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This article explores the emerging field of nanomedicine as a drug delivery system, aimed at enhancing the therapeutic efficacy of active pharmaceutical ingredients in medicinal plants. The traditional methods of applying medicinal plants present several limitations, such as low bioavailability, poor solubility, challenges in accurately controlling drug dosage, and inadequate targeting. Nanoformulations represent an innovative approach in drug preparation that employs nanotechnology to produce nanoscale particles or carriers, which are designed to overcome these limitations. Nanoformulations offer distinct advantages, significantly enhancing the solubility and bioavailability of drugs, particularly for the poorly soluble components of medicinal plants. These formulations effectively enhance solubility, thereby facilitating better absorption and utilization by the human body, which in turn improves drug efficacy. Furthermore, nanomedicine enables targeted drug delivery, ensuring precise administration to the lesion site and minimizing side effects on healthy tissues. Additionally, nanoformulations can regulate drug release rates, extend the duration of therapeutic action, and enhance the stability of treatment effects. However, nanoformulations present certain limitations and potential risks; their stability and safety require further investigation, particularly regarding the potential toxicity with long-term use. Nevertheless, nanomaterials demonstrate substantial potential in augmenting the efficacy of active pharmaceutical ingredients in medicinal plants, offering novel approaches and methodologies for their development and application. [ABSTRACT FROM AUTHOR]

The consequences of intramolecular ionic interactions in determining the reactivity of functional groups are of interest because they provide insights into how nature deploys seemingly reactive functionalities to be rather ubiquitous. Of specific interest are the quaternary ammonium ions in lipids. In this work, we investigate the effect of intramolecular electrostatic interactions in zwitterionic functionalities by judiciously incorporating them as leaving groups at the α‐position of α,β‐unsaturated ester‐based lipid head groups. We find that electrostatic stabilization indeed plays a critical role in both the reaction kinetics with nucleophiles and the thermodynamics of lipid formation. We further leverage these findings to fabricate both triggerable assembly and disassembly of liposomal supramolecular assemblies in the presence of nucleophiles. [ABSTRACT FROM AUTHOR]

The consequences of intramolecular ionic interactions in determining the reactivity of functional groups are of interest because they provide insights into how nature deploys seemingly reactive functionalities to be rather ubiquitous. Of specific interest are the quaternary ammonium ions in lipids. In this work, we investigate the effect of intramolecular electrostatic interactions in zwitterionic functionalities by judiciously incorporating them as leaving groups at the α‐position of α,β‐unsaturated ester‐based lipid head groups. We find that electrostatic stabilization indeed plays a critical role in both the reaction kinetics with nucleophiles and the thermodynamics of lipid formation. We further leverage these findings to fabricate both triggerable assembly and disassembly of liposomal supramolecular assemblies in the presence of nucleophiles. [ABSTRACT FROM AUTHOR]

Triggerable coatings, such as pH-responsive polymethacrylate copolymers, can be used to protect the active pharmaceutical ingredients contained within oral solid dosage forms from the acidic gastric environment and to facilitate drug delivery directly to the intestine. However, gastrointestinal pH can be highly variable, which can reduce delivery efficiency when using pH-responsive drug delivery technologies. We hypothesized that biomaterials susceptible to proteolysis could be used in combination with other triggerable polymers to develop novel enteric coatings. Bioinformatic analysis suggested that silk fibroin is selectively degradable by enzymes in the small intestine, including chymotrypsin, but resilient to gastric pepsin. Based on the analysis, we developed a silk fibroin-polymethacrylate copolymer coating for oral dosage forms. In vitro and in vivo studies demonstrated that capsules coated with this novel silk fibroin formulation enable pancreatin-dependent drug release. We believe that this novel formulation and extensions thereof have the potential to produce more effective and personalized oral drug delivery systems for vulnerable populations including patients that have impaired and highly variable intestinal physiology. [ABSTRACT FROM AUTHOR]

The development of new approaches for the treatment of the increasingly antibiotic-resistant pathogen Pseudomonas aeruginosa was targeted by enhancing the effect of local antimicrobial photodynamic therapy (aPDT) using poly(ethylene glycol)-block-poly(lactic acid) (PEG114-block-PLAx) nanocarriers that were loaded with a ruthenium-based photosensitizer (PS). The action of tris(1,10-phenanthroline) ruthenium (II) bis(hexafluorophosphate) (RuPhen3) encapsulated in PEG114-block-PLAx micelles and vesicles was shown to result in an appreciable aPDT inactivation efficiency against planktonic Pseudomonas aeruginosa. In particular, the encapsulation of the PS, its release, and the efficiency of singlet oxygen (1O2) generation upon irradiation with blue light were studied spectroscopically. The antimicrobial effect was analyzed with two strains of Pseudomonas aeruginosa. Compared with PS-loaded micelles, formulations of the PS-loaded vesicles showed 10 times enhanced activity with a strong photodynamic inactivation effect of at least a 4.7 log reduction against both a Pseudomonas aeruginosa lab strain and a clinical isolate collected from the lung of a cystic fibrosis (CF) patient. This work lays the foundation for the targeted eradication of Pseudomonas aeruginosa using aPDT in various medical application areas. [ABSTRACT FROM AUTHOR]

The use of pH-responsive polymeric micelles is a promising approach to afford the targeted, pH-mediated delivery of hydrophobic drugs within the low-pH tumour milieu and intracellular organelles of cancer cells. However, even for a common pH-responsive polymeric micelle system—e.g., those utilising poly(ethylene glycol)-b-poly(2-vinylpyridine) (PEG-b-PVP) diblock copolymers—there is a lack of available data describing the compatibility of hydrophobic drugs, as well as the relationships between copolymer microstructure and drug compatibility. Furthermore, synthesis of the constituent pH-responsive copolymers generally requires complex temperature control or degassing procedures that limit their accessibility. Herein we report the facile synthesis of a series of diblock copolymers via visible-light-mediated photocontrolled reversible addition-fragmentation chain-transfer polymerisation, with a constant PEG block length (90 repeat units (RUs)) and varying PVP block lengths (46–235 RUs). All copolymers exhibited narrow dispersity values (Đ ≤ 1.23) and formed polymeric micelles with low polydispersity index (PDI) values (typically <0.20) at physiological pH (7.4), within a suitable size range for passive tumour targeting (<130 nm). The encapsulation and release of three hydrophobic drugs (cyclin-dependent kinase inhibitor (CDKI)-73, gossypol, and doxorubicin) were investigated in vitro at pH 7.4–4.5 to simulate drug release within the tumour milieu and cancer cell endosome. Marked differences in drug encapsulation and release were observed when the PVP block length was increased from 86 to 235 RUs. With a PVP block length of 235 RUs, the micelles exhibited differing encapsulation and release properties for each drug. Minimal release was observed for doxorubicin (10%, pH 4.5) and CDKI-73 exhibited moderate release (77%, pH 4.5), whereas gossypol exhibited the best combination of encapsulation efficiency (83%) and release (91% pH 4.5) overall. These data demonstrate the drug selectivity of the PVP core, where both the block molecular weight and hydrophobicity of the core (and accordingly the hydrophobicity of the drug) have a significant effect on drug encapsulation and release. These systems remain a promising means of achieving targeted, pH-responsive drug delivery—albeit for select, compatible hydrophobic drugs—which warrants their further investigation to develop and evaluate clinically relevant micelle systems. [ABSTRACT FROM AUTHOR]

