Synergistic effect of Gemcitabin-loaded metal organic frameworks nanoparticles with particle therapy.

Combination of nanoagents with radiations has opened up new perspectives in cancer treatment, improving both tumor diagnosis and therapeutic index. This work presents the first investigation of an innovative strategy that combines porous metal-organic frameworks (nanoMOFs) loaded with the anti-cancer drug Gemcitabine monophosphate (GemMP) and particle therapy-a globally emerging technique that offers more precise radiation targeting and enhanced biological efficacy compared to conventional radiotherapy. This radiochemotherapy has been confronted with two major obstacles limiting the efficacy of therapeutics when tested in vivo: (i) the presence of hypoxia, one of the most important causes for radiotherapy failure and (ii) the presence of a microenvironment, main biological barrier to the direct penetration of nanoparticles into cancer cells. On the one hand, this study explore the effects of hypoxia on drug delivery systems in combination with radiation, demonstrating that GemMP-loaded nanoMOFs significantly enhance the anticancer efficacy of particle therapy under both normoxic (pO2 = 20 %) and hypoxic (pO2 = 0.5 %) conditions. Notably, the presence of GemMP-loaded nanoMOFs allows the irradiation dose to be reduced by 1.4-fold in normoxia and at least 1.6-fold in hypoxia, achieving the same cytotoxic effect (SF=10 %) as carbon or helium ions alone. Synergistic effects between GemMP-loaded nanoMOFs and radiations have been observed and quantified. On the other hand, we also highlighted the ability of the nanoMOFs to diffuse through an extracellular matrix and accumulate in cells. An higher effect of the encapsulated GemMP than the free drug was observed, confirming the key role of the nanoMOFs in transporting the active substance to the cancer cells as a Trojan horse. This paves the way to the design of "all-in-one" nanodrugs where each component plays a role in the optimization of cancer therapy to maximize cytotoxic effects on hypoxic tumor cells while minimizing toxicity on healthy tissue.

A journey through the history of PEGylated drug delivery nanocarriers.

This note aims to inspire through providing a personal view of the development and potential Drug Delivery Nanocarriers functionalized with polythyleneglycol (PEG). This polymer has been used extensively in Pharmaceutical Technology in a variety of compositions, including polyethylene oxide (PEO)-based surfactants. However, the concept of PEGylation, which started in the 70's, differs from the functionality of a surfactant, already discloses in the 50's. Here, we strictly adhere to the biological functionality of PEGylated nanocarriers intended to have a reduced interaction with proteins and, therefore, modify their biodistribution as well as facilitate their diffusion across mucus and other biological barriers. We analyze how this concept has evolved over the years and the benefit obtained so far in terms of marketed nanomedicines and provide the readers with a prospect view of the topic.

A comprehensive investigation of the interactions of human serum albumin with polymeric and hybrid nanoparticles.

Nanoparticles (NPs) engineered as drug delivery systems continue to make breakthroughs as they offer numerous advantages over free therapeutics. However, the poor understanding of the interplay between the NPs and biomolecules, especially blood proteins, obstructs NP translation to clinics. Nano-bio interactions determine the NPs' in vivo fate, efficacy and immunotoxicity, potentially altering protein function. To fulfill the growing need to investigate nano-bio interactions, this study provides a systematic understanding of two key aspects: (i) protein corona (PC) formation and (ii) NP-induced modifications on protein's structure and stability. A methodology was developed by combining orthogonal techniques to analyze both quantitative and qualitative aspects of nano-bio interactions, using human serum albumin (HSA) as a model protein. Protein quantification via liquid chromatography-mass spectrometry, and capillary zone electrophoresis (CZE) clarified adsorbed protein quantity and stability. CZE further unveiled qualitative insights into HSA forms (native, glycated HSA and cysteinylated), while synchrotron radiation circular dichroism enabled analyzing HSA's secondary structure and thermal stability. Comparative investigations of NP cores (organic vs. hybrid), and shells (with or without polyethylene glycol (PEG)) revealed pivotal factors influencing nano-bio interactions. Polymeric NPs based on poly(lactic-co-glycolic acid) (PLGA) and hybrid NPs based on metal-organic frameworks (nanoMOFs) presented distinct HSA adsorption profiles. PLGA NPs had protein-repelling properties while inducing structural modifications on HSA. In contrast, HSA exhibited a high affinity for nanoMOFs forming a PC altering thereby the protein structure. A shielding effect was gained through PEGylation for both types of NPs, avoiding the PC formation as well as the alteration of unbound HSA structure.

