Triggered Drug Delivery Systems Research Articles

Zeolitic Imidazolate Frameworks Based Anticancer Drug Delivery System Associated with Dual Action of Surface Charge and Lewis Base Ligand

AbstractZeolitic imidazole frameworks (ZIFs), which combine the favorable characteristics of tunable porosity, controlled structure, and facile functionalization, are explored as a novel class of nanocarriers for biomedical applications. In this study, different ZIF materials are investigated, including ZIF‐8, ZIF‐67, ZIF‐90, ZIF‐92, and ZIF‐108, with the same sodalite topology as the adenosine‐5′‐triphosphate (ATP)‐triggered drug delivery systems. Results indicated that ZIF‐90 and ZIF‐108 displayed good biological compatibility and efficiently accumulated in the mitochondria through competitive coordination between the metal nodes of the ZIFs and ATP, suggesting efficient intracellular delivery. With further interactions between these metal ions and ATP, the encapsulated drugs are released from the ZIF nanoparticles, thereby achieving optimal anti‐tumor activity. Through a systematic evaluation of the physicochemical properties of different ZIFs, it demonstrates that the surface charges of ZIFs have a significant impact on the cytotoxicity of cells, whereas the Lewis basicity of imidazole‐based ligands plays an essential role in the competitive coordination between the metal ions and ATP. These findings provide a potential method for screening ZIFs based nanocarriers with minimal toxicity and explain the different delivery efficiencies of these materials with similar topologies.

Exploring Film Forming Ability of Newly Synthesized Rosin Esters

The present investigation was planned to confirm the film-forming potential of synthesized rosin esters. The free films of rosin esters were prepared by solvent evaporation and characterized for the physicochemical and mechanical attributes. Suitable concentrations of rosin esters were used for coating tablets, and coated tablets were evaluated for official and unofficial quality control tests. The free films had low tensile strength, higher percent elongation value, and smooth surfaces. Therefore, the plasticizer was used to provide tensile strength to the films. The tablets were coated rapidly without agglomeration, confirming the suitability of rosin esters as a coating agent. The drug release from tablets was delayed up to 6 to 8 hours because of 10% w/w coating of rosin ester, and regioselectivity was achieved by coating with hydroxypropyl methylcellulose with sodium bicarbonate. The pH-dependent solubility of rosin esters produces chrono-triggered drug release from coated tablets. The present investigation confirms the suitability of newly synthesized rosin esters in in designing a region selective chrono- triggered drug delivery system.

Synthesis and Antimicrobial Activity Assay of Nanometal Oxide-Doped Liquid Crystal

The spread of infectious diseases across the globe as a result of numerous bacterial and fungal variations has become a serious threat to human life. A critical global situation is the need to search for antibiotic resistance and develop new treatments. The most crucial role is for academics to advise the pharmaceutical industry about substances with antimicrobial assessments. One of the challenges in implementing novel medicine delivery is the discovery of compounds having antibacterial and antifungal characteristics against Gram-positive and Gram-negative bacteria and fungi. The superiority of the metal oxide-doped liquid crystal technology for antibiotic resistance is revealed. In this work, a bacterially triggered drug delivery system using a nanometal oxide-doped lipid-based liquid crystal system was explored. Copper oxide (CU) and cholesteryl stearate (CS) are processed using ultrasonication to produce the complex chemical in powder form (CSCU). Functional groups are predicted by Fourier transform infrared (FTIR) analyses, while surface appearance and dimensions that support the compound CSCU’s biological characteristics are revealed by scanning electron microscope (SEM) and transmission electron microscope (TEM) analyses. Using the agar-well diffusion method, this substance was tested for antibacterial and antifungal activities against the Gram-positive bacteria Streptococcus pyogenes at various concentrations ranging from 0.6 to 1.25 µg/ml. Additionally, this substance exhibits a range of moderate to good antifungal efficacy against Aspergillus niger.

Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons.

Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.

Review of the Delivery Kinetics of Thermosensitive Liposomes.