Melanoma is the most aggressive and metastasis-prone form of skin cancer. Conventional therapies include chemotherapeutic agents, either as small molecules or carried by FDA-approved nanostructures. However, systemic toxicity and side effects still remain as major drawbacks. With the advancement of nanomedicine, new delivery strategies emerge at a regular pace, aiming to overcome these challenges. Stimulus-responsive drug delivery systems might considerably reduce systemic toxicity and side-effects by limiting drug release to the affected area. Herein, we report the development of paclitaxel-loaded lipid-coated manganese ferrite magnetic nanoparticles (PTX-LMNP) as magnetosomes synthetic analogs, envisaging the combined chemo-magnetic hyperthermia treatment of melanoma. PTX-LMNP physicochemical properties were verified, including their shape, size, crystallinity, FTIR spectrum, magnetization profile, and temperature profile under magnetic hyperthermia (MHT). Their diffusion in porcine ear skin (a model for human skin) was investigated after intradermal administration via fluorescence microscopy. Cumulative PTX release kinetics under different temperatures, either preceded or not by MHT, were assessed. Intrinsic cytotoxicity against B16F10 cells was determined via neutral red uptake assay after 48 h of incubation (long-term assay), as well as B16F10 cells viability after 1 h of incubation (short-term assay), followed by MHT. PTX-LMNP-mediated MHT triggers PTX release, allowing its thermal-modulated local delivery to diseased sites, within short timeframes. Moreover, half-maximal PTX inhibitory concentration (IC50) could be significantly reduced relatively to free PTX (142,500×) and Taxol® (340×). Therefore, the dual chemo-MHT therapy mediated by intratumorally injected PTX-LMNP stands out as a promising alternative to efficiently deliver PTX to melanoma cells, consequently reducing systemic side effects commonly associated with conventional chemotherapies. [ABSTRACT FROM AUTHOR]

Liver cancer, especially hepatocellular carcinoma, is an important cause of cancer-related death, and its incidence is increasing worldwide. Nano drug delivery systems have shown great promise in the treatment of cancers. In order to improve their therapeutic efficacy, it is very important to realize the high accumulation and effective release of drugs at the tumor site. In this manuscript, using doxorubicin (DOX) as a model drug, CD13-targeted mesoporous silica nanoparticles coated with NGR-peptide-modified pegylated carboxymethyl chitosan were constructed (DOX/MSN-CPN). DOX/MSN-CPN comprises a spherical shape with an obvious capping structure and a particle size of 125.01 ± 1.52 nm. With a decrease in pH, DOX/MSN-CPN showed responsive desorption from DOX/MSN-CPN and pH-responsive release of DOX was observed. Meanwhile, DOX/MSN-CPN could be efficiently absorbed through NGR-mediated internalization in vitro and could efficiently deliver DOX to tumor tissues with long accumulation times in vivo, suggesting good active targeting properties. Moreover, significant tumor inhibition has been observed in antitumor studies in vivo. This study provides a strategy of utilizing DOX/MSN-CPN as a nano-platform for drug delivery, which has superb therapeutic efficacy and safety for the treatment of hepatocellular carcinoma both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Chronic wound infections with antibiotic-resistant bacteria have become a significant problem for modern healthcare systems since they are often associated with high costs and require profound topical wound management. Successful wound healing is achieved by reducing the bacterial load of the wound and providing an environment that enhances cell growth. In this context, nanofibers show remarkable success because their structure offers a promising drug delivery platform that can mimic the native extracellular matrix and accelerate cell proliferation. In our study, single-needle electrospinning, a versatile and cost-efficient technique, was used to shape polymers into an applicable and homogeneous fleece capable of a photothermally triggered drug release. It was combined with antimicrobial photodynamic therapy, a promising procedure against resistant bacteria. Therefore, poly(d,l-lactide) nanofibers loaded with curcumin and indocyanine green (ICG) were produced for local antimicrobial treatment. The mesh had a homogeneous structure, and the nanofibers showed a smooth surface. Recordings with a thermal camera showed that near-infrared light irradiation of ICG increased the temperature (>44 °C) in the surrounding medium. Release studies confirmed more than 29% enhanced curcumin release triggered by elevated temperature. The antimicrobial activity was tested against the gram-positive strain Staphylococcus saprophyticus subsp. bovis and the gram-negative strain Escherichia coli DH5 alpha. The nanofibers loaded with both photosensitizers and irradiated with both wavelengths reduced the bacterial viability (~4.4 log10, 99.996%) significantly more than the nanofibers loaded with only one photosensitizer (<1.7 log10, 97.828%) or irradiated with only one wavelength (<2.0 log10, 98.952%). In addition, our formulation efficiently eradicated persistent adhered bacteria by >4.3 log10 (99.995%), which was also confirmed visually. Finally, the produced nanofibers showed good biocompatibility, proven by the cellular viability of mouse fibroblasts (L929). The data demonstrate that we have developed a new economic nanofiber formulation, which offers a triggered drug release, excellent antimicrobial properties, and good biocompatibility. [ABSTRACT FROM AUTHOR]

Nanocarriers (NCs) were designed from three polymer blends (B1, B2 and B3) and investigated as smart drug delivery systems (SDDS). The blends are composed of a "smart" copolymer, where methoxy poly(ethylene glycol) and poly(lactic acid) are connected via a redox-responsive disulfide bond (mPEG-SS-PLA), and of a "conventional" polymer, poly(lactic acid) (PLA). They differ by mPEG-SS-PLA/PLA ratio and PLA molecular weight. Nanoprecipitation was used to prepare NCs. Three concentrations were tested, and fluorescent dye Nile red (NR) was used as a model payload. The results show that the characteristics of the NCs, such as size and drug release kinetics, are influenced by the type of blend and the concentration used during the nanoprecipitation process. The more redox-responsive blend was B2 (ratio 1:3, PLA 5 kDa) at 16 mg/mL: the quantity of NR released was tripled upon 24 h of incubation in a reducing medium. This study reveals that the amount of disulfide bonds present in a NC is not the only parameter to be considered to design an SDDS. The stability of the SDDS in a presumably non-stimulating environment is also important to limit uncontrolled release during storage or in the body before the biological target is reached. [ABSTRACT FROM AUTHOR]

Introduction: In targeted enzyme prodrug constructs, it is critical to control the bioactivity of the drug in its prodrug form. The preparation of such constructs often involves conjugation reactions directed to functional groups on amino acid side chains of the protein, which result in random conjugation and incomplete control of bioactivity of a prodrug, which may result in significant nontarget effect. Thus, more specific method of modification is desired. If the drug is a glycoprotein, enzymatic oxidation may offer an alternative approach for therapeutic glycoproteins. Methods: Tissue plasminogen activator (tPA), a model glycoprotein enzyme, was treated with galactose oxidase (GO) and horseradish peroxidase, followed by thiolation reaction and conjugation with low molecular weight heparin (LMWH). The LMWH-tPA conjugate was isolated by ion-exchange chromatography followed by centrifugal filtration. The conjugate was characterized for its fibrinolytic activity and for its plasminogen activation through an indirect amidolytic assay with a plasmin-specific substrate S-2251 when LMWH-tPA conjugate is complexed with protamine-albumin conjugate, followed by triggered activation in the presence of heparin. Results: LMWH-tPA conjugate prepared via enzymatic oxidation retained ~95% of its fibrinolytic activity with respect to native tPA. Upon complexation with protamine-albumin conjugate, the activity of LMWH-tPA was effectively inhibited (~90%) whereas the LMWH-tPA prepared by random thiolation exhibited ~55% inhibition. Addition of heparin fully generated the activities of both conjugates. Conclusion: The tPA was successfully modified via enzymatic oxidation by GO, resulting in enhanced control of its activity in the prodrug construct. This approach can be applied to other therapeutic glycoproteins. [ABSTRACT FROM AUTHOR]

This paper is to discuss the potential of using CuZn in an electrical biosensor drug carrier for drug delivery systems. CuZn is the main semiconductor ingredient that has great promise as an electrochemical detector to trigger releases of active pharmaceutical ingredients (API). This CuZn biosensor is produced with a green metal of frameworks, which is an anion node in conductive polymers linked by bioactive ligands using metal–polymerisation technology. The studies of Cu, Zn, and their oxides are highlighted by their electrochemical performance as electrical biosensors to electrically trigger API. The three main problems, which are glucose oxidisation, binding affinity, and toxicity, are highlighted, and their solutions are given. Moreover, their biocompatibilities, therapeutic efficacies, and drug delivery efficiencies are discussed with details given. Our three previous investigations of CuZn found results similar to those of other authors' in terms of multiphases, polymerisation, and structure. This affirms that our research is on the right track, especially that related to green synthesis using plant extract, CuZn as a nanochip electric biosensor, and bioactive ligands to bind API, which are limited to the innermost circle of the non-enzymatic glucose sensor category. [ABSTRACT FROM AUTHOR]