Advanced Characterization Methodology to Unravel the Biodegradability of Metal-Organic Framework Nanoparticles in Extremely Diluted Conditions.

Porous iron(III) carboxylate metal-organic frameworks (MIL-100; MIL stands for Material of Institute Lavoisier) of submicronic size (nanoMOFs) have attracted a growing interest in the field of drug delivery due to their high drug payloads, excellent entrapment efficiencies, biodegradable character, and poor toxicity. However, only a few studies have dealt with the nanoMOF degradation mechanism, which is key to their biological applications. Complementary methods have been used here to investigate the degradation mechanism of Fe-based nanoMOFs under neutral or acidic conditions and in the presence of albumin. High-resolution STEM-HAADF coupled with energy-dispersive X-ray spectroscopy enabled the monitoring of the crystalline organization and elemental distribution during degradation. NanoMOFs were also deposited onto silicon substrates by dip-coating, forming stable thin films of high optical quality. The mean film thickness and structural changes were further monitored by IR ellipsometry, approaching the "sink conditions" occurring in vivo. This approach is essential for the successful design of biocompatible nano-vectors under extreme diluted conditions. It was revealed that while the presence of a protein coating layer did not impede the degradation process, the pH of the medium in contact with the nanoMOFs played a major role. The degradation of nanoMOFs occurred to a larger extent under neutral conditions, rapidly and homogeneously within the crystalline matrices, and was associated with the departure of their constitutive organic ligand. Remarkably, the nanoMOFs' particles maintained their global morphology during degradation.

An in-depth physicochemical investigation of drug-loaded core-shell UiO66 nanoMOFs.

Nanosized UiO66 are among the most studied MOF materials. They have been extensively applied in various areas, such as catalysis, gas absorption, electrochemistry, chemical sensing, and biomedical applications. However, the preparation of stable nano-sized UiO66 for drug delivery applications is challenging because of the high tendency of UiO66 to aggregate during storage. To address this issue, we coated UiO66 with oligomers made of crosslinked cyclodextrins. The coated UiO66 exhibited a good stability upon storage for more than three weeks, even for low quantities of coating materials. The resulting core-shell UiO66 were characterized using a set of complementary methods including microscopies, spectroscopies, X-ray diffraction, and thermogravimetric investigations. Size distribution was assessed by orthogonal methods. Cisplatin was loaded in the core-shell nanoparticles, followed by an in-depth analysis by asymmetric flow field-flow fractionation (AF4) hyphenated with inductively coupled plasma-mass spectrometry (ICP-MS). This method combines the extremely high elemental selectivity and ultratrace detection limits of mass spectrometry with the capacity of AF4 to differentiate the diverse populations present in the sample. Free cisplatin and UiO66-associated cisplatin could be well separated by AF4. AF4-ICP-MS/MS analysis provided the exact drug loading, without the need of separating the nanoparticles from their suspension media. These data suggest the potential of AF4-ICP-MS/MS in the optimization of drug delivery systems.

Degradation and Erosion of Metal-Organic Frameworks: Comparative Study of a NanoMIL-100 Drug Delivery System.

To make a drug work better, the active substance can be incorporated into a vehicle for optimal protection and control of the drug delivery time and space. For making the drug carrier, the porous metal-organic framework (MOF) can offer high drug-loading capacity and various designs for effective drug delivery performance, biocompatibility, and biodegradability. Nevertheless, its degradation process is complex and not easily predictable, and the toxicity concern related to the MOF degradation products remains a challenge for their clinical translation. Here, we describe an in-depth molecular and nanoscale degradation mechanism of aluminum- and iron-based nanoMIL-100 materials exposed to phosphate-buffered saline. Using a combination of analytical tools, including X-ray photoelectron spectroscopy, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and electron microscopy, we demonstrate qualitatively and quantitatively the formation of a new coordination bond between metal(III) and phosphate, trimesate release, and correlation between these two processes. Moreover, the extent of material erosion, i.e., bulk or surface erosion, was examined from the transformation of nanoparticles' surface, morphology, and interaction with water. Similar analyses show the impact of drug loading and surface coating on nanoMIL-100 degradation and drug release as a function of the metal-ligand binding strength. Our results indicate how the chemistry of nanoMIL-100(Al) and nanoMIL-100(Fe) drug carriers affects their degradation behaviors in a simulated physiological medium. This difference in behavior between the two nanoMIL-100s enables us to better correlate the nanoscale and atomic-scale mechanisms of the observed phenomena, thus validating the presented multiscale approach.

