Angiopep-2-Functionalized Lipid Cubosomes for Blood-Brain Barrier Crossing and Glioblastoma Treatment.

Glioblastoma multiforme (GBM) is an aggressive brain cancer with high malignancy and resistance to conventional treatments, resulting in a bleak prognosis. Nanoparticles offer a way to cross the blood-brain barrier (BBB) and deliver precise therapies to tumor sites with reduced side effects. In this study, we developed angiopep-2 (Ang2)-functionalized lipid cubosomes loaded with cisplatin (CDDP) and temozolomide (TMZ) for crossing the BBB and providing targeted glioblastoma therapy. Developed lipid cubosomes showed a particle size of around 300 nm and possessed an internal ordered inverse primitive cubic phase, a high conjugation efficiency of Ang2 to the particle surface, and an encapsulation efficiency of more than 70% of CDDP and TMZ. In vitro models, including BBB hCMEC/D3 cell tight monolayer, 3D BBB cell spheroid, and microfluidic BBB/GBM-on-a-chip models with cocultured BBB and glioblastoma cells, were employed to study the efficiency of the developed cubosomes to cross the BBB and showed that Ang2-functionalized cubosomes can penetrate the BBB more effectively. Furthermore, Ang2-functionalized cubosomes showed significantly higher uptake by U87 glioblastoma cells, with a 3-fold increase observed in the BBB/GBM-on-a-chip model as compared to that of the bare cubosomes. Additionally, the in vivo biodistribution showed that Ang2 modification could significantly enhance the brain accumulation of cubosomes in comparison to that of non-functionalized particles. Moreover, CDDP-loaded Ang2-functionalized cubosomes presented an enhanced toxic effect on U87 spheroids. These findings suggest that the developed Ang2-cubosomes are prospective for improved BBB crossing and enhanced delivery of therapeutics to glioblastoma and are worth pursuing further as a potential application of nanomedicine for GBM treatment.

Cell interactions with lipid nanoparticles possessing different internal nanostructures: Liposomes, bicontinuous cubosomes, hexosomes, and discontinuous micellar cubosomes.

HYPOTHESIS: Lyotropic liquid crystalline nanoparticles (LLCNPs) with complex internal nanostructures hold promise for drug delivery. Cubosomes, in particular, have garnered interest for their ability to fuse with cell membranes, potentially bypassing endosomal escape challenges and improving cellular uptake. The mesostructure of nanoparticles plays a crucial role in cellular interactions and uptake. Therefore, we hypothesise that the specific internal mesophase of the LLCNPs will affect their cellular interactions and uptake efficiencies, with cubosomes exhibiting superior cellular uptake compared to other LLCNPs. EXPERIMENTS: LLCNPs with various mesophases, including liposomes, cubosomes, hexosomes, and micellar cubosomes, were formulated and characterised. Their physicochemical properties and cytotoxicity were assessed. Chinese Hamster Ovarian (CHO) cells were treated with fluorescently labelled LLCNPs, and their interactions were monitored and quantified through confocal microscopy and flow cytometry. FINDINGS: The non-lamellar LLCNPs showed significantly higher cellular interactions compared to liposomes, with cubosomes exhibiting the highest level. However, there was no significant difference in relative cell uptake between cubosomes, hexosomes, and micellar cubosomes. Cell uptake experiments at 4 °C revealed the presence of an energy-independent uptake mechanism. This study provides the first comparative analysis of cellular interactions and uptake efficiencies among LLCNPs with varying mesophases, while maintaining similar size, composition, and surface charge.

Paclitaxel-loaded cubosome lipid nanocarriers stabilised with pH and hydrogen peroxide-responsive steric stabilisers as drug delivery vehicles.