Efficient conventional chemotherapy is limited by its nonspecific nature, which causes severe systemic toxicity that can lead to patient discomfort and low therapeutic efficacy. The emergence of smart drug delivery systems (SDDSs) utilizing nanoparticles as drug nanocarriers has shown great potential in enhancing the targetability of anticancer agents and limiting their side effects. Liposomes are among the most investigated nanoplatforms due to their promising capabilities of encapsulating hydrophilic, lipophilic, and amphiphilic drugs, biocompatibility, physicochemical and biophysical properties. Liposomal nanodrug systems have demonstrated the ability to alter drugs' biodistribution by sufficiently delivering the entrapped chemotherapeutics at the targeted diseased sites, sparing normal cells from undesired cytotoxic effects. Combining liposomal treatments with ultrasound, as an external drug release triggering modality, has been proven effective in spatially and temporally controlling and stimulating drug release. Therefore, this paper reviews recent literature pertaining to the therapeutic synergy of triggering nanodrugs from liposomes using ultrasound. It also highlights the effects of multiple physical and chemical factors on liposomes' sonosensetivity, several ultrasound-induced drug release mechanisms, and the efficacy of ultrasound-responsive liposomal systems in cancer therapy. Overall, liposomal nanodrug systems triggered by ultrasound are promising cancer therapy platforms that can potentially alleviate the detriments of conventional cancer treatments. [ABSTRACT FROM AUTHOR]

[Display omitted] According to the importance of time in treatment of thrombosis disorders, faster than current treatments are required. For the first time, this research discloses a novel strategy for rapid dissolution of blood clots by encapsulation of a fibrinolytic (Reteplase) into a Thrombin sensitive shell formed by polymerization of acrylamide monomers and bisacryloylated peptide as crosslinker. Degradability of the peptide units in exposure to Thrombin, creates the Thrombin-sensitive Reteplase nanocapsules (TSRNPs) as a triggered release system. Accelerated thrombolysis was achieved by combining three approaches including: deep penetration of TSRNPs into the blood clots, changing the clot dissolution mechanism by altering the distribution pattern of TSRNPs to 3D intra-clot distribution (based on the distributed intra-clot thrombolysis (DIT) model) instead of peripheral and unidirectional distribution of unencapsulated fibrinolytics and, enzyme-stimulated release of the fibrinolytic. Ex-vivo study was carried out by an occluded tube model that mimics in-vivo brain stroke as an emergency situation where faster treatment in short time is a golden key. In in vivo , efficacy of the developed formulation was confirmed by PET scan and laser Doppler flowmetry (LDF). As the most important achievements, 40.0 ± 0.7 (n = 3) % and 37.0 ± 0.4 (n = 3) % reduction in the thrombolysis time (faster reperfusion) were observed by ex-vivo and in-vivo experiments, respectively. Higher blood flow and larger digestion mass of clot at similar times in comparison to non-encapsulated Reteplase were observed that means more effective thrombolysis by the developed strategy. [ABSTRACT FROM AUTHOR]

[Display omitted] pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of cytotoxic drugs at specific target sites. Despite significant advances in this area, there is a lack of versatile and adaptable strategies to render micelles pH-responsive that could be widely applied to different payloads and applications. To address this deficiency, we introduce the concept of oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive polymeric micelles as a highly effective approach with broad scope. Herein, we investigate the influence of the oligoelectrolyte, oligo(2-vinyl pyridine) (OVP), loading and polymer molecular weight on the pH-sensitivity, drug loading/release and cytotoxicity of poly(ethylene glycol- b -ε-caprolactone) (PEG- b -PCL) micelles using copolymers with either short or long hydrophobic blocks (PEG 4 PCL 4 and PEG 10 PCL 10 , respectively). The micelles were characterized as a function of pH (7.4 to 3.5). Dynamic light scattering (DLS) revealed narrow particle size distributions (PSDs) for both the blank and OVP-loaded micelles at pH 7.4. While OVP encapsulation resulted in an increase in the hydrodynamic diameter (D h) (cf. blank micelles), a decrease in the pH below 6.5 led to a decrease in the D h consistent with the ionization and release of OVP and core collapse, which were further supported by proton nuclear magnetic resonance (1H NMR) spectroscopy and UV–visible (UV–vis) spectrophotometry. The change in zeta potential (ζ) with pH for the OVP-loaded PEG 4 PCL 4 and PEG 10 PCL 10 micelles was different, suggesting that the location/distribution of OVP in the micelles is influenced by the polymer molecular weight. In general, co-encapsulation of drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX) or 7-ethyl-10-hydroxycamptothecin (SN38)) and OVP in the micelles proceeded efficiently with high encapsulation efficiency percentages (EE%). In vitro release studies revealed the rapid, pH-triggered release of drugs from OVP-loaded PEG 10 PCL 10 micelles within hours, with higher OVP loadings providing faster and more complete release. In comparison, no triggered release was observed for the OVP-loaded PEG 4 PCL 4 micelles, implying a strong molecular weight dependency. In metabolic assays the drug- and OVP-loaded PEG 10 PCL 10 micelles were found to result in significant enhancement of the cytotoxicity compared to drug-loaded micelles (no OVP) or other controls. Importantly, micelles with low OVP loadings were found to be nearly as effective as those with high OVP loadings. These results provide key insights into the tunability of the oligoelectrolyte-mediated approach for the effective formulation of pH-responsive micelles and pH-triggered drug release. [ABSTRACT FROM AUTHOR]

Multidrug‐resistant bacteria have become a global health problem for which new prophylactic strategies are now needed, including surface‐coatings for hospital spaces and medical equipment. This work reports the preparation and functional validation of a metal‐organic framework (MOF) based composite for the triggered controlled release of iodine, an antimicrobial element that does not generate resistance. It comprises beads of the iodophilic MOF UiO‐66 containing encapsulated gold nanorods (AuNRs) coated with a silica shell. Irradiation of the AuNRs with near‐infrared light (NIR) provokes a photothermal effect and the resultant heat actively liberates the iodine. After validating the performance of this composite, it is integrated into a polymer for the development of antibacterial films. This work assesses the adsorption of iodine into these composite films, as well as its passive long‐term release and active light‐triggered. Finally, this work validates the antibacterial activity of the composite films in vitro against gram‐positive and gram‐negative bacteria. The findings will surely inform the development of new prophylactic treatments. [ABSTRACT FROM AUTHOR]

The potential of semiochemicals for the targeted behavior manipulation of insects has been known for a long time. Their low impact on non-target organisms makes them interesting candidates for use in insect control for various applications such as agricultural and forestry pest control, stored-product protection and protection against hematophagous insects. Due to their high volatility and chemical instability against UV light and oxidation, their use often remains limited. Tailor-made formulations can protect semiochemicals from environmental factors and can improve release performance and duration triggering a desired reaction in the target insect at the place of application. This review provides an overview of recent formulation types developed for insect behavior manipulation by semiochemicals, with emphasis on formulation aspects and formulation potential for slow and controlled release. The focus was set on inventions and studies aiming to elucidate material and formulation properties that affect the semiochemical release and, with specific attention, enable targeted release manipulation. [ABSTRACT FROM AUTHOR]

The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S–S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid–polyethylene glycol (FA–PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors. [ABSTRACT FROM AUTHOR]

Hybrid lipopolymer vesicles are membrane vesicles that can be self-assembled on both the micro- and nanoscale. On the nanoscale, they are potential novel smart materials for drug delivery systems that could combine the relative strengths of liposome and polymersome drug delivery systems without their respective weaknesses. However, little is known about their properties and how they could be tailored. Currently, most methods of investigation are limited to the microscale. Here we provide a brief review on hybrid vesicle systems with a specific focus on recent developments demonstrating that nanoscale hybrid vesicles have different properties from their macroscale counterparts. [ABSTRACT FROM AUTHOR]