LipoParticles: a lipid membrane coating onto polymer particles to enhance the internalization in osteoblast cells.

LipoParticles, core-shell assemblies consisting of a polymer core coated by a lipid membrane, are promising carriers for drug delivery applications with intracellular targets. This is of great interest since it is actually challenging to treat infections involving intracellular bacteria such as bone and joint infections where the bacteria are hidden in osteoblast cells. The present work reports for the first time to the best of our knowledge the proof of enhanced internalization of particles in osteoblast cells thanks to a lipid coating of particles (= LipoParticles). The ca. 300 nm-sized assemblies were elaborated by reorganization of liposomes (composed of DPPC/DPTAP 10/90 mol/mol) onto the surface of poly(lactic-co-glycolic acid) (PLGA) particles, and were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and zetametry. Optimization of these assemblies was also performed by adding poly(ethylene glycol) (PEG) chains on their surface (corresponding to a final formulation of DPPC/DPTAP/DPPE-PEG5000 8/90/2 mol/mol/mol). Interestingly, this provided them colloidal stability after their 20-fold dilution in PBS or cell culture medium, and made possible their freeze-drying without forming aggregates after their re-hydration. Their non-cytotoxicity towards a human osteoblast cell line (MG63) was also demonstrated. The enhanced internalization of LipoParticles in this MG63 cell line, in comparison with PLGA particles, was proven by observations with a confocal laser scanning microscope, as well as by flow cytometry assays. Finally, this efficient internalization of LipoParticles in MG63 cells was confirmed by TEM on ultrathin sections, which also revealed localization close to intracellular Staphylococcus aureus.

Colloidal Silver Nanoparticles Obtained via Radiolysis: Synthesis Optimization and Antibacterial Properties.

Silver nanoparticles (AgNPs) with broad-spectrum antimicrobial properties are gaining increasing interest in fighting multidrug-resistant bacteria. Herein, we describe the synthesis of AgNPs, stabilized by polyvinyl alcohol (PVA), with high purity and homogeneous sizes, using radiolysis. Solvated electrons and reducing radicals are induced from solvent radiolysis and no other chemical reducing agents are needed to reduce the metal ions. Another advantage of this method is that it leads to sterile colloidal suspensions, which can be directly used for medical applications. We systematically investigated the effect of the silver salt precursor on the optical properties, particle size, and morphology of the resulting colloidal AgNPs. With Ag2SO4 precursor, the AgNPs displayed a narrow size distribution (20 ± 2 nm). In contrast, AgNO3 and AgClO4 precursors lead to inhomogeneous AgNPs of various shapes. Moreover, the optimized AgNPs synthesized from Ag2SO4 were stable upon storage in water and phosphate-buffered saline (PBS) and were very effective in inhibiting the growth of Staphylococcus aureus (S. aureus) at a concentration of 0.6 µg·mL-1 while completely eradicating it at a concentration of 5.6 µg·mL-1. When compared with other AgNPs prepared by other strategies, the remarkable bactericidal ability against S. aureus of the AgNPs produced here opens up new perspectives for further applications in medicine, cosmetics, the food industry, or in elaborating antibacterial surfaces and other devices.

Nanoscale Multimodal Analysis of Sensitive Nanomaterials by Monochromated STEM-EELS in Low-Dose and Cryogenic Conditions.