Responsive nanoparticle delivery systems hold great potential for next-generation chemotherapeutic treatment with reduced off-target side effects. In this work, we formulated responsive lipid-based cubosomes loaded with paclitaxel (PTX) as a model drug and stabilised by novel amphiphilic block copolymers (ABCs) containing the pH-responsive poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and/or the hydrogen peroxide (H2O2)-responsive poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) blocks. The results showed that these cubosomes with a particle size of around 250 nm exhibited excellent PTX encapsulation efficiency of up to 60% and had the ability to control the release rate of the drug in response to pH and H2O2 changes. Specifically, compared to the physiological pH of 7.4, PTX was released faster from the cubosome carriers when exposed to pH 5.5 and/or 50 mM H2O2 conditions, which are pathological conditions found in a tumour microenvironment. In vitro cytotoxicity and cell uptake studies further investigated the cellular interactions of these cubosomes. It was found that cubosomes containing PTX had more toxic effects than the control free PTX sample. Compared to cubosomes stabilised by the non-responsive block copolymer Pluronic® F127, the ABC-stabilised cubosomes also had higher cell internalisation efficiency demonstrated by the cytoplasmic fluorescence intensities using confocal microscopy. These results demonstrated that ABCs containing responsive moieties can stabilise lipid cubosomes and enhance controlled release of poorly soluble chemotherapeutics and cellular uptake.

Novel pH-Responsive Cubosome and Hexosome Lipid Nanocarriers of SN-38 Are Prospective for Cancer Therapy.

pH-responsive nanoparticles enable the selective delivery of a chemotherapeutic agent to tumours while reducing adverse effects. Herein we synthesised four novel aminolipids and developed pH-responsive nanostructured lipid nanoparticles (LNP), which exhibited a slow-releasing hexagonal structure (H2) at physiological pH and quick release bicontinuous cubic phase (Q2) at the acidic tumour pH. The nanoparticles were used to encapsulate and control the release of the chemotherapeutic agent SN-38. High-throughput formulation techniques were employed to fabricate LNP by mixing various amounts of aminolipid with monoolein (MO). The effect of aminolipids on MO self-assembled structures was studied using small-angle X-ray scattering (SAXS) at various pH values. Out of the four studied aminolipid-MO LNP systems, the nanoparticles containing N-(Pyridin-4-ylmethyl) oleamide (OAPy-4) or N-(2(piperidin-1yl)ethyl) oleamide (OAPi-1) exhibited a pH-induced H2 to Q2 phase transition in a tumour-relevant pH range (pH 5.5-7.0). SN-38 is 1000 times more efficacious than the commercially available prodrug irinotecan. However, low solubility in water and instability at physiological pH makes it unsuitable for clinical use. SN-38 was loaded into LNP containing MO and aminolipid OAPy-4. The drug loading and entrapment efficiency were determined, and the results indicated that the aqueous solubility of SN-38 loaded in LNP dispersions was ~100 times higher compared to the solubility of the pure drug in aqueous solution. Furthermore, we demonstrated that the in vitro SN-38 release rate from LNPs was faster at lower pH (pH 5) than at neutral pH. Therefore, pH-responsive LNPs developed in this study can potentially be employed in delivering and controlling the release of the potent drug SN-38 to tumour sites.

Application of Fluconazole-Loaded pH-Sensitive Lipid Nanoparticles for Enhanced Antifungal Therapy.

Cryptococcus neoformans is a yeast-like fungus that can cause the life-threatening disease cryptococcal meningitis. Numerous reports have shown increased resistance of this fungus against antifungal treatments, such as fluconazole (Fluc), contributing to an 80% global mortality rate. This work presents a novel approach to improve the delivery of the antifungal agent Fluc and increase the drug's targetability and availability at the infection site. Exploiting the acidic environment surrounding a C. neoformans infected site, we have developed pH-sensitive lipid nanoparticles (LNP) encapsulating Fluc to inhibit the growth of resistant C. neoformans. The LNP-Fluc delivery system consists of a neutral lipid monoolein (MO) and a novel synthetic ionizable lipid 2-morpholinoethyl oleate (O2ME). At neutral pH, because of the presence of O2ME, the nanoparticles are neutral and exhibit a liquid crystalline hexagonal nanostructure (hexosomes). At an acidic pH, they are positively charged with a cubic nanostructure (cubosomes), which facilitates the interaction with the negatively charged fungal cell wall. This interaction results in the MIC50 and MIC90 values of the LNP-Fluc being significantly lower than that of the free-Fluc control. Confocal laser scanning microscopy and scanning electron microscopy further support the MIC values, showing fungal cells exposed to LNP-Fluc at acidic pH were heavily distorted, demonstrating efflux of cytoplasmic molecules. In contrast, fungal cells exposed to Fluc alone showed cell walls mostly intact. This current study represents a significant advancement in delivering targeted antifungal therapy to combat fungal antimicrobial resistance.