The low oral bioavailability of some bioactive ingredients is a challenge in the supplement and functional food areas. Consequently, there is a need for innovative carrier technologies that can increase the solubility, stability, release, and absorption of these ingredients within the human gastrointestinal tract. Furthermore, some bioactive ingredients may exert their synergistic activities when delivered together. The objective of this study was to design natural carriers that could simultaneously deliver both hydrophobic and hydrophilic bioactive ingredients, thereby increasing their ability to exert synergistic effects. Initially, model hydrophobic (lycopene) and hydrophilic (riboflavin) ingredients were encapsulated in the oil and internal water phases of water-in-oleic acid-in-water (W/O/W) emulsions, respectively. These emulsions were then dispersed into two kinds of alginate-based matrices, which may be suitable for different applications: calcium alginate gels (solid) or EDTA-calcium alginate sols (fluid). Oleic acid was used as an oil phase in the W/O/W emulsions to provide temperature-triggered release, whereas alginate-based matrices were used to provide pH-triggered release. The carriers were stable in a simulated gastric juice but released the bioactive ingredients in a simulated small intestinal juice. The calcium alginate matrix increased the light stability of the bioactive ingredients. Encapsulation improved the bioaccessibility of the co-delivered bioactive ingredients. This study provides new strategies that can be used for designing pH- and temperature-sensitive carrier for intestinal targeted delivery of hydrophobic and hydrophilic food bioactive ingredients. [Display omitted] • Natural pH and temperature-sensitive hydrogel-emulsion carriers were established. • These carriers can be used to co-deliver hydrophobic carotenoids and hydrophilic riboflavin. • The gel-sol state transition of the carriers can be controlled by calcium ions. • Carriers with gel state gave better photostability and bioaccessibility of the carotenoid. [ABSTRACT FROM AUTHOR]

A hydrogel microcapsule with an intermediate thin oil layer is presented to achieve smart release of a broad range of cargoes triggered via diverse stimuli. A microfluidic technique is used to produce triple emulsion droplets with a thin oil layer that separates the innermost aqueous phase from the hydrogel prepolymer phase, which transforms into a hydrogel shell via photo-polymerization. The intermediate oil layer within the hydrogel microcapsule acts as an effective diffusion barrier, allowing encapsulation of various small cargoes within a porous hydrogel shell until a stimulus is applied to destabilize the oil layer. It is demonstrated that diverse stimuli including chemical dissolution, mechanical stress, and osmotic pressure can be utilized to release the encapsulated cargo on-demand. In addition, osmotic pressure and the hydrogel shell thickness can be independently tuned to control the onset time of release as well as the release behavior of multi-cargo encapsulated hydrogel microcapsule. The release can be either simultaneous or selective. [ABSTRACT FROM AUTHOR]

Triggered release from responsive drug reservoirs activated by remote stimuli is desired in a range of fields. Critical bottlenecks are cost-efficient formulation avenues applicable for industrial scale-up, viable triggers and immediate release rather than continuous release upon activation. UV-sensitive microcapsules based on self-immolating polymers in combination with thin shells and morphological weak spots should allow for immediate triggered release. Polyphthalaldehyde-based microcapsules were prepared using several variations of the internal phase separation route. In addition, a fluorescence microscopy method was developed to study both the microcapsule morphology and the triggered release in-situ. The microcapsule formation was driven by the surface activity of the stabilizer, effectively lowering the high polymer-water interfacial tension, which is in sharp contrast to conventional encapsulation systems. Contrary to previous findings, a core–shell morphology was obtained via slow emulsion-to-suspension transformation. Rapid transformation captured intermediate inverted core–shell structures. The capsules were highly sensitive to both acid- and UV-mediated triggers, leading to an unzipping and rupturing of the shell that released the core content. Poly(methacrylic acid)-stabilized microcapsules displayed immediate UV-triggered release provided by their stimuli-sensitive blueberry morphology. Both capsules in aqueous and dry environment started to lose their core content after less than one minute of UV light exposure. [ABSTRACT FROM AUTHOR]

Triggered release is an elegant approach to achieving "just-in-time" delivery of active substances. Nevertheless, most previous research has focused on hydrogels, leaving nonaqueous organic coatings that are capable of on-demand rupture relatively unexplored. The current investigation examined new light-triggered coatings based on shellac—a natural resin derived from the secretion of insects—modified with Jeffamine® to enhance its mechanical durability and stability. Light sensitivity was appended to the modified shellac by embedding nanoparticles (NP) of polydopamine, a polymer with excellent photothermal capabilities that emits heat when exposed to light. Combining a low percentage of polydopamine (<1 wt%) with the composite films facilitated their rapid rupture upon irradiation with green light. We demonstrate that the NPs are evenly distributed in the shellac matrix, and do not form a heat conduction network. Thus, heat generated by the nanoparticles does not dissipate, but rather increases the shellac's temperature at the shellac–NP interface until the shellac melts or degrades. Thermal degradation mainly occurs in areas directly irradiated with green light, where heat is generated. This mechanism opens possibilities for precisely controlling the degradation site and extent of the film using a focused light source. This capability may pave the way for using such remote releases from encapsulated devices at desired times and locations. • A new light-triggered coating based on modified shellac and polydopamine was developed. • Polydopamine nanoparticles displayed high thermal efficiency. • A low percentage of polydopamine facilitated rapid film rupture upon irradiation with green light. • Heat generated by the nanoparticles does not dissipate but rather heats the shellac. [ABSTRACT FROM AUTHOR]

Self-assembled particles, based on non-covalent interactions, are attractive drug carriers with a relatively simple structure and easy preparation. Tannic acid (TA) is an anionic polyphenolic compound with a wide range of molecular interactions and diverse applications in drug delivery research. Here, we propose the use of TA complexes with cationic antibiotics as a new pH-responsive drug carrier of high drug loading and optimal stability. TA complexes were prepared with three water-soluble antibiotics; colistin sulfate (COL), gentamicin sulfate (GEN) and gatifloxacin (GAT). Complexes' size ranged from several-hundred nanometers to few microns. For selected particles, drug loading ranged from 30 to 36%. Importantly, we demonstrate the impact of drug-carrier interactions, studied via infrared spectroscopy and molecular modeling, on final complex stability and performance; the complexes resisted dissociation in presence of serum at physiological pH to variable degrees and showed different drug release profiles. However, all complexes dissociated upon medium acidification, releasing their drug payload and demonstrating expected antibacterial effect. These results demonstrate that TA/antibiotic self-assembled complexes represent an excellent carrier for pH-sensitive delivery of water-soluble drugs. In addition to system's simplicity and low cost, complexes were easily prepared with high drug loading and desirable pH-dependent association/dissociation profile. [ABSTRACT FROM AUTHOR]

The development of platforms for the controlled release of therapeutic molecules remains a crucial research focus, as controlled release reduces the frequency of administration, minimizes side effects and improves compliance. However, biological conditions and diseases with a progression that exhibits strong temporal dependence, or those that can result in the evolution of tolerance to the therapeutic during continuous exposure, require the development of sophisticated release systems tailored to the needs to the individual and the disease. Thus, there has been emphasis on the development of platforms with remotely controlled release mechanisms. Specifically, magnetically triggered release utilizes magnetic nanoparticles as the remote control modality. Many reviews discuss the magnetically triggered release of small molecule drugs, however, the release of biomacromolecules has not been reviewed. This review examines the limited work on the magnetically triggered release of biomacromolecules and the challenges associated with their delivery. Important material parameters that have been used in this pursuit are discussed. [ABSTRACT FROM AUTHOR]

