis of normal tissues surrounding the tumour.
The addition of lysolipids was proposed in subsequent efforts to improve the thermal response sensitivity of conventional TSLs. Incorporating 10% MPPS into PEGylated TSLs could lower the Tc to 39-40 °C and accelerate drug release upon mild heating. However, numerous studies have shown that lysolipids can be easily desorbed from the lipid bilayer to neutralise TSL stability and thermal sensitivity. As an alternative, combining TSLs with external energy sources for local thermally induced drug release has shown great promise for improving intratumoral drug concentrations, and the method’s efficacy and potential side effects are currently being studied in clinical trials. TSLs, in combination with regional hyperthermia or high-intensity focused ultrasound and other heat means, are a promising tool in the clinical setting for targeted and triggered drug delivery to solid tumours, as well as achieving controllable drug release. The current state of development for a wide range of TSLs represents a step toward the design of nanocarriers with dramatically improved efficiency. This review adds to our understanding of TSL functional properties and suggests additional strategies for improving TSL formulation design.