Controlling the pH dependent transition between monoolein Fd3m micellar cubosomes and hexosomes using fatty acetate and fatty acid additive mixtures.

HYPOTHESIS: Cubosomes made from the inverse micellar cubic mesophase (I2) with Fd3m symmetry possess a unique structure of closely packed inverse micelles. These have prospective functionality in sustained drug release. In this study, we hypothesised that similar to fatty acids, various fatty acetate compounds can induce the formation of micellar Fd3m cubosomes in monoolein (MO) nanoparticles. They are different to micellar cubosomes made of MO and a fatty acid, which are pH responsive and can transition from an Fd3m phase to an inverse hexagonal phase (H2) as pH increases. We hypothesised that by co-doping a fatty acetate and fatty acid into MO, precise control of the Fd3m-H2 phase transition pH in nanoparticles can be achieved. EXPERIMENTS: Five unsaturated fatty acetates with hydrocarbon chain lengths between 18 and 24 were added to MO at a weight ratio of 0.45 - 0.60 to form nanoparticles. The nanoparticles were prepared using high-throughput formulation and characterised with synchrotron small angle X-ray scattering (SAXS). MO nanoparticles doped with vaccenyl acetate and vaccenic acid were used to demonstrate the fine control over Fd3m-H2 phase transition pH. FINDINGS: Micellar cubosomes (Fd3m phase) were found in MO nanoparticles doped with fatty acetates. The Fd3m structure was stable in a wide pH range of 2.6 - 8 and at temperatures up to 45 °C. In MO nanoparticles doped with the acetate/acid mixture, the Fd3m-H2 phase transition pH was tuned between pH 5 and pH 7 by adjusting the ratio of vaccenyl acetate and vaccenic acid. As a H2 phase generally offers faster drug release than an Fd3m phase, the pH responsive lipid nanoparticles developed here may find application in orally administrated formulation, where the vehicles must pass a low pH environment in the stomach before reaching neutral pH in the blood.

Generation of programmable dynamic flow patterns in microfluidics using audio signals.

Customised audio signals, such as musical notes, can be readily generated by audio software on smartphones and played over audio speakers. Audio speakers translate electrical signals into the mechanical motion of the speaker cone. Coupling the inlet tube to the speaker cone causes the harmonic oscillation of the tube, which in turn changes the velocity profile and flow rate. We employ this strategy for generating programmable dynamic flow patterns in microfluidics. We show the generation of customised rib and vortex patterns through the application of multi-tone audio signals in water-based and whole blood samples. We demonstrate the precise capability to control the number and extent of the ribs and vortices by simply setting the frequency ratio of two- and three-tone audio signals. We exemplify potential applications of tube oscillation for studying the functional responses of circulating immune cells under pathophysiological shear rates. The system is programmable, compact, low-cost, biocompatible, and durable. These features make it suitable for a variety of applications across chemistry, biology, and physics.

Single-Step Fabrication Method toward 3D Printing Composite Diamond-Titanium Interfaces for Neural Applications.

