A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

Unlocking new dimensions in long-acting injectables using lipid mesophase-based beads.

In this study, we explored the use of lipid mesophases (LMPs) as a biocompatible and biodegradable material for sustained drug delivery. Our hypothesis centered on leveraging the high surface-to-volume ratio of LMP-based beads to enhance strength, stability, and surface interaction compared to the LMP bulk gel. To modulate drug release, we introduced antioxidant vitamin E into the beads, influencing mesophase topologies and controlling drug diffusion coefficients. Four drugs with distinct chemical properties and intended for three different pathologies and administration routes were successfully loaded into the beads with a drug entrapment efficiency exceeding 80 %. Notably, our findings revealed sustained drug release, irrespective of the drugs' chemical properties, culminating in the development of an injectable formulation. This formulation allows direct administration into the target site, minimizing systemic exposure, and thereby mitigating adverse effects. Our approach demonstrates the potential of LMP-based beads for tailored drug delivery systems with broad applications in diverse therapeutic scenarios.

Rapid liposomal formulation for nucleolin targeting to rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations.

3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases.

The peritoneal cavity offers an attractive administration route for challenging-to-treat diseases, such as peritoneal carcinomatosis, post-surgical adhesions, and peritoneal fibrosis. Achieving a uniform and prolonged drug distribution throughout the entire peritoneal space, though, is difficult due to high clearance rates, among others. To address such an unmet clinical need, alternative drug delivery approaches providing sustained drug release, reduced clearance rates, and a patient-centric strategy are required. Here, we describe the development of a 3D-printed composite platform for the sustained release of the tyrosine kinase inhibitor gefitinib (GEF), a small molecule drug with therapeutic applications for peritoneal metastasis and post-surgical adhesions. We present a robust method for the production of biodegradable liposome-loaded hydrogel microbeads that can overcome the pharmacokinetic limitations of small molecules with fast clearance rates, a current bottleneck for the intraperitoneal (IP) administration of these therapeutics. By means of an electromagnetic droplet printhead, we 3D printed microbeads employing an alginate-based ink loaded with GEF-containing multilamellar vesicles (MLVs). The sustained release of GEF from microbeads was demonstrated. In vitro studies on an immortalized human hepatic cancer cell line (Huh-7) proved concentration-dependent cell death. These findings demonstrate the potential of 3D-printed alginate microbeads containing liposomes for delivering small drug compounds into the peritoneum, overcoming previous limitations of IP drug delivery.

Polyenylphosphatidylcholine as bioactive excipient in tablets for the treatment of liver fibrosis.

Liver fibrosis is a condition characterized by the accumulation of extracellular matrix (ECM) arising from the myofibroblastic transdifferentiation of hepatic stellate cells (HSCs) occurring as the natural response to liver damage. To date, no pharmacological treatments have been specifically approved for liver fibrosis. We recently reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs. However, unsaturated phospholipids' properties pose a constant challenge to the development of tablets as preferred patient-centric dosage form. Profiting from the advantageous physical properties of the PPCs-rich Soluthin® S 80 M, we developed a tablet formulation incorporating 70% w/w of this bioactive lipid. Tablets were characterized via X-ray powder diffraction, thermogravimetry, and Raman confocal imaging, and passed the major compendial requirements. To mimic physiological absorption after oral intake, phospholipids extracted from tablets were reconstituted as protein-free chylomicron (PFC)-like emulsions and tested on the fibrogenic human HSC line LX-2 and on primary cirrhotic rat hepatic stellate cells (PRHSC). Lipids extracted from tablets and reconstituted in buffer or as PFC-like emulsions exerted the same antifibrotic effect on both activated LX-2 and PRHSCs as observed with plain S 80 M liposomes, showing that the manufacturing process did not interfere with the bioactivity of PPCs.

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction.