Scanning transmission electron microscopy coupled with electron energy loss spectroscopy (STEM-EELS) provides spatially resolved chemical information down to the atomic scale. However, studying radiation-sensitive specimens such as organic-inorganic composites remains extremely challenging. Here, we analyzed metal-organic framework nanoparticles (nanoMOFs) at low-dose (10 e-/Å2) and liquid nitrogen temperatures, similar to cryo-TEM conditions usually employed for high-resolution imaging of biological specimens. Our results demonstrate that monochromated STEM-EELS enables damage-free analysis of nanoMOFs, providing in a single experiment, signatures of intact functional groups comparable with infrared, ultraviolet, and X-ray data, with an energy resolution down to 7 meV. The signals have been mapped at the nanoscale (<10 nm) for each of these energy spectral ranges, including the chemical features observed for high energy losses (X-ray range). By controlling beam irradiation and monitoring spectral changes, our work provides insights into the possible pathways of chemical reactions occurring under electron exposure. These results demonstrate the possibilities for characterizing at the nanoscale the chemistry of sensitive systems such as organic and biological materials.

Nanoscale Iron-Based Metal-Organic Frameworks: Incorporation of Functionalized Drugs and Degradation in Biological Media.

Metal-organic frameworks (MOFs) attract growing interest in biomedical applications. Among thousands of MOF structures, the mesoporous iron(III) carboxylate MIL-100(Fe) (MIL stands for the Materials of Lavoisier Institute) is among the most studied MOF nanocarrier, owing to its high porosity, biodegradability, and lack of toxicity. Nanosized MIL-100(Fe) particles (nanoMOFs) readily coordinate with drugs leading to unprecedented payloads and controlled release. Here, we show how the functional groups of the challenging anticancer drug prednisolone influence their interactions with the nanoMOFs and their release in various media. Molecular modeling enabled predicting the strength of interactions between prednisolone-bearing or not phosphate or sulfate moieties (PP and PS, respectively) and the oxo-trimer of MIL-100(Fe) as well as understanding the pore filling of MIL-100(Fe). Noticeably, PP showed the strongest interactions (drug loading up to 30 wt %, encapsulation efficiency > 98%) and slowed down the nanoMOFs' degradation in simulated body fluid. This drug was shown to bind to the iron Lewis acid sites and was not displaced by other ions in the suspension media. On the contrary, PS was entrapped with lower efficiencies and was easily displaced by phosphates in the release media. Noticeably, the nanoMOFs maintained their size and faceted structures after drug loading and even after degradation in blood or serum after losing almost the totality of the constitutive trimesate ligands. Scanning electron microscopy with high annular dark field (STEM-HAADF) in conjunction with X-Ray energy-dispersive spectrometry (XEDS) was a powerful tool enabling the unraveling of the main elements to gain insights on the MOF structural evolution after drug loading and/or upon degradation.

Nanosized Drug Delivery Systems to Fight Tuberculosis.

Tuberculosis (TB) is currently the second deadliest infectious disease. Existing antitubercular therapies are long, complex, and have severe side effects that result in low patient compliance. In this context, nanosized drug delivery systems (DDSs) have the potential to optimize the treatment's efficiency while reducing its toxicity. Hundreds of publications illustrate the growing interest in this field. In this review, the main challenges related to the use of drug nanocarriers to fight TB are overviewed. Relevant publications regarding DDSs for the treatment of TB are classified according to the encapsulated drugs, from first-line to second-line drugs. The physicochemical and biological properties of the investigated formulations are listed. DDSs could simultaneously (i) optimize the therapy's antibacterial effects; (ii) reduce the doses; (iii) reduce the posology; (iv) diminish the toxicity; and as a global result, (v) mitigate the emergence of resistant strains. Moreover, we highlight that host-directed therapy using nanoparticles (NPs) is a recent promising trend. Although the research on nanosized DDSs for TB treatment is expanding, clinical applications have yet to be developed. Most studies are only dedicated to the development of new formulations, without the in vivo proof of concept. In the near future, it is expected that NPs prepared by "green" scalable methods, with intrinsic antibacterial properties and capable of co-encapsulating synergistic drugs, may find applications to fight TB.

Nanoscale metal-organic frameworks for the delivery of nucleic acids to cancer cells.

Therapeutic nucleic acids (TNAs) are gaining increasing interest in the treatment of severe diseases including viral infections, inherited disorders, and cancers. However, the efficacy of intracellularly functioning TNAs is also reliant upon their delivery into the cellular environment, as unmodified nucleic acids are unable to cross the cell membrane mainly due to charge repulsion. Here we show that TNAs can be effectively delivered into the cellular environment using engineered nanoscale metal-organic frameworks (nanoMOFs), with the additional ability to tailor which cells receive the therapeutic cargo determined by the functional moieties grafted onto the nanoMOF's surface. This study paves the way to integrate the highly ordered programmable nucleic acids into larger-scale functionalized nanoassemblies.