Thermosensitive liposomes (TSL) are triggered nanoparticles that release the encapsulated drug in response to hyperthermia. Combined with localized hyperthermia, TSL enabled loco-regional drug delivery to tumors with reduced systemic toxicities. More recent TSL formulations are based on intravascular triggered release, where drug release occurs within the microvasculature. Thus, this delivery strategy does not require enhanced permeability and retention (EPR). Compared to traditional nanoparticle drug delivery systems based on EPR with passive or active tumor targeting (typically <5%ID/g tumor), TSL can achieve superior tumor drug uptake (>10%ID/g tumor). Numerous TSL formulations have been combined with various drugs and hyperthermia devices in preclinical and clinical studies over the last four decades. Here, we review how the properties of TSL dictate delivery and discuss the advantages of rapid drug release from TSL. We show the benefits of selecting a drug with rapid extraction by tissue, and with quick cellular uptake. Furthermore, the optimal characteristics of hyperthermia devices are reviewed, and impact of tumor biology and cancer cell characteristics are discussed. Thus, this review provides guidelines on how to improve drug delivery with TSL by optimizing the combination of TSL, drug, and hyperthermia method. Many of the concepts discussed are applicable to a variety of other triggered drug delivery systems.

Selecting ideal drugs for encapsulation in thermosensitive liposomes and other triggered nanoparticles

Objective Thermosensitive liposomes (TSL) and other triggered drug delivery systems (DDS) are promising therapeutic strategies for targeted drug delivery. However, successful designs with candidate drugs depend on many variables, including nanoparticle formulation, drug properties, and cancer cell properties. We developed a computational model based on experimental data to predict the potential efficacies of drugs when used with triggered DDS, such as TSL. Methods A computer model based on the Krogh cylinder was developed to predict uptake and cell survival with four anthracyclines when delivered by intravascular triggered DDS (e.g., TSL): doxorubicin (DOX), idarubicin (IDA), pirarubicin (PIR), and aclarubicin (ACLA). We simulated three tumor types derived from SVR angiosarcoma, LLC lung cancer, or SCC-1 oral carcinoma cells. In vitro cellular drug uptake and cytotoxicity data were obtained experimentally and incorporated into the model. Results For all three cell lines, ACLA and IDA had the fastest cell uptake, with slower uptake for DOX and PIR. Cytotoxicity was highest for IDA and lowest for ACLA. The computer model predicted the highest tumor drug uptake for ACLA and IDA, resulting from their rapid cell uptake. Overall, IDA was most effective and produced the lowest tumor survival fraction, with DOX being the second best. Perivascular drug penetration was reduced for drugs with rapid cell uptake, potentially limiting delivery to cancer cells distant from the vasculature. Conclusion Combining simple in vitro experiments with a computer model could provide a powerful screening tool to evaluate the potential efficacy of candidate investigative drugs preceding TSL encapsulation and in vivo studies.

Triggered azobenzene-based prodrugs and drug delivery systems.

Azobenzene-based molecules show unique trans-cis isomerization upon ultraviolet light irradiation, which induce the change of polarity, crystallinity, stability, and binding affinity with pharmacological target. Moreover, azobenzene is the substrate of azoreductase that is often overexpressed in many pathological sites, e.g. hypoxic solid tumor. Therefore, azobenzene can be a multifunctional molecule in material science, pharmaceutical science and biomedicine because of its sensitivity to light, hypoxia and certain enzymes, hence showing potential application in site-specific smart therapy. Herein we focus on the employment of azobenzene and its derivatives for engineering triggered prodrugs and drug delivery systems, and provide an overview of photoswitchable azo-based prodrugs, the associated problems regarding the reversible isomerization and tissue penetration of ultraviolet (UV) light, as well as the potential solutions. We also present the advance of azo-bearing delivery vehicles wherein azobenzene acts as the linker, capping agent, and building block, and discuss the corresponding mechanisms for controlled cargo release, endocytosis enhancement and sensitization of free radical cancer therapy.

Drug transport kinetics of intravascular triggered drug delivery systems

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.

UVA-Triggered Drug Release and Photo-Protection of Skin.

Light has attracted special attention as a stimulus for triggered drug delivery systems (DDS) due to its intrinsic features of being spatially and temporally tunable. Ultraviolet A (UVA) radiation has recently been used as a source of external light stimuli to control the release of drugs using a “switch on- switch off” procedure. This review discusses the promising potential of UVA radiation as the light source of choice for photo-controlled drug release from a range of photo-responsive and photolabile nanostructures via photo-isomerization, photo-cleavage, photo-crosslinking, and photo-induced rearrangement. In addition to its clinical use, we will also provide here an overview of the recent UVA-responsive drug release approaches that are developed for phototherapy and skin photoprotection.

Ultrasound-Mediated Drug Delivery in Cancer Therapy: A Review.