Liposomes show promise as biolubricants for damaged cartilage, but their small size results in low joint and cartilage retention. We developed a zinc ion-based liposomal drug delivery system for local osteoarthritis therapy, focusing on sustained release and tribological protection from phospholipid lubrication properties. Our strategy involved inducing aggregation of negatively charged liposomes with zinc ions to extend rapamycin (RAPA) release and improve cartilage lubrication. Liposomal aggregation occurred within 10 min and was irreversible, facilitating excess cation removal. The aggregates extended RAPA release beyond free liposomes and displayed irregular morphology influenced by RAPA. At nearly 100 µm, the aggregates were large enough to exceed the previously reported size threshold for increased joint retention. Tribological assessment on silicon surfaces and ex vivo porcine cartilage revealed the system's excellent protective ability against friction at both nano- and macro-scales. Moreover, RAPA was shown to attenuate the fibrotic response in human OA synovial fibroblasts. Our findings suggest the zinc ion-based liposomal drug delivery system has potential to enhance OA therapy through extended release and cartilage tribological protection, while also illustrating the impact of a hydrophobic drug like RAPA on liposome aggregation and morphology.

Temperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis.

Ulcerative colitis is a chronic inflammatory bowel disease that strongly affects patient quality of life. Side effects of current therapies necessitate new treatment strategies that maximise the drug concentration at the site of inflammation, while minimizing systemic exposure. Capitalizing on the biocompatible and biodegradable structure of lipid mesophases, we present a temperature-triggered in situ forming lipid gel for topical treatment of colitis. We show that the gel is versatile and can host and release drugs of different polarities, including tofacitinib and tacrolimus, in a sustained manner. Further, we demonstrate its adherence to the colonic wall for at least 6 h, thus preventing leakage and improving drug bioavailability. Importantly, we find that loading known colitis treatment drugs into the temperature-triggered gel improves animal health in two mouse models of acute colitis. Overall, our temperature-triggered gel may prove beneficial in ameliorating colitis and decreasing adverse effects associated with systemic application of immunosuppressive treatments.

Mucoadhesive 3D printed vaginal ovules to treat endometriosis and fibrotic uterine diseases.

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

Open pathways for cerebrospinal fluid outflow at the cribriform plate along the olfactory nerves.

BACKGROUND: Routes along the olfactory nerves crossing the cribriform plate that extend to lymphatic vessels within the nasal cavity have been identified as a critical cerebrospinal fluid (CSF) outflow pathway. However, it is still unclear how the efflux pathways along the nerves connect to lymphatic vessels or if any functional barriers are present at this site. The aim of this study was to anatomically define the connections between the subarachnoid space and the lymphatic system at the cribriform plate in mice. METHODS: PEGylated fluorescent microbeads were infused into the CSF space in Prox1-GFP reporter mice and decalcification histology was utilized to investigate the anatomical connections between the subarachnoid space and the lymphatic vessels in the nasal submucosa. A fluorescently-labelled antibody marking vascular endothelium was injected into the cisterna magna to demonstrate the functionality of the lymphatic vessels in the olfactory region. Finally, we performed immunostaining to study the distribution of the arachnoid barrier at the cribriform plate region. FINDINGS: We identified that there are open and direct connections from the subarachnoid space to lymphatic vessels enwrapping the olfactory nerves as they cross the cribriform plate towards the nasal submucosa. Furthermore, lymphatic vessels adjacent to the olfactory bulbs form a continuous network that is functionally connected to lymphatics in the nasal submucosa. Immunostainings revealed a discontinuous distribution of the arachnoid barrier at the olfactory region of the mouse. INTERPRETATION: Our data supports a direct bulk flow mechanism through the cribriform plate allowing CSF drainage into nasal submucosal lymphatics in mice. FUNDING: This study was supported by the Swiss National Science Foundation (310030_189226), Dementia Research Switzerland-Synapsis Foundation, the Heidi Seiler Stiftung and the Fondation Dr. Corinne Schuler.

Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine.