Acetic Acid-Modulated Room Temperature Synthesis of MIL-100 (Fe) Nanoparticles for Drug Delivery Applications.

Due to their flexible composition, large surface areas, versatile surface properties, and degradability, nanoscale metal organic frameworks (nano MOFs) are drawing significant attention in nanomedicine. In particular, iron trimesate MIL-100 (Fe) is studied extensively in the drug delivery field. Nanosized MIL-100 (Fe) are obtained mostly by microwave-assisted synthesis. Simpler, room-temperature (RT) synthesis methods attract growing interest and have scale-up potential. However, the preparation of RT MIL100 is still very challenging because of the high tendency of the nanoparticles to aggregate during their synthesis, purification and storage. To address this issue, we prepared RT MIL100 using acetic acid as a modulator and used non-toxic cyclodextrin-based coatings to ensure stability upon storage. Hydrodynamic diameters less than 100 nm were obtained after RT synthesis, however, ultrasonication was needed to disaggregate the nanoparticles after their purification by centrifugation. The model drug adenosine monophosphate (AMP) was successfully encapsulated in RT MIL100 obtained using acetic acid as a modulator. The coated RT MIL100 has CD-exhibited degradability, good colloidal stability, low cytotoxicity, as well as high drug payload efficiency. Further studies will focus on applications in the field of cancer therapy.

Correction: Toxicity of metal-organic framework nanoparticles: from essential analyses to potential applications.

Correction for 'Toxicity of metal-organic framework nanoparticles: from essential analyses to potential applications' by Romy Ettlinger et al., Chem. Soc. Rev., 2022, 51, 464-484, https://doi.org/10.1039/D1CS00918D.

Degradation of Polymer-Drug Conjugate Nanoparticles Based on Lactic and Itaconic Acid.

Tuberculosis (TB) is still a significant threat to human health. A promising solution is engineering nanoparticulate drug carriers to deliver anti-TB molecules. Itaconic acid (ITA) potentially has anti-TB activity; however, its incorporation in nanoparticles (NP) is challenging. Here we show an approach for preparing polymer-ITA conjugate NPs and a methodology for investigating the NP degradation and ITA release mechanism. The conjugate was synthesized by the two-directional growing of polylactic acid (PLA) chains, followed by capping their extremities with ITA. The poly(lactate)-itaconate PLA-ITA was then used to formulate NPs. The degradation and drug release processes of the polymer conjugate NPs were studied qualitatively and quantitatively. The molecular structures of released species were characterized by using liquid NMR spectroscopy and mass spectrometry. We discovered a complex NP hydrolysis process forming diverse oligomers, as well as monomeric lactic acid (LA) and drug ITA. The slow degradation process led to a low release of free drugs, although raising the pH from 5.3 to 7.4 induced a slight increase in the amounts of released products. TEM images showed that bulk erosion is likely to play the primary role in the degradation of PLA-ITA NPs. The overall results and methodology can be of interest for understanding the mechanisms of NP degradation and drug release of this new polymer-drug conjugate system.

Quantification of drug loading in polymeric nanoparticles using AFM-IR technique: a novel method to map and evaluate drug distribution in drug nanocarriers.

Researchers are increasingly thinking smaller to solve some of the biggest challenges in nanomedicine: the control of drug encapsulation. Although recent years have witnessed a significant increase in the development and characterization of polymeric drug nanocarriers, several key features are still to be addressed: Where is the drug located within each nanoparticle (NP)? How much drug does each NP contain? Is the drug loading homogeneous on an individual NP basis? To answer these questions, individual NP characterization was achieved here by using atomic force microscopy-infrared spectroscopy (AFM-IR). A label-free quantification methodology was proposed to estimate with a nanoscale resolution the drug loadings of individual poly(lactic acid) (PLA) NPs loaded with an anticancer drug. First, a drug loading calibration curve was established using conventional IR microspectroscopy employing PLA/drug homogeneous films of well-known compositions. Then, single NPs were investigated by AFM-IR acquiring both IR mappings of PLA and drug as well as local IR spectra. Besides, drug location within single NPs was unravelled. The measured drug loadings were drastically different (0 to 21 wt%) from one NP to another, emphasizing the particular interest of this methodology in providing a simple quantification method for the quality control of nanomedicines.