The use of ultrasound as a medical diagnostic tool began in the 1940s. Ever since, the medical applications of ultrasound have included imaging, tumor ablation, and lithotripsy; however, an ever-increasing body of literature demonstrates that ultrasound has potential in other medical applications, including targeted drug delivery. Site-specific drug delivery involves delivering drugs to diseased areas with a high degree of precision, which is particularly advantageous in cancer treatment as it would minimize the adverse side effects experienced by patients. This review addresses the ability of ultrasound to induce localized and controlled drug release from nanocarriers, namely micelles and liposomes, utilizing thermal and/or mechanical effects. The interactions of ultrasound with micelles and liposomes, the effects of the lipid composition, and ultrasound parameters on the release of encapsulated drugs are discussed. In addition, a survey of the literature detailing some in vitro and in vivo ultrasound triggered drug delivery systems is presented.

LCST polymers: Thermoresponsive nanostructured assemblies towards bioapplications

Thermoresponsive polymers constitute an important class of materials for biomedical application due to their thermally reversible coil-to-globule transition which can be exploited in a multitude of biomedical applications spanning from triggered drug delivery systems in the form of bulk hydrogels and nanoparticles, “smart” cell culture setups, sensors and actuators, and separation technologies. In this perspective article we present the basic physicochemical properties of poly (N-isopropylacrylamide) (PNIPAM), which is the most widely studied thermoresponsive polymer with a lower critical solution temperature. We describe the basic thermodynamic and physicochemical parameters that affect the LCST and present selective applications that utilize thermoresponsive polymers in the form of nano-assemblies including micelles, polymersomes, microcapsules and microgels, as well as injectable hydrogels for biomedical applications.

Dual stimuli-responsive chitosan grafted poly(NIPAM-co-AAc)/poly(vinyl alcohol) hydrogels for drug delivery applications

Herein, we synthesized poly(vinyl alcohol) (PVA) decorated chitosan grafted poly(NIPAM-co-AAc) hydrogels through free-radical copolymerization. Increased PVA concentration revealed enhancement of temperature and pH sensitivity of the hydrogel by changing the porous structure and surface properties. Further, in vitro drug delivery studies carried out with a model dye revealed a six-fold increased release of the content at pH 7.4 with respect to pH 4.4. This new combination of three component hydrogels could be effectively used as an alternative material in the development of stimuli triggered drug delivery systems that are stable at tissues and organs with a low pH environment.

Tumor-targeted Drug Delivery by Nanocomposites.

Tumor-targeted delivery by nanoparticles is a great achievement towards the use of highly effective drug at very low doses. The conventional development of tumor-targeted delivery by nanoparticles is based on enhanced permeability and retention (EPR) effect and endocytosis based on receptor-mediated are very demanding due to the biological and natural complications of tumors as well as the restrictions on the design of the accurate nanoparticle delivery systems. Different tumor environment stimuli are responsible for triggered multistage drug delivery systems (MSDDS) for tumor therapy and imaging. Physicochemical properties, such as size, hydrophobicity and potential transform by MSDDS because of the physiological blood circulation different, intracellular tumor environment. This system accomplishes tumor penetration, cellular uptake improved, discharge of drugs on accurate time, and endosomal discharge. Maximum drug delivery by MSDDS mechanism to target therapeutic cells and also tumor tissues and sub cellular organism. Poorly soluble compounds and bioavailability issues have been faced by pharmaceutical industries, which are resolved by nanoparticle formulation. In our review, we illustrate different types of triggered moods and stimuli of the tumor environment, which help in smart multistage drug delivery systems by nanoparticles, basically a multi-stimuli sensitive delivery system, and elaborate their function, effects, and diagnosis.

Novel 3D printed device with integrated macroscale magnetic field triggerable anti-cancer drug delivery system

With the growing demand for personalized medicine and medical devices, the impact of on-demand triggerable (e.g., via magnetic fields) drug delivery systems increased significantly in recent years. The three-dimensional (3D) printing technology has already been applied in the development of personalized dosage forms because of its high-precision and accurate manufacturing ability. In this study, a novel magnetically triggerable drug delivery device composed of a magnetic polydimethylsiloxane (PDMS) sponge cylinder and a 3D printed reservoir was designed, fabricated and characterized. This system can realize a switch between “on” and “off” state easily through the application of different magnetic fields and from different directions. Active and repeatable control of the localized drug release could be achieved by the utilization of magnetic fields to this device due to the shrinking extent of the macro-porous magnetic sponge inside. The switching “on” state of drug-releasing could be realized by the magnetic bar contacted with the side part of the device because the times at which 50%, 80% and 90% (w/w) of the drug were dissolved are observed to be 20, 55 and 140 min, respectively. In contrast, the switching “off” state of drug-releasing could be realized by the magnetic bar placed at the bottom of the device as only 10% (w/w) of the drug could be released within 12 h. An anti-cancer substance, 5-fluorouracil (FLU), was used as the model drug to illustrate the drug release behaviour of the device under different strengths of magnetic fields applied. In vitro cell culture studies also demonstrated that the stronger the magnetic field applied, the higher the drug release from the deformed PDMS sponge cylinder and thus more obvious inhibition effects on Trex cell growth. All results confirmed that the device can provide a safe, long-term, triggerable and reutilizable way for localized disease treatment such as cancer.