Owing to several key attributes, diamond is an attractive candidate material for neural interfacing electrodes. The emergence of additive-manufacturing (AM) of diamond-based materials has addressed multiple challenges associated with the fabrication of diamond electrodes using the conventional chemical vapor deposition (CVD) approach. Unlike the CVD approach, AM methods have enabled the deposition of three-dimensional diamond-based material at room temperature. This work demonstrates the feasibility of using laser metal deposition to fabricate diamond-titanium hybrid electrodes for neuronal interfacing. In addition to exhibiting a high electrochemical capacitance of 1.1 mF cm-2 and a low electrochemical impedance of 1 kΩ cm2 at 1 kHz in physiological saline, these electrodes exhibit a high degree of biocompatibility assessed in vitro using cortical neurons. Furthermore, surface characterization methods show the presence of an oxygen-rich mixed-phase diamond-titanium surface along the grain boundaries. Overall, we demonstrated that our unique approach facilitates printing biocompatible titanium-diamond site-specific coating-free conductive hybrid surfaces using AM, which paves the way to printing customized electrodes and interfacing implantable medical devices.

Broad-Spectrum Solvent-free Layered Black Phosphorus as a Rapid Action Antimicrobial.

Antimicrobial resistance has rendered many conventional therapeutic measures, such as antibiotics, ineffective. This makes the treatment of infections from pathogenic micro-organisms a major growing health, social, and economic challenge. Recently, nanomaterials, including two-dimensional (2D) materials, have attracted scientific interest as potential antimicrobial agents. Many of these studies, however, rely on the input of activation energy and lack real-world utility. In this work, we present the broad-spectrum antimicrobial activity of few-layered black phosphorus (BP) at nanogram concentrations. This property arises from the unique ability of layered BP to produce reactive oxygen species, which we harness to create this unique functionality. BP is shown to be highly antimicrobial toward susceptible and resistant bacteria and fungal species. To establish cytotoxicity with mammalian cells, we showed that both L929 mouse and BJ-5TA human fibroblasts were metabolically unaffected by the presence of BP. Finally, we demonstrate the practical utility of this approach, whereby medically relevant surfaces are imparted with antimicrobial properties via functionalization with few-layer BP. Given the self-degrading properties of BP, this study demonstrates a viable and practical pathway for the deployment of novel low-dimensional materials as antimicrobial agents without compromising the composition or nature of the coated substrate.

Synthetic ionizable aminolipids induce a pH dependent inverse hexagonal to bicontinuous cubic lyotropic liquid crystalline phase transition in monoolein nanoparticles.

A prospective class of materials for drug delivery is lyotropic liquid crystalline (LLC) nanoparticles, such as cubosomes and hexosomes. Efforts are being made to generate a pH dependent system, which exhibits slow release hexosomes (H2) at physiological pH and relatively fast release cubosomes (Q2) at acidic disease sites such as in various cancers and bacterial infection (pH ~ 5.5-6.5). Herein, we report the synthesis of nine ionizable aminolipids, which were doped into monoolein (MO) lipid nanoparticles. Using high throughput formulation and synchrotron small angle X-ray scattering (SAXS), the effects of aminolipid structure and concentration on the mesophase of MO nanoparticles at various pHs were determined. As the pH changed from neutral to acidic, mesophases, could be formed in an order L2 (inverse micelles) â†’ H2 â†’ Q2. Specifically, systems with heterocyclic oleates exhibited the H2 to Q2 transition at pH 5.5-6.5. Furthermore, the phase transition pH could be fine-tuned by incorporating two aminolipids into the nanoparticles. Nanoparticles with a pH dependent phase transition as described in this study may be useful as drug delivery carriers for the treatment of cancers and certain bacterial infection.

Cuboplex-Mediated Nonviral Delivery of Functional siRNA to Chinese Hamster Ovary (CHO) Cells.