The increase in pectin methylesterase (PME) activity on fresh-cut apple surface can smartly trigger the controlled release of bactericidal agents encapsulated within intelligent responsive Pickering emulsions. In this study, we developed a PME-responsive nanocomplex (W-H-II) to stabilize Pickering emulsion containing thyme essential oil (TEO), preserving fresh-cut apples. W-H-II, formed by heat-induced whey protein isolate (WPI) and high methoxyl pectin (HMP) (pH 4.5, 85 °C, 15 min, WPI:HMP ratio 1:2), exhibited good pH stability due to the stabilizing effects of hydrophobic, hydrogen bonding, and electrostatic interactions. The presence of PME triggered the demethylation of HMP within W-H-II, conferring PME response characteristics. Subsequently, a bacteriostasis experiment with pectinase-producing Bacillus subtilis provided evidence of PME-triggered TEO release from W-H-II-stabilized Pickering emulsion. Furthermore, microscopy techniques were employed to verify the demulsification behavior of the emulsion when PME activity ranged from 0.25 to 2.50 U mL−1. Finally, the PME-responsive TEO Pickering emulsion effectively preserved fresh-cut apples. Stored for 6 days at 5 °C and 10 °C, as the PME activity on the apple surface increased, the decay rate of the coated group was 0 %, with a total colony count below 3.0 log CFU g−1. This study introduces a novel intelligent preservation strategy for storing fresh-cut apples. [Display omitted] • Heat-induced nanogel exhibited a pectinesterase-responsive core-shell structure. • Smart Pickering emulsion enzymatically triggers thyme essential oil release. • The pectinesterase-responsive coating showed triggered release and antibacterial. • The pectinesterase-responsive system offers a novel preservation strategy. [ABSTRACT FROM AUTHOR]

Abstract: We designed and synthesized a “hybrid” molecular container 1, which is structurally related to both cucurbit[n]uril (CB[n]) and pillar[n]arene type receptors. Receptor 1 was fully characterized by 1H NMR, 13C NMR, IR, MS and X‐ray single crystal diffraction. The self‐association behavior, host–guest recognition properties of 1, and the [salt] dependence of Ka were investigated in detail by 1H NMR and isothermal titration calorimetry (ITC). Optical transmittance and TEM measurements provide strong evidence that receptor 1 undergoes co‐assemble with amphiphilic guest C10 in water to form supramolecular bilayer vesicles (diameter 25.6±2.7 nm, wall thickness ≈3.5 nm) that can encapsulate the hydrophilic anticancer drug doxorubicin (DOX) and the hydrophobic dye Nile red (NR). The release of encapsulated DOX or NR from the vesicles can be triggered by hexamethonium (8 c) or spermine (10) which leads to the disruption of the supramolecular vesicles. [ABSTRACT FROM AUTHOR]

Light triggered drug delivery systems offer attractive possibilities for sophisticated therapy, providing both temporal and spatial control of drug release. We have developed light triggered liposomes with clinically approved indocyanine green (ICG) as the light sensitizing compound. Amphiphilic ICG can be localized in different compartments of the liposomes, but the effect of its presence, on both triggered release and long term stability, has not been studied. In this work, we report that ICG localization has a significant effect on the properties of the liposomes. Polyethylene glycol (PEG) coating of the liposomes leads to binding and stabilization of the ICG molecules on the surface of the lipid bilayer. This formulation showed both good storage stability in buffer solution (at +4–37 °C) and adequate stability in serum and vitreous (at +37 °C). The combination of ICG within the lipid bilayer and PEG coating lead to poor stability at elevated temperatures of +22 °C and + 37 °C. The mechanisms of the increased instability due to ICG insertion in the lipid bilayer was elucidated with molecular dynamics simulations. Significant PEG insertion into the bilayer was induced in the presence of ICG in the lipid bilayer. Finally, feasibility of freeze-drying as a long term storage method for the ICG liposomes was demonstrated. Overall, this is the first detailed study on the interactions of lipid bilayer, light sensitizer (ICG) and PEG coating on the liposome stability. The localization of the light triggering agent significantly alters the structure of the liposomes and it is important to consider these aspects in triggered drug delivery system design. [ABSTRACT FROM AUTHOR]

The aim of this study was to deliver ribonuclease A (RNase A) intracellularly using dextran nanogels for cancer treatment. To this end, positively charged RNase A was electrostatically loaded in anionic dextran nanogels with an average size of 205 nm, which were prepared by an inverse mini-emulsion technique. To chemically immobilize the loaded protein in the nanogels and prevent its unwanted release in the extracellular environment, the protein was covalently linked to the nanogel network via disulfide bonds, which are cleavable in the reductive cytosolic environment. A high loading efficiency and loading content of RNase A (75% and 20%, respectively) were obtained. Coating of the nanogels with the cationic polymer polyethyleneimine reversed the zeta potential of nanogels from −31.6 mV to +7.6 mV. The nanogels showed a fast and triggered release of RNase in the presence of glutathione. Negatively charged RNase A loaded nanogels did not show cytotoxicity, likely due to their limited cellular uptake. In contrast, PEI coated RNase A loaded nanogels showed high uptake by MDA-MB 231 breast cancer cells and exhibited a concentration-dependent cytotoxic effect by apoptosis. The results demonstrate that PEI coated nanogels are promising nano-carriers for intracellular protein delivery, encouraging further evaluation of this formulation in preclinical models. [ABSTRACT FROM AUTHOR]

Thermally triggered drug release from temperature-sensitive liposomes (TSL) holds great promise for cancer therapy. Different types of TSL have been designed recently for heat triggered drug release inside tumor blood vessels or after accumulation into the tumor interstitium. However, justification of drug release profiles is for far mainly based on in vitro release data. While these methods could be good enough to give early indication about the thermal sensitivity of TSL, they are still far from being optimum. This is because these methods do not take into consideration the actual adsorption of proteins onto the surface of TSL after their in vivo administration, also known as “protein corona” and the influence this could have on drug release. Therefore, in this study we compared thermal triggered drug release profile of two different types of doxorubicin encapsulated TSL; namely the lysolipid-containing TSL (LTSL) and traditional TSL (TTSL) after their in vivo recovery from the blood circulation of CD-1 mice. Ex vivo release profile at 42 °C was then tested either in the presence of full plasma or after removal of unbound plasma proteins (i.e. protein corona coated TSL). Our data showed that the influence of the environment on drug release profile was very much dependent on the type of TSL. LTSL release profile was consistently characterized by ultrafast drug release independent on the conditions tested. On the contrary, TTSL release profile changed significantly. Doxorubicin release from in vivo recovered TTSL was slow and incomplete in the presence of unbound plasma proteins, whereas very rapid drug release was detected from in vivo recovered and purified protein corona-coated TTSL in the absence of unbound proteins. Using mass spectrometry and quantification of protein adsorption, we confirmed that this discrepancy is due to the changes in protein adsorption onto TTSL when heated in the presence of unbound proteins leading to reduction in drug release. In summary this study showed that the formation of the in vivo corona on TSL will have a dramatic impact on their release profile and is dependent on both their lipid composition and the protein content of the environment in which drug release is triggered. [ABSTRACT FROM AUTHOR]

Development of multifunctional biodegradable nanomaterials to encapsulate hydrophobic drugs and their triggered release in cancer theranostics is a challenge. In the current study, we report the encapsulation of potent anticancer − chlorophyll rich biomolecular fraction from the plant Anthocephalus cadamba into a polymeric nanosystem. The biomolecular fraction was combined with an NIR dye IR-780 to make it photo-thermally active. It was evaluated for its combinatorial (biomolecular extract and photothermal mediated) synergistic cytotoxicity in skin cancer cells. The inherent fluorescence of chlorophyll in the fraction was deployed to understand the cellular uptake and drug release. Cellular uptake of hydrophobic CFAc was enhanced with the aid of nanoformulation. It was observed that photo stability of IR-780 improved when incorporated with CFAc in polymeric nanosystem, which resulted in enhanced photothermal transduction efficiency. The combinational approach exhibited synergistic cytotoxicity which can be applied for skin cancer theranostics. [ABSTRACT FROM AUTHOR]

Triggered drug release is a promising strategy for delivering anticancer drugs to cancer cells and tissues. We found that liposomes co-encapsulating calcein (a water-soluble model drug and fluorescence marker) and talaporfin sodium (TPS, a water-soluble photosensitizer) released the drug upon irradiation with a near-infrared (NIR)-laser. The liposomes were composed of phospholipid (DSPC)/helper lipid (DOPE)/cholesterol/PEG-lipid (PEG 2000 -DSPE) at a molar ratio of 85/10/5/5 and released a large amount of drug (70%<, within 10 min) upon irradiation, but no drug in the absence of NIR-laser irradiation and/or TPS. NIR-laser-triggered drug release was facilitated by the incorporation of DOPE into the liposomes, and the amount of DOPE incorporated affected drug leakage in the absence of NIR-laser-irradiation at 37 °C (body temperature). Drug leakage was tuned by incorporating cholesterol into the liposomes. NIR-laser-triggered drug release from the liposomes was confirmed using the anticancer drug gemcitabine. NIR-laser treatment of liposomes co-encapsulating gemcitabine and TPS provided the maximum cytotoxic effect towards EMT6/P cells. These results suggest that these novel light sensitive liposomes may be useful for drug delivery to cancer cells. [ABSTRACT FROM AUTHOR]