A near infrared light-triggerable modular formulation for the delivery of small biomolecules

BackgroundExternally triggered drug delivery systems hold considerable promise for improving the treatment of many diseases, in particular, diseases where the spatial–temporal release of the drug is critical to maximize their biological effect whilst minimizing undesirable, off-target, side effects.ResultsHerein, we developed a light-triggerable formulation that takes advantage of host–guest chemistry to complex drugs functionalized with a guest molecule and release it after exposure to near infrared (NIR) light due to the disruption of the non-covalent host–guest interactions. The system is composed by a gold nanorod (AuNR), which generates plasmonic heat after exposure to NIR, a thin layer of hyaluronic acid immobilized to the AuNR upon functionalization with a macrocycle, cucurbit[6]uril (CB[6]), and a drug functionalized with a guest molecule that interacts with the macrocycle. For proof of concept, we have used this formulation for the intracellular release of a derivative of retinoic acid (RA), a molecule known to play a key role in tissue development and homeostasis as well as during cancer treatment. We showed that the formulation was able to conjugate approximately 65 μg of RA derivative per mg of CB[6] @AuNR and released it within a few minutes after exposure to a NIR laser. Importantly, the bioactivity of RA released from the formulation was demonstrated in a reporter cell line expressing luciferase under the control of the RA receptor.ConclusionsThis NIR light-triggered supramolecular-based modular platform holds great promise for theranostic applications.

Preparation of docetaxel-loaded nanomicelles and their anti-Lewis lung cancer effect in vitro

Docetaxel-loaded nanomicelles were prepared in this study to improve the solubility and tumor targeting effect of docetaxel(DTX),and further evaluate their anticancer effects in vitro. PBAE-DTX nanomicelles were prepared by film-hydration method with amphiphilic block copolymer polyethyleneglycol methoxy-polylactide(PELA) and pH sensitive triblock copolymer polyethyleneglycol methoxy-polylactide-poly-β-aminoester(PBAE) were used respectively to prepare PELA-DTX nanomicelles and PBAE-DTX nanomicelles. The nanomicelles were characterized by physicochemical properties and the activity of mice Lewis lung cancer cells was studied. The results of particle size measurement showed that the blank micelles and drug-loaded micelles had similar particle sizes, ranging from 10 to 100 nm. The particle size of PBAE micelles was changed under weak acidic conditions, with good pH response. The encapsulation efficiency of the above two types of DTX-loaded nanomicelles determined by HPLC was(93.8±1.70)% and(87.2±4.10)%, and the drug loading amount was(5.3±0.10)% and(4.9±0.05)%,respectively. Furthermore,the DTX micelles also showed significant inhibitory effects on Lewis lung cancer cells by MTT assay, and pH-sensitive PBAE-DTX showed better cytotoxicity. The results of flow cytometry indicated that,the apoptosis rate of lung cancer Lewis cells was(20.72±1.47)%,(29.71±2.38)%,and(40.91±1.90)%(P<0.05) at 48 h after treatment in DTX,PELA-DTX,and PBAE-DTX groups. The results showed that different docetaxel preparations could promote the apoptosis of Lewis cells, and PBAE-DTX had stronger apoptotic-promoting effect. The pH-sensitive DTX-loaded micelles are promising candidates in developing stimuli triggered drug delivery systems in acidic tumor micro-environments with improved inhibitory effects of tumor growth on Lewis lung cancer.

Dual Controlled Delivery of Gemcitabine and Cisplatin Using Polymer-Modified Thermosensitive Liposomes for Pancreatic Cancer.