Lipid nanoparticles of internal cubic symmetry, termed cuboplexes, are potential nonviral delivery vehicles for gene therapy due to their "topologically active" nature, which may enhance endosomal escape and improve delivery outcomes. In this study, we have used cationic cuboplexes, based on monoolein (MO) doped with a cationic lipid, for the encapsulation and delivery of antisense green fluorescent protein (GFP)-small interfering RNA (siRNA) into Chinese Hamster Ovary (CHO)-GFP cells. Agarose gel electrophoresis has confirmed the successful encapsulation of siRNA within cationic cubosomes, while synchrotron small-angle X-ray scattering (SAXS) demonstrated that the underlying cubic nanostructure of the particles was retained following encapsulation. The cationic cubosomes were shown to be reasonably nontoxic against the CHO-GFP cell line. Fluorescence-activated cell sorting (FACS) provided evidence of the successful transfection to CHO-GFP cells. Knockdown efficiency was strongly linked to the type of cationic lipid used, although all cubosomes had essentially the same internal nanostructure. The gene knockdown efficiency for some cationic cubosomes was shown to be higher than lipofectamine, which is a commercially available liposome-based formulation, while the controlled release of the siRNA from the cubosomes over a 72 h period was observed using confocal microscopy. This combination exemplifies the potential of cationic cuboplexes as a novel, nonviral, controlled-release delivery vector for siRNA.

Osteoblast Cell Response on Polycrystalline Diamond-Coated Additively Manufactured Scaffolds.

Additive manufacturing of metals using selective laser melting can create customized parts with various degrees of complexity and geometry for medical implants. However, challenges remain in accepting orthopedic implants due to the bio-inert surface of metal scaffolds, resulting in a lack of osseointegration. Here, we show that polycrystalline diamond (PCD) coatings on selective laser melted titanium (SLM-Ti) scaffolds can improve the cell-to-material interaction of osteoblasts. The results show that by controlling the uniformity of the diamond coatings, we can mediate the biological response of osteoblasts, such as cell adhesion, proliferation, and spreading. The osteoblasts show favorable cell adhesion and spreading on non-planar PCD-coated scaffolds compared to the un-coated SLM-Ti scaffold. This study plays an important role in understanding the key physicochemical behavior of bone cell growth on customized orthopedic implant materials.

Tuning Nanostructured Lyotropic Liquid Crystalline Mesophases in Lipid Nanoparticles with Protic Ionic Liquids.

We herein report 13 protic ionic liquids (PILs) as tunable solvation media to regulate the internal lyotropic liquid crystalline mesophase of monoolein-based nanoparticles. A range of nanostructures, including inverse bicontinuous cubic, inverse hexagonal, and sponge/lamellar mesophases, were produced and verified by synchrotron small-angle X-ray scattering. Notably, manipulating the cation/anion structures of the PILs can alter the monoolein packing behavior and cause a sequential phase transition (hexagonal → cubic → lamellar) in the nanoparticles. The solvent channels inside the nanoparticles were enlarged up to 40% under certain PIL-water conditions, making these materials prospective for encapsulation of large molecules. Finally, a freeze-drying study demonstrated the ability of PILs to preserve nanostructure upon reconstitution of the nanoparticles compared to that in pure water. This study opens a new route for fine-tuning lyotropic liquid crystalline structures using PILs, which circumvents issues encountered using conventional salts.

Nanomaterials for Treating Bacterial Biofilms on Implantable Medical Devices.

Bacterial biofilms are involved in most device-associated infections and remain a challenge for modern medicine. One major approach to addressing this problem is to prevent the formation of biofilms using novel antimicrobial materials, device surface modification or local drug delivery; however, successful preventive measures are still extremely limited. The other approach is concerned with treating biofilms that have already formed on the devices; this approach is the focus of our manuscript. Treating biofilms associated with medical devices has unique challenges due to the biofilm's extracellular polymer substance (EPS) and the biofilm bacteria's resistance to most conventional antimicrobial agents. The treatment is further complicated by the fact that the treatment must be suitable for applying on devices surrounded by host tissue in many cases. Nanomaterials have been extensively investigated for preventing biofilm formation on medical devices, yet their applications in treating bacterial biofilm remains to be further investigated due to the fact that treating the biofilm bacteria and destroying the EPS are much more challenging than preventing adhesion of planktonic bacteria or inhibiting their surface colonization. In this highly focused review, we examined only studies that demonstrated successful EPS destruction and biofilm bacteria killing and provided in-depth description of the nanomaterials and the biofilm eradication efficacy, followed by discussion of key issues in this topic and suggestion for future development.