By direct deposition of the drug at the local site of action, injectable depot formulations - intended for treatment of a local disease or for local intervention - are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots. In vivo imaging of the fluorescently-labelled liposomes showed a significantly higher retention of the PG liposomes at the injection site with respect to zwitterionic ones. In situ mixing of PG liposomes with calcium salts significantly extended the area under the curve of BUP in plasma compared to the non-depot system. Overall, controlling the aggregation of negatively charged liposomes with divalent cations not only modulated the particle clearance from the injection site but also the release in vivo of a small amphipathic drug such as BUP.

A lipidic mesophase with tunable release properties for the local delivery of macromolecules: the apoferritin nanocage, a case study.

Lipid mesophases are able to incorporate and release a plethora of molecules, spanning from hydrophobic drugs to small hydrophilic proteins and therefore they have been widely used as drug delivery systems. However, their 3-5 nm water channels do not allow the release of large hydrophilic molecules such as monoclonal antibodies and therapeutic proteins. To overcome this major geometrical constraint, we designed a gel by mixing monoacylglycerol lipids, generally recognized as safe for human and/or animal use by FDA, and phospholipids, to obtain a material with swollen water channels suitable to host and further release macromolecules. Apoferritin, a 12 nm nanocage protein with intrinsic tumor-targeting properties able to incorporate several molecules, was selected here as the hydrophilic model protein to be embedded in the biocompatible gel. When immersed completely in the release media, mesophases with a swollen water channel of 22 nm, composed of monoolein and doped with 5 mole% of DOPS and 10 mole% of Chol allowed us to achieve a protein release of 60%, which is 120 times higher with respect to that obtained by employing non swollen-LMPs composed only of monoolein. Thus, the formulation can be administered locally to the rectal or vaginal mucosa, reducing the drawbacks often associated with the parenteral administration of bio-therapeutics. This approach would pave the way for the local application of other biomacromolecules (including human ferritin, monoclonal antibodies and antibody drug-conjugates) in those diseases easily reachable by a local application such as rectal or vaginal cancer.

Overcoming Endocytosis Deficiency by Cubosome Nanocarriers.

The use of lipid-based nanoparticles for the delivery of biomacromolecules has attracted considerable attention due to the current interest in protein-based therapeutics. Cubosomes protect the incorporated therapeutics, which are susceptible to degradation by enzymes, thereby improving their bioavailability, and concomitantly enhance cellular uptake. The cubosome nanoparticles presented herein were loaded with bovine serum albumin (BSA) and characterized by small-angle X-ray scattering and dynamic light scattering techniques, while the BSA encapsulation and its release were evaluated in vitro. The ability of this formulation to increase the cellular uptake of albumin by 2-fold was tested on various types of renal tubular cells and confirmed by in vivo renal uptake experiments in mice. The obtained results show that cubosomes are able to deliver BSA inside the cell through distinct uptake and intracellular routing. These data were substantiated, with evidence of a high cubosome-mediated uptake of BSA in Clcn5 knockout mice characterized by defective receptor-mediated endocytosis. The use of cubosomes as a delivery system thus represents a promising approach to overcome the low endocytic uptake in diseased epithelial cells and to treat dysfunctions of the kidney proximal tubule.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review.

OBJECTIVES: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. KEY FINDINGS: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. SUMMARY: Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

Towards a better understanding of solid dispersions in aqueous environment by a fluorescence quenching approach.

Solid dispersions (SDs) represent an important formulation technique to achieve supersaturation in gastro-intestinal fluids and to enhance absorption of poorly water-soluble drugs. Extensive research was leading to a rather good understanding of SDs in the dry state, whereas the complex interactions in aqueous medium are still challenging to analyze. This paper introduces a fluorescence quenching approach together with size-exclusion chromatography to study drug and polymer interactions that emerge from SDs release testing in aqueous colloidal phase. Celecoxib was used as a model drug as it is poorly water-soluble and also exhibits native fluorescence so that quenching experiments were enabled. Different pharmaceutical polymers were evaluated by the (modified) Stern-Volmer model, which was complemented by further bulk analytics. Drug accessibility by the quencher and its affinity to celecoxib were studied in physical mixtures as well as with in SDs. The obtained differences enabled important molecular insights into the different formulations. Knowledge of relevant drug-polymer interactions and the amount of drug embedded into polymer aggregates in the aqueous phase is of high relevance for understanding of SD performance. The novel fluorescence quenching approach is highly promising for future research and it can provide guidance in early formulation development of native fluorescent compounds.