Although combinational anticancer chemotherapies have been proven to improve the life expectancy of patients in the clinic, their full potential is severely limited by the additive toxicities of the drug molecules. Targeted drug delivery systems could alleviate this major limitation by the design of nanocarriers that can cocarry multiple drug molecules in order to augment drug synergism at the site of interest while reducing the systemic side effects. In this study, we report on a thermoresponsive polymer-coated liposome nanocarrier that is capable to cocarry two potent anticancer drugs and release them via a thermally triggered mechanism. A synthetic polymer ([poly(diethylene glycol) methacrylate-co-poly(oligoethylene glycol) methacrylate]-b-poly(2-ethylhexyl) methacrylate) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and was used as a thermoresponsive polymer coating shell on thermosensitive liposome carriers. The formulations were tested in vitro against two pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, and their cytotoxic potency was studied with respect to their targeted release properties as well as their biological interactions with cellular organelles. The polymer-modified liposomes (PMTLs) could cocarry and release Gemcitabine (Gem) and cisplatin (Cis) in a thermally controlled rate and were also found to exhibit specific hydrophobic interactions with the cell membranes above the temperature transition of the formulations. In addition, the nanocarriers were found to induce more than 10-fold improvement of the IC50 of both drugs, either as monotherapies or in combination, in both cell lines tested, in a temperature dependent manner. The proposed formulations constitute a potent nanomedicinal approach for the codelivery of multiple drug molecules and could find potential uses as thermally triggered drug delivery systems for precision medicine and oncology and also as modulators of drug efficacy at the cellular level owing to their unique interactions with the cell membranes.

Development and characteristics of novel sonosensitive liposomes for vincristine bitartrate

The aim of drug delivery is to increase therapeutic efficacy. Externally triggered drug delivery systems enable site-specific and time-controlled drug release. To achieve this goal, our strategy was based on ultrasound-triggered release of an anticancer agent from sonosensitive liposomes (SL). To realize the ultrasound-triggered drug release, a lipophilic sonosensitizer, hematoporphyrin monomethyl ether (HMME) was incorporated into the lipid bilayer of liposomes. Once irradiated by the ultrasound in tumor tissues, the sonodynamic effect generated by HMME could lead to an efficient disruption of the lipid bilayer in the SL. After encapsulating vincristine bitartrate (VIN) as the model drug, the ultrasound-triggered lipid bilayer breakdown can trigger the instant release of VIN, enabling ultrasound-controlled chemotherapy with great specificity. In the in vitro and in vivo studies, by integrating tumor-specific targeting and stimuli-responsive controlled release into one system, VIN-loaded SL showed excellent antitumor efficacy. The SL could potentially produce viable clinical strategies for improved targeting efficiency of VIN for the treatment of related cancer. More importantly, this report provides an example of controlled release by means of a novel class of ultrasound triggering system.

Visible-light-triggered supramolecular valves based on β-cyclodextrin-modified mesoporous silica nanoparticles for controlled drug release.

A high-efficiency drug delivery system has been successfully constructed based on visible-light triggered binding and releasing between tetra-ortho-methoxy-substituted azobenzene (mAzo) and β-cyclodextrin (β-CD) modified mesoporous silica nanoparticles. The drug releasing efficiency is calculated to be 56%. The high-efficiency visible-light-triggered drug delivery system may afford great potential for cancer therapy.

Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II - co-loading of pheophorbide A and black hole quencher.

Previously, we have shown that the use of a cyclopeptidic carrier could be of great interest for the design of fully characterized prodrugs for further use in photodynamic therapy. In order to further optimize the design, we decided to modify the highly quenched conjugate uPA-cPPP4/5 by co-loading a long-distance fluorescence quencher. For this purpose we tethered two black hole quenchers (BHQ3) together with two pheophorbide A moities onto the same PEGylated backbone and assessed the modified photophysical properties. In addition, to prove the reliability of our concept, we designed two analogues, uPA-cPPQ2+2/5 and CathB-cPPQ2+2/5, by using two different peptidic linkers as substrates for uPA and cathepsin B, respectively. These two conjugates proved to be much more water-soluble than their analogues bearing only Phas. These conjugates are not only highly quenched in their native state with regard to their fluorescence emission (up to 850 ± 287 times less fluorescent for CathB-cPPQ2+2/5 as compared to the unquenched monosubstituted reference uPA-cPPP1/5), but also prevent singlet oxygen production (with a total quenching of the emission when the quenchers are co-loaded with photosensitizers) when the photosentistizers are excited. After proteolytic activation, these conjugates recover their photophysical properties in the same way as occurred for uPA-cPPP4/5, with up to a 120-fold increase in fluorescence emission for uPA-cPPQ2+2/5 after two hours of incubation with uPA.