Iridescence and hydrophobicity have no clear delineation that explains flower petal micro-surface.

Plant organs including flowers and leaves typically have a variety of different micro-structures present on the epidermal surface. These structures can produce measurable optical effects with viewing angle including shifts in peak reflectance and intensity; however, these different structures can also modulate hydrophobic properties of the surfaces. For some species optical effects have been proposed to act as signals to enhance pollination interactions, whilst the ability to efficiently shed water provides physiological advantages to plants in terms of gas exchange and reducing infections. Currently, little is known about epidermal surface structure of flowering plants in the Southern Hemisphere, and how micro-surface may be related with either hydrophobicity or visual signalling. We measured four Australian native species and two naturalised species using a combination of techniques including SEM imaging, spectral sampling with a goniometer and contact angle measurements. Spectral data were evaluated in relation to published psychophysics results for important pollinators and reveal that potential visual changes, where present, were unlikely to be perceived by relevant pollinators. Nevertheless, hydrophobicity also did not simply explain petal surfaces as similar structures could in some cases result in very different levels of water repellency.

Micellar Fd3m cubosomes from monoolein - long chain unsaturated fatty acid mixtures: Stability on temperature and pH response.

HYPOTHESIS: Control of the nanostructure of self-assembled systems may be achieved through manipulation of surfactant molecular packing and interfacial curvature. In order to phase engineer the inverse micellar cubosomes in some monoolein-fatty acid systems, lipids with wedge shaped molecular geometry were incorporated to promote the formation of this phase, that is of interest as potential sustained released nanocarriers. EXPERIMENTS: Liquid crystalline nanoparticle dispersions of monoolein with some cis unsaturated fatty acids were prepared and their partial temperature-composition phase diagrams and structure were established using high throughput Small Angle X-ray Scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM). The pH responsiveness of these systems was evaluated in the presence of phosphate buffered saline (PBS). FINDINGS: The partial temperature-composition phase diagrams of five nanoparticle formulations containing monoolein and unsaturated fatty acids were established and identified the presence of micellar cubosomes in each of these systems. The results indicate that temperature, fatty acid concentration and structure, as well as pH all directly impact the formation and stability of this phase. Low energy inverse micellar cubic to emulsion phase transformations were identified in the monoolein with oleic acid and vaccenic acid systems at physiological temperatures that may be advantageous for staged therapeutic release strategies in nanomedicine.

Size-Dependent Encapsulation and Release of dsDNA from Cationic Lyotropic Liquid Crystalline Cubic Phases.

The potential of gene therapy has not yet been realized, largely due to difficulties in the targeted delivery of DNA to tissues and cells. Lipid-based nanovectors are of potential use in gene therapy due to their ability to enhance fusion with cellular membranes and transport the large polyanionic DNA molecules into the cytoplasm. While the research to date has mainly focused on liposome-based vectors, recently, nonlamellar phases with more complex internal architectures based on hexagonal or cubic symmetry have received increasing research attention due to their fusogenic properties, which may promote uptake of the DNA into the cell. Herein, we have carried out a fundamental physicochemical study to systematically analyze the encapsulation and release of nonfunctional double-stranded (ds) DNA fragments within monoolein (MO)-based cationic lipid phases of cubic symmetry (cationic cubic phases) and their dispersed submicron particles (cationic cubosomes). MO-based cationic cubic phases, both as the bulk phase and cubosomes, were formulated using six different cationic lipids, and their nanostructure was characterized in a high-throughput manner by synchrotron small-angle X-ray scattering (SAXS). dsDNA encapsulation was confirmed using agarose gel electrophoresis, and the effect on the internal nanostructure, size, and morphology of the cubosomes was investigated using synchrotron SAXS, dynamic light scattering, and cryo-transmission electron microscopy. Synchrotron radiation circular dichroism confirmed that the structure of the dsDNA fragments was unaffected by encapsulation within the cationic cubosome. The use of commercially available dsDNA ladders consisting of a controlled mixture of dsDNA fragments allowed us to determine release rates as a function of fragment size in a reasonably high throughput manner. An improved understanding of the loading capacity and release profile of nonfunctional biomolecules in cationic cubosomes will assist in the design of novel lipid nanovectors for gene delivery.