Precise delivery of antineoplastic drugs to specific tumor region has drawn much attention in recent years. Herein, a light/magnetic hyperthermia triggered drug delivery with multiple functionality is designed based on methotrexate (MTX) modified thermo-sensitive magnetoliposomes (MTX-MagTSLs). In this system, MTX and oleic acid modified magnetic nanoparticles (MNPs) can be applied in biological and magnetic targeting. Meanwhile, lipophilic fluorescent dye Cy5.5 and MNPs are encapsulated into the bilayer of liposomes, which can not only achieve dual-imaging effect to verify the MTX-MagTSLs accumulation in tumor region, but also provide an appropriate laser irradiation region to release Doxorubicin (Dox) under alternating magnetic field (AMF). Both in vitro and in vivo results revealed that MTX-MagTSLs possessed an excellent targeting ability towards HeLa cells and HeLa tumor-bearing mice. Furthermore, the heating effect of MTX-MagTSLs was amplified 4.2-fold upon combination with AMF and local precise near-infrared laser irradiation (808 nm) (DUAL-mode) to rapidly reach the phase change temperature (Tm) of MTX-MagTSLs in 5 min compared with either AMF or laser stimulation alone, resulting in a significantly enhanced release of Dox at tumor region and precise cancer synergetic theranostics. [ABSTRACT FROM AUTHOR]

Recently developed lipids with the trans -2-aminocyclohexanol (TACH) moiety represent unique pH-sensitive conformational switches (“flipids”) that can trigger the membrane of liposome-based drug delivery systems at lowered pH as seen in many pathological scenarios. A library of flipids with various TACH-based headgroups and hydrocarbon tails were designed, prepared, and characterized to systematically elucidate the relationship between their chemical structures and their ability to form and to trigger liposomes. Liposomes (fliposomes) consisting of a flipid, POPC and PEG-ceramide were stable at 4 °C, pH 7.4 for up to several months and yet released the encapsulated fluorophore in seconds upon acidification. The colloidal properties and encapsulation efficiencies of the fliposomes depended on the structure features of the flipids such as the polarity of the headgroups and the shape and fluidity of the lipid tails. The pH-triggered release also depended on the flipid structure, where shorter linear tails yielded more efficient release. The release of fliposomes was enhanced at different narrow pH ranges, depending on the basicity of the flipid headgroup, which can be estimated either by calculated pKa or by acid/base titration of the flipids while its conformation is monitored by 1 H NMR. The structure-activity relationship of the flipids supports “lipid tail conformational shortening” as the mechanism to disrupt lipid membranes and would provide great flexibility in the design of pH-sensitive drug delivery systems. [ABSTRACT FROM AUTHOR]

The application of pulsed and continuous wave (CW) lasers in nanomedicine has increased significantly over the last decade. Near infrared (NIR) lasers can be used for the precise control of drug release at the target site in a non-invasive manner. In this study, we have prepared nanographene oxide (nGO, size ~ 40 nm) integrated liposomes (size ~ 900 nm). The nGOs were not simply adsorbed onto the liposome surface but was embedded inside the liposomes as characterized by cryo-TEM, selected area electron diffraction (SAED), and fluorescence quenching studies. The embedded nGOs could act as a molecular switch for NIR light controlled drug release from the liposomes. Calcein was encapsulated into the liposome as a model drug to evaluate the efficiency of light controlled release. An on-demand pulsatile drug release was achieved by irradiation of CW/pulsed NIR lasers into the nGO-liposome suspension. Triggering with a pulsed laser resulted in larger release of calcein with a minimal temperature increase (~ 2 °C) of the liposome solution, compared to lower release rate and a significant temperature increase (~ 8 °C) by a CW laser with the same light energy, suggesting two separate mechanisms and different potential applications depending on the laser type. [ABSTRACT FROM AUTHOR]

We synthesized a dextrin (DEX)-conjugated graphene oxide (GO) nanocarrier (GO 100 -DEX) as a potential drug delivery system to respond to a tumor-associated stimulus, α-amylase, that has high permeability through the fenestrated endothelial barrier to the tumor site. At acidic pH and in the presence of α-amylase to simulate tumor conditions, GO 100 -DEX released a 1.5-fold higher amount of doxorubicin (DOX) than of GO 100 . Under the same conditions, the cytotoxic effects of GO 100 -DEX/DOX were 2-fold greater than those of free DOX and 2.9-fold greater than those of GO 100 /DOX. Employing an in vitro biomimetic microfluidic blood vessel model lined with human umbilical vein endothelial cells, we evaluated the tumor vasculature endothelial permeation of GO 100 -DEX and GO 100 using dextrans of 10 and 70 kDa for comparison and as standards to validate the microfluidic blood vessel model. The results showed that the permeabilities of GO 100 -DEX and GO 100 were 4.3- and 4.9-fold greater than that of 70 kDa dextran and 2.7- and 3.1-fold higher than that of 10 kDa dextran, thus demonstrating the good permeability of the GO-based nanocarrier through the fenestrated endothelial barrier. [ABSTRACT FROM AUTHOR]

Background: TARDOX is a Phase I single center study of ultrasound triggered targeted drug delivery in adult oncology patients with incurable liver tumours. This proof of concept study is designed to demonstrate the safety and feasibility of targeted drug release and enhanced delivery of doxorubicin from thermally sensitive liposomes (ThermoDox®) triggered by mild hyperthermia induced by focused ultrasound in liver tumours. A key feature of the study is the direct quantification of the doxorubicin concentration before and after ultrasound exposure from tumour biopsies, using high performance liquid chromatography (HPLC). Methods/Design: The study is conducted in two parts: Part 1 includes minimally-invasive thermometry via a thermistor or thermocouple implanted through the biopsy co-axial needle core, to confirm ultrasound-mediated hyperthermia, whilst Part 2 is carried out without invasive thermometry, to more closely mimic the ultimately intended clinical implementation of the technique. Whilst under a general anaesthetic, adult patients with incurable confirmed hepatic primary or secondary (metastatic) tumours receive a single cycle of ThermoDox®, immediately followed by ultrasound-mediated hyperthermia in a single target liver tumour. For each patient in Part 1, the HPLC-derived total doxorubicin concentration in the ultrasound-treated tumour is directly compared to the concentration before ultrasound exposure in that same tumour. For each patient in Part 2, as the tumour biopsy taken before ultrasound exposure is not available, the mean of those Part 1 tumour concentrations is used as the comparator. Success of the study requires at least a two-fold increase in the total intratumoural doxorubicin concentration, or final concentrations over 10 μg/g, in at least 50% of all patients receiving the drug, where tissue samples are evaluable by HPLC. Secondary outcome measures evaluate safety and feasibility of the intervention. Radiological response in the target tumour and control liver tumours are analysed as a tertiary outcome measure, in addition to plasma pharmacokinetics, fluorescence microscopy and immunohistochemistry of the biopsy samples. Discussion: If this early phase study can demonstrate that ultrasound-mediated hyperthermia can effectively enhance the delivery and penetration of chemotherapy agents intratumorally, it could enable application of the technique to enhance therapeutic outcomes across a broad range of drug classes to treat solid tumours. [ABSTRACT FROM AUTHOR]