Dynamic Light Scattering of Biopharmaceutics-Can Analytical Performance Be Enhanced by Laser Power?

BACKGROUND: Dynamic light scattering (DLS) is an important tool to characterize colloidal systems and adequate sizing is particularly critical in the field of protein formulations. Among the different factors that can influence the measurement result, the effect of laser power has so far not been studied thoroughly. METHODS: The sensitivity of a DLS instrument was first considered on a theoretical level, followed by experiments using DLS instruments, equipped with two different lasers of (nominal) 45 mW, and 100 mW, respectively. This work analyzes dilute colloidal dispersions of lysozyme as model protein. RESULTS: Theoretical findings agreed with experiments in that only enhanced laser power of 100 mW laser allowed measuring a 0.1 mg/mL protein dispersion in a reliable manner. Results confirmed the usefulness of the presented theoretical considerations in improving a general understanding of the limiting factors in DLS. CONCLUSIONS: Laser power is a critical aspect regarding adequate colloidal analysis by DLS. Practical guidance is provided to help scientists specifically with measuring dilute samples to choose both an optimal instrument configuration as well as a robust experimental procedure.

Temperature-Induced Surface Effects on Drug Nanosuspensions.

PURPOSE: The trial-and-error approach is still predominantly used in pharmaceutical development of nanosuspensions. Physicochemical dispersion stability is a primary focus and therefore, various analytical bulk methods are commonly employed. Clearly less attention is directed to surface changes of nanoparticles even though such interface effects can be of pharmaceutical relevance. Such potential effects in drug nanosuspensions were to be studied for temperatures of 25 and 37°C by using complementary surface analytical methods. METHODS: Atomic force microscopy, inverse gas chromatography and UV surface dissolution imaging were used together for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Fenofibrate and bezafibrate were selected as model drugs in presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. RESULTS: It was demonstrated that in case of bezafibrate nanosuspension, a surface modification occurred at 37°C compared to 25°C, which notably affected dissolution rate. By contrast, no similar effect was observed in case of fenofibrate nanoparticles. CONCLUSIONS: The combined usage of analytical surface methods provides the basis for a better understanding of phenomena that take place on drug surfaces. Such understanding is of importance for pharmaceutical development to achieve desirable quality attributes of nanosuspensions.

Study of Rheology and Polymer Adsorption Onto Drug Nanoparticles in Pharmaceutical Suspensions Produced by Nanomilling.

Nanosuspensions provide a drug delivery approach to cope with erratic absorption of poorly water-soluble compounds. Despite extensive research over the last years, there are still open pharmaceutical challenges so it is often unclear how quality attributes such as viscosity and physical stability are generated, which requires a more thorough study of the colloidal structures and interactions in nanosuspensions. In this study, diffusing wave spectroscopy and microfluidics-based rheology were used for the first time to assess pharmaceutical nanosuspensions that were obtained by wet milling. Further sample characterization following centrifugation was based on optical rotatory dispersion and conductivity experiments. Ketoconazole was selected as model drug in the presence of sodium dodecyl sulfate and hydroxypropyl cellulose as anionic and steric stabilizer, respectively. The results unexpectedly showed that the investigated nanosuspensions did not behave as Einstein-like suspensions because a viscosity decrease was evidenced for increased drug load. This effect was attributed to the polymer that formed a dominating network in the bulk solution from where adsorption occurred onto particle surfaces. This depletion of bulk polymer caused the observed rheological finding. Further colloidal research should be invested into different pharmaceutical nanosuspensions to gain a more complete structural understanding and to harness their full technological potential.