Treatment of Staphylococcus aureus skin infection in vivo using rifampicin loaded lipid nanoparticles.

We have previously reported on a novel nanoparticle formulation that was effective at killing Staphylococcus aureus in vitro. Here, we report for the first time, the antibacterial effects of a lipidic nano-carrier containing rifampicin (NanoRIF) which can be used to successfully treat Methicillin-Resistant S. aureus (MRSA) infection at a reduced antibiotic dosage compared to the free drug in a skin wound model in mice. The formulation used contains the lipid monoolein, a cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP) and the antibiotic. We have shown that rifampicin-loaded nanoparticles are more effective at treating infection in the skin wound model than the antibiotic alone. Cryo-TEM was used to capture for the first time, interactions of the formed nanoparticles with the cell wall of an individual bacterium. Our data strongly indicate enhanced binding of these charged nanoparticles with the negatively charged bacterial membrane. The efficacy we have now observed in vivo is of significant importance for the continued development of nanomedicine-based strategies to combat antibiotic resistant bacterial skin infections.

3D-Printed Diamond-Titanium Composite: A Hybrid Material for Implant Engineering.

Diamond-based implant materials make up an emerging research area where the materials could be prepared to promote cellular functions, decrease bacteria attachment, and be suitable for potential in situ imaging. Up until now, diamond implants have been fabricated using coating technologies or embedding diamond nanoparticles in polymer matrices. Here we demonstrated a method of manufacturing diamond implants using laser cladding technology to 3D print a composite of diamond and fused titanium material. Using this method, we could prepare composite scaffolds of up to 50% diamond, which has never been achieved before. We next investigated the interfacial properties of these scaffolds for potential applications in implants. The addition of diamond to the biomaterial results in a 30% decrease in the water contact angle, making the scaffolds more hydrophilic and improving cellular adhesion and proliferation.

In Vitro and In Vivo Toxicity and Biodistribution of Paclitaxel-Loaded Cubosomes as a Drug Delivery Nanocarrier: A Case Study Using an A431 Skin Cancer Xenograft Model.

Cubosomes with an internal three-dimensional (3D) periodic and porous particulate nanostructure have emerged as a promising drug delivery system for hydrophobic small molecules as well as large biomolecules over the past several decades. Limited understanding of their safety profiles and biodistribution, however, hinders clinical translation. This study used monoolein-based cubosomes stabilized by Pluronic F127 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)] polymers to encapsulate paclitaxel (PTX) as a model drug and investigated the in vitro cytotoxicity, in vivo acute response, and whole body biodistribution of the developed nanoparticles. Comparison of the PTX and nanoparticle cytotoxicity in two-dimensional and 3D spheroid cell models revealed distinct differences, with the cells in the 3D model found to be more tolerable to unloaded PTX as well as the PTX-loaded nanoparticle form. One-time intraperitoneal (i.p.) injection of unloaded cubosomes were generally well tolerated up to 400 mg/kg. Using the A431 skin cancer xenograft model, in vivo imaging studies showed the preferential accumulation of PTX-loaded cubosomes at the tumor sites following i.p. injection. Lastly, average tumor size was reduced by approximately 50% in the nanoparticle-based treatment group compared to the unloaded PTX drug group. The study provides significant information on the biological response of cubosomes and highlights their potential as a versatile drug delivery platform for safe and effective delivery of chemotherapeutic drugs.