The clinical use of liposomal drug delivery vehicles is often hindered by insufficient drug release. Here we present the rational design of liposomes optimized for secretory phospholipase A 2 (sPLA 2 ) triggered drug release, and test their utility in vitro and in vivo . We hypothesized that by adjusting the level of cholesterol in anionic, unsaturated liposomes we could tune the enzyme specificity based on membrane fluidity, thus obtaining liposomes with an improved therapeutic outcome and reduced side effects. Cholesterol is generally important as a component in the membranes of liposome drug delivery systems due to its stabilizing effects in vivo . The incorporation of cholesterol in sPLA 2 sensitive liposomes has not previously been possible due to reduced sPLA 2 activity. However, in the present work we solved this challenge by optimizing membrane fluidity. In vitro release studies revealed enzyme specific drug release. Treatment of two different cancer cell lines with liposomal oxaliplatin revealed efficient growth inhibition compared to that of clinically used stealth liposomes. The in vivo therapeutic effect was evaluated in nude NMRI mice using the sPLA 2 secreting mammary carcinoma cell line MT-3. Three days after first treatment all mice having received the novel sPLA 2 sensitive liposome formulation were euthanized due to severe systemic toxicity. Thus the present study demonstrates that great caution should be implemented when utilizing sPLA 2 sensitive liposomes and that the real utility can only be disclosed in vivo . The present studies have clinical implications, as sPLA 2 sensitive formulations are currently undergoing clinical trials (LiPlaCis®). [ABSTRACT FROM AUTHOR]

The first developed secretory phospholipase A 2 (sPLA 2 ) sensitive liposomal cisplatin formulation (LiPlaCis®) is currently undergoing clinical evaluation. In the present study we revisit and evaluate critical preclinical parameters important for the therapeutic potential and safety of platinum drugs, here oxaliplatin (L-OHP), formulated in sPLA 2 sensitive liposomes. We show the mole percentage of negatively charged phospholipid needed to obtain enzyme-sensitivity for saturated systems is ≥ 25% for 16-carbon chain lipid membranes, and > 40% for 18-chain lipid membranes, which was surprising as 25% is used clinically in LiPlaCis®. Efficient sPLA 2 -dependent growth inhibition of colorectal cancer cells was demonstrated in vitro , where cell membrane degradation and cytolysis depends on the sensitivity of the formulation towards the enzyme and is governed by the amount of lysolipids generated and the presence of serum proteins. We found that serum proteins did not affect the lipase activity of the enzyme towards the membranes but instead sequester the lysolipid byproducts consequently inhibiting their detergent-like cytotoxic properties. In vivo therapeutic potential and safety of the liposomes was investigated in nude mice bearing sPLA 2 -deficient FaDu squamous carcinoma and sPLA 2 -expressing Colo205 colorectal adenocarcinoma. After intravenous injections, the tumor growth was suppressed for liposomal L-OHP relative to free drug, but only a weak response was observed for both slow- and fast-releasing sPLA 2 -sensitive formulations compared to non-sensitive liposomes. Also, the mice did not show longer survival. In turn, for the highly sPLA 2 -sensitive liposomes, multiple high doses caused petechial cutaneous hemorrhages, along with multifocal hepatonecrotic lesions, suggestive of premature activation in skin and liver irrespective of sPLA 2 -status of the tumor engraft. These results indicate that although liposomal carriers can improve the antitumor efficacy of platinum drugs, sPLA 2 -triggered release suffers from a narrow therapeutic index and has safety concerns. [ABSTRACT FROM AUTHOR]

Supramolecular assemblies generated from self-assembling β-cyclodextrin were evaluated as hydrophobic drug carriers in vitro in aqueous conditions. The native β-cyclodextrin macrocycle was used to develop the novel host-guest assemblies with antitumor drug 2,2′-bibenzimidazole and its new derivate with n-nonyl groups at the nitrogen atoms. The morphology and sizes of these assemblies were characterized by NMR spectroscopy, DLS and TEM techniques. The interaction of the two bibenzimidazole guests with the carrier and their releasing properties under action of exogenous surfactant were investigated by means of UV–vis and fluorescence spectroscopy, DLS and TEM. The study of effect of a cationic surfactant, cetyltrimethylammonium bromide, on the stability of β-cyclodextrin–guest assemblies revealed the higher affinity of β-cyclodextrin for guest with n-nonyl groups and the higher stability of the resulting assemblies compared to those in the case of non-alkylated guest. The non-alkylated guest-rich carrier was disrupted rapidly when mixed with a surfactant trigger. The disruption of β-cyclodextrin–guest assemblies was accompanied by competitive inclusion of surfactant in β-cyclodextrin cavity which resulted in drug release from β-cyclodextrin carrier. The results of this study demonstrate the feasibility and usefulness of a trigger-responsive delivery of hydrophobic drugs using soft β-cyclodextrin assemblies. [ABSTRACT FROM AUTHOR]

In this study, a single-step microfluidic approach is reported for encapsulation of enzymes within microcapsules with ultrathin polymeric shell for controlled release triggered by an osmotic shock. Using a glass capillary microfluidic device, monodisperse water-in-oil-in-water double emulsion droplets are fabricated with enzymes in the core and an ultrathin middle oil layer that solidifies to produce a consolidated inert polymeric shell with a thickness of a few tens to hundreds of nanometers. Through careful design of microcapsule membranes, a high percentage of cargo release, over 90%, is achieved, which is triggered by osmotic shock when using poly(methyl methacrylate) as the shell material. Moreover, it is demonstrated that compared to free enzymes, the encapsulated enzyme activity is maintained well for as long as 47 days at room temperature. This study not only extends industrial applications of enzymes, but also offers new opportunities for encapsulation of a wide range of sensitive molecules and biomolecules that can be controllably released upon applying osmotic shock. [ABSTRACT FROM AUTHOR]

A strategy is proposed to design a safe and simple amphiphilic prodrug delivery system, based on the elevated expression of phospholipase D (PLD) in cancer cells. The method utilizes the transphosphatidylation ability of bacterial PLD on alcohol groups and the hydrolysis activity of overexpressed PLD on phospholipids in cancer cells. Doxorubicin (DOX) was selected as a test drug, and the phosphatidyl-doxorubicin (PX) was synthesized by bacterial PLD. The PX prodrug could be readily self-assembled to nanoparticles with uniform size and was stable during storage and circulation. The pharmacokinetics and biodistribution investigations indicated DOX could be selectively released from PX in cancer cells triggered by the local overexpressed PLD, and PX could significantly prolong the half-life of DOX in the tumors and decrease the distribution in heart and kidney. Moreover, the PX prodrug enhanced cellular uptake in MCF-7/ADR cells, demonstrating it could reverse the multi-drug resistance. Consequently, the prodrug displayed favorable anticancer efficacy in the MCF-7/ADR xenograft model without the cardiotoxicity and nephrotoxicity of DOX. The results demonstrated that phosphatidyl modification method can be used as an efficient strategy to develop a promising nanoscale drug delivery system for some drugs. [ABSTRACT FROM AUTHOR]

Individual dissimilar blocks were combined to obtain well-defined A nB n and (A-B-A) n types of cationic amphiphilic multiblock copolymers (MBCs) through mild sequential nucleophilic substitution without formation of byproducts. MBCs were synthesized by reacting end-functional polymer blocks of poly(caprolactone) (PCL), poly(ethylene glycol) (PEG), and PCL- b-PEG- b-PCL. For selective degradation, acid- and base-labile ester as well as reducible disulfide groups were introduced as linkers between the blocks. The micellar self-assemblies of these MBCs showed exceptional stability under normal physiological conditions with negligible release of the guest molecules. Selective disassembly under mildly acidic and basic conditions or in the presence of reducing agents caused triggered release of the guest molecules. This strategy is versatile and opens an opportunity to obtain a variety of tailor-made MBCs for selective and triggered release of therapeutics. [ABSTRACT FROM AUTHOR]