Liquid chromatography/mass spectrometry identification of intermediates and vulcanization products by using squalene as vulcanization model compound.

RATIONALE: Sulfur-vulcanized rubber is a three-dimensional polymer network, insoluble in all organic solvents. For this reason, vulcanization products are difficult to study and identify by conventional analytical techniques. To simplify this task, low molecular weight olefins have been used as model compounds (MCs) in place of rubber in vulcanization experiments. METHODS: In this work, the vulcanization process was investigated using squalene (SQ) as MC. By-products, intermediates and products were separated by semipreparative reversed-phase liquid chromatography (RPLC) with UV detection. Each fraction was collected, concentrated and characterized by flow injection analysis (FIA) and non-aqueous reversed-phase (NARP) LC coupled to positive atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Under the latter conditions, an Information-Dependent Acquisition (IDA) was performed on a linear ion trap mass spectrometer to obtain structural information. RESULTS: Several vulcanized compounds containing up to three SQ molecules, cross-linked with chains involving up to 14 sulfur atoms overall, have been identified along with some of their oxidized products (epoxides and hydroperoxides). The FIA-MS spectra showed peak clusters, each of which included two-three subclusters; the interpretation was complicated by the occurrence of more ion species per product, by the unsaturation grade and by the characteristic isotopic distribution of sulfur. The enhanced product ion scan (EPI) spectra, acquired during the IDA experiments, supported the FIA-MS identification allowing one to count the number of sulfur atoms. CONCLUSIONS: The sensitivity of the developed analytical strategy was due to the enrichment factor achieved via semipreparative chromatography and the very good response of the APCI detection. Pattern fragmentation and chromatographic behavior simplified the identification of the cured compounds and their oxidized products, whose occurrence was related to the grade of oxidation of SQ used as reagent. Copyright © 2016 John Wiley & Sons, Ltd.

Biotinylated Cubosomes: A Versatile Tool for Active Targeting and Codelivery of Paclitaxel and a Fluorescein-Based Lipid Dye.

The functionalization of cubosomes with biotin is reported here as an alternative method for the preparation of drug delivery systems capable of active targeting specific receptors that are (over)expressed by cancer cells. We describe the design, synthesis, assembly, and characterization of these novel cubosome nanoparticles by small-angle X-ray scattering (SAXS) and dynamic laser light scattering (DLS) and show their application to human adenocarcinoma cell line HeLa. These cubosomes are stabilized and functionalized with a novel, designed biotin-based block copolymer and are able to simultaneously transport paclitaxel, a potent anticancer drug, and a hydrophobic fluorescent dye in the active targeting of cancer cells. Such biotinylated cubosomes are potentially applicable in diagnosis, drug delivery, and monitoring of the therapeutic response for active targeting versus cancer cells.

Design of Light-Triggered Lyotropic Liquid Crystal Mesophases and Their Application as Molecular Switches in "On Demand" Release.

Here, we present the design and assembly of a new light-responsive functional lyotropic liquid crystal system using host-guest lipidic mesophases (LMPs). Light as an external stimulus has many advantages in comparison to other stimuli: it is milder than acids or bases, and variation of intensity and duration can provide a high level of pharmacological control. The LMPs are composed of monoolein (MO) and oleic acid (OA) as host lipids and a small amount of a judiciously synthesized lipid bearing an azobenzene photoactive unit as a guest. While preserving the structure and stability of the host lipidic aggregates, the guest lipids render them specific functionalities. Single-step and sequential light-triggered release and retention of the embedded dye molecules are demonstrated, thereby achieving exquisite temporal, spatial, and dosage control of the release, opening up the possibility of using such lipidic biomaterials as effective matrices in therapy, when a continuous release of active drugs might be toxic.