Search

Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Mobius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4+ and CD8+T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.

Due to the circadian rhythm regulation of almost every biological process in the human body, physiological and biochemical conditions vary considerably over the course of a 24-h period. Thus, optimal drug delivery and therapy should be effectively controlled to achieve the desired therapeutic plasma concentrations and therapeutic drug responses at the required time according to chronopharmacological concepts, rather than continuous maintenance of constant drug concentrations for an extended time period. For many drugs, it is not always necessary to constantly deliver a drug into the human body under disease conditions due to rhythmic variations. Pulsatile drug delivery systems (PDDSs) have been receiving more attention in pharmaceutical development by providing a predetermined lag period, followed by a fast or rate-controlled drug release after application. PDDSs are characterized by a programmed drug release, which may release a drug at repeatable pulses to match the biological and clinical needs of a given disease therapy. This review article focuses on thermoresponsive gating membranes embedded with liquid crystals (LCs) for transdermal drug delivery using PDDS technology. In addition, the principal rationale and the advanced approaches for the use of PDDSs, the marketed products of chronotherapeutic DDSs with pulsatile function designed by various PDDS technologies, pulsatile drug delivery designed with thermoresponsive polymers, challenges and opportunities of transdermal drug delivery, and novel approaches of LC systems for drug delivery are reviewed and discussed. A brief overview of all academic research articles concerning single LC- or binary LC-embedded thermoresponsive membranes with a switchable on-off permeation function through topical application by an external temperature control, which may modulate the dosing interval and administration time according to the therapeutic needs of the human body, is also compiled and presented. In the near future, since thermal-based approaches have become a well-accepted method to enhance transdermal delivery of different water-soluble drugs and macromolecules, a combination of the thermal-assisted approach with thermoresponsive LCs membranes will have the potential to improve PDDS applications but still poses a great challenge.

A liquid crystal (cholesteryl oleyl carbonate, COC)-embedded membrane with a controlled rate and higher reversibly thermo-responsive function was successfully fabricated by the vacuum filtration method. The aim of this study was to investigate the effect of the pH of aqueous solutions and gel preparations on the penetration of salbutamol sulfate through this thermo-responsive COC-embedded membrane. The results indicate that the on-off switching penetration behavior of salbutamol sulfate through the COC-embedded membrane in response to a repeatedly exchanging temperature cycle (10 25 degreesC) is not influenced by the pH of the medium. However, the pH-dependent ionization of salbutamol and the viscosity of the gel base, as well as the interaction between salbutamol and carbopol, might change the amount and the rate of salbutamol sulfate that penetrates across this COC-embedded membrane.

Cholesteryl oleyl carbonate (COC) was embedded in a cellulose nitrate membrane for the purpose of developing a drug delivery system with a thermal stimulus response. The thermophysical properties of COC were determined by thermal analysis and microscopic Fourier transform infrared spectroscopy with differential scanning calorimetry (Micro FTIR-DSC) to confirm its thermo-responsive property. The COC-embedded membrane was prepared by filtrating a certain amount of COC chloroform solution through the cellulose nitrate membrane using a vacuum filtration method. The thermo-responsive functions of COC-embedded membranes were investigated using a step-wise temperature change between 10°C and 25°C (below and above the gel-liquid crystal phase transition temperature of COC). The results indicate that the amount of COC adsorbed increased linearly with the increase of the COC concentration used. The permeation rate of salbutamol sulfate through the COC-embedded membrane was controlled by the amount of COC absorbed in the cellulose nitrate membrane, which could be confirmed by the observations of scanning electron microscopy (SEM) and contact angle measurements. The permeation of salbutamol sulfate through the membrane could be sensitively controlled by temperature changes. This implies the COC-embedded membrane may be used as a thermally on-off switching membrane for a stimuli-response controlled drug delivery system.

In order to design a self-adhesive drug-loaded film for transdermal application of drugs, piroxicam was used as a model drug and triacetin-plasticized Eudragit E was chosen as a film-forming material. In a previous study, we had examined the effect of secondary plasticizers on the mechanical properties and adhesion strength of drug-free Eudragit E film [1]. In the present study, piroxicam did not serve as a simple model drug, but acted as an additive by molecularly dispersing it in the Eudragit E film. The effect of piroxicam on the mechanical properties, adhesion strength and release kinetics of piroxicam-loaded Eudragit E films plasticized with four secondary plasticizers (polyethylene glycol 200, propylene glycol, diethyl phthalate and oleic acid) was investigated. The results indicated that piroxicam was compatible with Eudragit E. A yellowish, transparent film was formed. The tensile strength decreased but the elongation increased with the increase in plasticizer concentration v.hether Eudragit E film contained piroxicam or not, suggesting the plasticizing efficiency of the plasticizer added. It was also found that the tensile strength of the piroxicam-loaded film was significantly higher and the elongation significantly tower than that of the drug-free film. The drug-polymer interaction between piroxicam and Eudragit E film by intermolecular hydrogen bonding might be responsible for this result. The adhesion strength of the piroxicam-loaded film without secondary plasticizer was significantly lower, but this adhesion strength increased again with the plasticizer concentration. The tendency of the adhesive strength of these piroxicam-loaded films to increase whether plasticized with hydrophilic or hydrophobic plasticizers, was similar, This might be attributed to the decrease in the aggregate force caused by the intermolecular attraction of the polymer, resulting in an increase of the adhesive strength of the film. Piroxicam released from the Eudragit E film with or without secondary plasticizer was mainly dependent on the amount of drug-loaded and showed a rate-controlled release behaviour. The release behaviour of piroxicam from the film can be described by a Higuchi equation for matrix controlled release. All the results demonstrate that the release rate of piroxicam from film clearly increases with the amount of drug-loaded but is only slightly enhanced by the increasing the plasticizer concentration. The release rate of piroxicam from four different films whether plasticized with hydrophilic or Hydrophobic plasticizer was almost the same. The drug-polymer interaction occurring between piroxicam and Eudragit E seems to cause a drag effect, leading to a delay of the piroxicam release from the Eudragit E film.

The curing kinetics of silicone elastomer was investigated using a newly developed method of microscopic Fourier transform infrared (micro FT-IR) spectroscopy equipped with differential scanning calorimetry (DSC). The change in IR peak intensity of Si-H at 2162 cm−1 for the curing agent acted as a marker. The curing temperature and normal hydrocarbon alcohols significantly influenced the curing process of silicone elastomer, in which the curing reaction might be described by first-order kinetics. The length of the alkyl chain or the solubility parameter of normal hydrocarbon alcohols was supposed to be a predominant factor in the curing kinetics of silicone ealstomer. The higher the curing temperature, the faster was the curing reaction. Greater alkyl chain length or a lower solubility parameter of hydrocarbon alcohols might also result in a slower curing reaction of silicone elastomer.