Nanoscale MOFs: From synthesis to drug delivery and theranostics applications.

Since the first report in 1989, Metal-Organic Frameworks (MOFs) self-assembled from metal ions or clusters, as well as organic linkers, have attracted extensive attention. Due to their flexible composition, large surface areas, modifiable surface properties, and their degradability, there has been an exponential increase in the study of MOFs materials, specifically in drug delivery system areas such as infection, diabetes, pulmonary disease, ocular disease, imaging, tumor therapy, and especially cancer theranostics. In this review, we discuss the trends in MOFs biosafety, from "green" synthesis to applications in drug delivery systems. Firstly, we present the different "green" synthesis approaches used to prepare MOFs materials. Secondly, we detail the methods for the functional coating, either through grafting targeting units, poly(ethylene glycol) (PEG) chains or by using cell membranes. Then, we discuss drug encapsulation strategies, host-guest interactions, as well as drug release mechanisms. Lastly, we report on the drug delivery applications of nanoscale MOFs. In particular, we discuss MOFs-based imaging techniques, including magnetic resonance imaging (MRI), photoacoustic imaging (PAI), positron emission tomography (PET), and fluorescence imaging. MOFs-based cancer therapy methods are also presented, such as photothermal therapy (PTT), photodynamic therapy (PDT), radiotherapy (RT), chemotherapy, and immunotherapy.

A customized long acting formulation of the kisspeptin analog C6 triggers ovulation in anestrus ewe.

The modulation of the kisspeptin system holds promise as a treatment for human reproductive disorders and for managing livestock breeding. The design of analogs has overcome some unfavorable properties of the endogenous ligands. However, for applications requiring a prolongation of drug activity, such as ovulation induction in the ewe during the non-breeding season, additional improvement is required. To this aim, we designed and tested three formulations containing the kisspeptin analog C6. Two were based on polymeric nanoparticles (NP1 and NP2) and the third was based on hydrogels composed of a mixture of cyclodextrin polymers and dextran grafted with alkyl side chains (MD/pCD). Only the MD/pCD formulation prolonged C6 activity, as shown by monitoring luteinizing hormone (LH) plasma concentration (elevation duration 23.4 ± 6.1, 13.7 ± 4.7 and 12.0 ± 2.4 h for MD/pCD, NP1 and NP2, respectively). When compared with the free C6 (15 nmol/ewe), the formulated (MD/pCD) doses of 10, 15 and 30 nmol/ewe, but not the 90 nmol/ewe dose, provided a more gradual release of C6 as shown by an attenuated LH release during the first 6 h post-treatment. When tested during the non-breeding season without progestogen priming, only, the formulated 30 nmol/ewe dose triggered ovulation (50% of ewes). Hence, we showed that a formulation with an adapted action time would improve the efficacy of C6 with respect to inducing ovulation during the non-breeding season. This result suggests that formulations containing a kisspeptin analog might find applications in the management of livestock reproduction but also point to the possibility of their use for the treatment of some human reproductive pathologies.

Toxicity of metal-organic framework nanoparticles: from essential analyses to potential applications.

In the last two decades, the field of metal-organic frameworks (MOFs) has exploded, and MOF nanoparticles in particular are being investigated with increasing interest for various applications, including gas storage and separation, water harvesting, catalysis, energy conversion and storage, sensing, diagnosis, therapy, and theranostics. To further pave their way into real-world applications, and to push the synthesis of MOF nanoparticles that are 'safe-and-sustainable-by-design', this tutorial review aims to shed light on the importance of a systematic toxicity assessment. After clarifying and working out the most important terms and aspects from the field of nanotoxicity, the current state-of-the-art of in vitro and in vivo toxicity studies of MOF nanoparticles is evaluated. Moreover, the key aspects affecting the toxicity of MOF nanoparticles such as their chemical composition, their physico-chemical properties, including their colloidal and chemical stability, are discussed. We highlight the need of more targeted synthesis of MOF nanoparticles that are 'safe-and-sustainable-by-design', and their tailored hazard assessment in the context of their potential applications in order to tap the full potential of this versatile material class in the future.