Reduction-sensitive chondroitin sulfate A (CSA)-based micelles were developed. CSA was conjugated with deoxycholic acid (DOCA) via a disulfide linkage. The bioreducible conjugate (CSA-ss-DOCA) can form self-assembled micelles in aqueous medium. The critical micelle concentration (CMC) of CSA-ss-DOCA conjugate is 0.047 mg/mL, and its mean diameter is 387 nm. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the micelles with high loading efficiency. Reduction-sensitive micelles and reduction-insensitive control micelles displayed similar DOX release behavior in phosphate buffered saline (PBS, pH 7.4). Notably, DOX release from the reduction-sensitive micelles in vitro was accelerated in the presence of 20 mM glutathione-containing PBS environment. Moreover, DOX-loaded CSA-ss-DOCA (CSA-ss-DOCA/DOX) micelles exhibited intracellular reduction-responsive characteristics in human gastric cancer HGC-27 cells determined by confocal laser scanning microscopy (CLSM). Furthermore, CSA-ss-DOCA/DOX micelles demonstrated higher antitumor efficacy than reduction-insensitive control micelles in HGC-27 cells. These results suggested that reduction-sensitive CSA-ss-DOCA micelles had the potential as intracellular targeted carriers of anticancer drugs. [ABSTRACT FROM AUTHOR]

Aims The objective of this work was to assess the antibacterial effect of 2-mercaptobenzothiazole ( MBT), used as model-biocide, immobilized in a layered double hydroxide ( LDH) structure, under different conditions of pH and salinity, envisaging possible applications of the system in active antifouling and anticorrosion coatings. Methods and Results Biological effects of MBT immobilized in LDH were assessed by monitoring bacterial bioluminescence of cell suspensions of either Allivibrio fischeri or a recombinant strain of Escherichia coli, as a proxy for bacterial activity. Salinity (1, 2 and 3% NaCl) and pH (4, 5, 6 and 7) of the suspension media were experimentally manipulated and biocide release tests were performed in parallel. The release profiles obtained by UV-visible spectrophotometry indicated a fast release of biocide from MBT@ LDH, slightly enhanced in 3% NaCl and under alkaline conditions. However, biological effects were more pronounced at 1% NaCl and at neutral pH. Conclusions The release and toxic effect of MBT immobilized in LDH is dependent on the concentration of solutes in the suspension medium. Significance and Impact of the Study The results confirm LDH as a biologically compatible material with potential to be used for biocide delivery. [ABSTRACT FROM AUTHOR]

Thermosensitive liposomes have been put forward as a strategy to improve upon the limited tumor drug availability associated with conventional non-thermosensitive liposomes. ThermoDox® is the first and only thermosensitive liposome formulation to reach clinical development. The initial Phase III clinical trial on ThermoDox® ( i.e. HEAT trial) evaluating the combination of ThermoDox® and radiofrequency ablation (RFA) in comparison to RFA alone for treatment of inoperable hepatocellular carcinoma (HCC) failed to reach its primary endpoint in progression-free survival (PFS). Nevertheless, a subgroup analysis demonstrated a marked improvement in PFS and a significant improvement in overall survival (OS) for patients who underwent RFA treatment for at least 45 min. Potential reasons for failure of the HEAT trial have been summarized in this review and include issues with clinical trial design, lack of supporting preclinical data, and improvements in the control arm ( i.e. RFA alone). In recent years, there have been many developments and improvements in heating infrastructure, thermometry and treatment planning of hyperthermia and ablation treatments. Still, there are many barriers to the clinical implementation and accessibility of heat treatment. This review provides an in-depth analysis of the current status, as well as potential challenges faced by continued clinical translation of thermosensitive liposomes. [ABSTRACT FROM AUTHOR]

Triggerable devices capable of on-demand, controlled release of therapeutics are attractive options for the treatment of local diseases because of their potential to enhance therapeutic effectiveness with reduced systemic toxicity. Here, the design and fabrication of a miniaturized device, termed a microspouter, is described. This device is shown to provide active and precise control of localized delivery of drugs on demand. The microspouter is composed of a magnetic sponge to provide the force for drug release through magnetic field-induced reversible deformation, a reservoir for the sponge installation and drug loading, and a soft membrane for sealing the device. Following application of a magnetic field to the microspouter, the shrinking of the sponge may trigger a spouting of drug through a membrane's microaperture. The efficiency of the device in controlling the dose and time course of drug release under different external magnetic fields has been demonstrated using methylene blue and docetaxel as model drugs. Additionally, the microspouter is found to have low background drug leakage that allows for tunable drug release in an ex vivo implantation experiment. All the results confirm the microspouter as a potential device for safe, long-time, and controlled drug release in local disease treatment. [ABSTRACT FROM AUTHOR]

Liposomes, which release their contents in answer to tripolyphosphate (TPP, a penta-anion), were prepared by immobilizing hydrophobically modified poly(ethylene imine) (HmPEI) on the surface of egg phosphatidylcholine (egg PC) liposome. HmPEI was prepared by covalently attaching decanoyl chloride to PEI through a condensation reaction. According to the1H NMR spectrum, the number of decanoyl chloride per one molecule of PEI was about 21, and HmPEI was air/water interface-active. HmPEI could readily complex with TPP in HEPES buffer (30 mM, pH 7.0), confirmed by Fourier transformed infrared spectrophotometer spectroscopy. The complexation increased with increasing the concentration of HmPEI and TPP, investigated through the measurement of optical density and light scattering intensity. Liposomes incorporating HmPEI were prepared by a film hydration and sonication method. The liposomes were multi-lamellar vesicles, observed on transmission electron microscope. Liposomes free of HmPEI did not release calcien when they were mixed with TPP. Liposomes whose egg PC/HmPEI was relatively low (e.g., 20:1 and 20:2) released calcein but not extensively (less than 10%) when mixed with TPP. Liposomes whose egg PC/HmPEI was relatively high (e.g., 20:4 and 20:20) released calcein extensively. For example, when the liposomes with lager amount of HmPEI were mixed with TPP so that HmPEI/TPP weight ratio was 8:1, the release degree in 60 sec was more than 70%. HmPEI can complex with TPP through electrostatic interaction and the complexation was thought to cause perturbation in the liposomal membranes and trigger the release. [ABSTRACT FROM PUBLISHER]

Phospholipase A 2 (PLA 2 ) is expressed in inflammation-related tissue, including cancer tumors. We report that a hybrid liposome composed of phospholipid (DPPC) and PEGylated block-copolymer (Poloxamer 188) can rapidly release an encapsulated hydrophilic drug in the presence of PLA 2 . DPPC/P188 liposomes released approximately 80% of the encapsulated calcein (a fluorescence marker) within 10 min in the presence of 120 mU of PLA 2 at 37 °C in vitro , whereas several other liposomal compositions used for inhalation therapy did not. DPPC/P188 liposomes were stable in the absence of PLA 2 at 37 °C after 60 min incubation and drug release by PLA 2 was dependent on the amount of P188 incorporated into the DPPC liposomes. Drug release from doxorubicin (DOX, anticancer drug)-loaded DPPC/P188 liposomes was facilitated at higher PLA 2 concentrations and was dependent on the temperature and the presence of calcium ion, thus partially explaining PLA 2 -responsive drug release. DOX release from liposomes triggered by PLA 2 exhibited the same cytotoxic effects on the A549 lung cancer cell line as did DOX in free solution. These findings suggest that DPPC/P188 liposomes are a promising drug carrier for delivering drug efficiently at PLA 2 -expressing sites such as inflammatory lung cancer. [ABSTRACT FROM AUTHOR]

A novel strategy of rapid transport across the blood-brain barrier (BBB) via phosphatidylethanolamine-triggered release is developed through both molecular dynamics (MD) simulation and experiments. Hydrophobic drugs, namely, propofol, iodine, and 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide, were loaded with propionylated amylose helix (HLPAH) nanoclusters to form PLPAH, ILPAH, and DLPAH nanoclusters, respectively. These clusters were subjected to MD simulation, structure measurement, in vitro triggered study, in vivo DLPAH imaging, and analysis of PLPAH sedative effects on rabbits. Results indicated that HLPAH nanoclusters were initially located on the BBB, and the helix was unfolded to release the loaded hydrophobic drugs. The released drugs crossed the BBB and performed their functions in the central nervous system (CNS) through concentration gradient and hydrophobicity. This mechanism of HLPAH across the BBB featured high membrane permeability and specificity, rapid onset, short maintenance, rapid recovery, and lower dosage of drugs. Hence, this novel strategy is very meaningful for the development of CNS drug carriers and the proposed system could be used to improve the therapeutic effects of CNS diseases. [ABSTRACT FROM AUTHOR]