Multifunctional Platforms: Metal-Organic Frameworks for Cutaneous and Cosmetic Treatment

•A systemic assay package was developed to seek MOFs for biomedical applications•Fe-based MOFs exhibited superb features that are suitable for cutaneous treatment•The relationship between MOFs’ structure and their performance was in-depth analyzed•This study provides guidance to design biomedical materials for cutaneous treatment Nowadays, cutaneous treatment has been widely applied in the cosmetic and pharmaceutical fields. However, traditional biomedical materials used in cutaneous treatment often showed low efficiency and limited applications due to monotonous structures and functionalities. Developing new biomedical materials with multifunctionalities and superb properties is urgently needed. Our study addresses this issue by constructing a versatile MOF-based biomedical platform, which presents multifunctionalities and avoids the introduction of unnecessary additives in preparation. More importantly, the evaluation systems developed in this study can be broadly applied for the comprehensive screening of biocompatible and multifunctional platforms in this field and provide valuable guidance for the design of advanced biomedical materials. Cutaneous treatment possesses advantages, including the decrease of transient drug overdosage or systematic side effects. The evolution of biomedical materials with multifunctionalities to overcome the limitations of existing materials can bring revolutionary development in this field. A promising solution can turn to the emerging materials known as metal-organic frameworks (MOFs), featuring high porosity, easy modification, and multifunctionality. The work herein developed a systemic assay package to seek suitable MOFs for cutaneous applications. Versatile platforms based on MOFs were built, which integrated superb functions and features, including biocompatibilities, sebum adsorbability, selective adsorption, antimicrobial activity, controlled release, and skin permeability promotion. Such features endow MOFs as high-performance matrixes for cutaneous applications. This study paves a new avenue for the reformation of cosmetic and biomedicinal materials. Moreover, this comprehensive MOF screening system can be broadly applied for material evaluation in this field, which also provides valuable guidance for the design of advanced biomedical materials. Cutaneous treatment possesses advantages, including the decrease of transient drug overdosage or systematic side effects. The evolution of biomedical materials with multifunctionalities to overcome the limitations of existing materials can bring revolutionary development in this field. A promising solution can turn to the emerging materials known as metal-organic frameworks (MOFs), featuring high porosity, easy modification, and multifunctionality. The work herein developed a systemic assay package to seek suitable MOFs for cutaneous applications. Versatile platforms based on MOFs were built, which integrated superb functions and features, including biocompatibilities, sebum adsorbability, selective adsorption, antimicrobial activity, controlled release, and skin permeability promotion. Such features endow MOFs as high-performance matrixes for cutaneous applications. This study paves a new avenue for the reformation of cosmetic and biomedicinal materials. Moreover, this comprehensive MOF screening system can be broadly applied for material evaluation in this field, which also provides valuable guidance for the design of advanced biomedical materials. Skin, the largest organ of our body, offers an efficient and safe route of drug administration. Cutaneous administration1Prausnitz M.R. Langer R. Transdermal drug delivery.Nat. Biotechnol. 2008; 26: 1261-1268Crossref PubMed Scopus (1828) Google Scholar can avoid the transient drug overdosage, can prevent drug degradation caused by hepatic first-pass metabolism, can decrease the systematic side effects, and concentrate active substances at the targeted skin lesion.2Ita K.B. Transdermal drug delivery: progress and challenges.J. Drug Deliv. Sci. Technol. 2014; 24: 245-250Crossref Scopus (73) Google Scholar, 3Xie Y. Xu B. Gao Y. Controlled transdermal delivery of model drug compounds by MEMS microneedle array.Nanomedicine. 2005; 1: 184-190Crossref PubMed Scopus (105) Google Scholar, 4Prausnitz M.R. Mitragotri S. Langer R. Current status and future potential of transdermal drug delivery.Nat. Rev. Drug Discov. 2004; 3: 115-124Crossref PubMed Scopus (1004) Google Scholar, 5Langer R. Drug delivery. Drugs on target.Science. 2001; 293: 58-59Crossref PubMed Scopus (501) Google Scholar, 6Hayes B.D. Klein-Schwartz W. Clark R.F. Muller A.A. Miloradovich J.E. Comparison of toxicity of acute overdoses with citalopram and escitalopram.J. Emerg. Med. 2010; 39: 44-48Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar In the past several decades, cutaneous treatment has made great progress in cosmetic and pharmaceutical applications due to the advancement of biotechnology in the improvement of drug molecules.7Sloan K.B. Wasdo S. Designing for topical delivery: prodrugs can make the difference.Med. Res. Rev. 2003; 23: 763-793Crossref PubMed Scopus (76) Google Scholar,8Sloan K.B. Wasdo S.C. Rautio J. Design for optimized topical delivery: prodrugs and a paradigm change.Pharm. Res. 2006; 23: 2729-2747Crossref PubMed Scopus (57) Google Scholar However, the development of related materials lags far behind. The traditional biomedical materials used in cutaneous treatment often perform merely as physical supports or dispersers due to their monotonous structures and functionalities, which hinder their efficiency and application. To achieve the expected performance, additives such as a chemical enhancer,9Haq A. Michniak-Kohn B. Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study.Drug Deliv. 2018; 25: 1943-1949Crossref PubMed Scopus (44) Google Scholar,10Ita B.K. Chemical penetration enhancers for transdermal drug delivery-success and challenges.Drug Deliv. 2015; 12: 645-651Google Scholar preservative,11Orton D.I. Wilkinson J.D. Cosmetic allergy.Am. J. Clin. Dermatol. 2004; 5: 327-337Crossref PubMed Scopus (85) Google Scholar and annexing agents,12Gupta R. Sridhar D.B. Rai B. Molecular Dynamics simulation study of permeation of molecules through skin lipid bilayer.J. Phys. Chem. B. 2016; 120: 8987-8996Crossref PubMed Scopus (60) Google Scholar are usually added into cosmetics or dermatological preparations, which can raise biosafety risks, costs, and complexities for users.13Ita K.B. Transdermal drug delivery: progress and challenges.J. Drug Deliv. Sci. Technol. 2014; 24: 245-250Crossref Google Scholar,14Howell-Jones R.S. Wilson M.J. Hill K.E. Howard A.J. Price P.E. Thomas D.W. A review of the microbiology, antibiotic usage and resistance in chronic skin wounds.J. Antimicrob. Chemother. 2005; 55: 143-149Crossref PubMed Scopus (236) Google Scholar Meanwhile, the most commonly used biomedical nanomaterials in cutaneous and cosmetic treatment, such as liposomes, micelles, and nanoemulsions, often have a relatively low physical stability, poor machining property, difficulty in modification/functionality, etc., which impede their broader applications in cutaneous and cosmetic treatments.15Sercombe L. Veerati T. Moheimani F. Wu S.Y. Sood A.K. Hua S. Advances and challenges of liposome assisted drug delivery.Front. Pharmacol. 2015; 6: 286Crossref PubMed Scopus (944) Google Scholar Therefore, developing new types of biomedicinal materials with multifunctionalities, high stability, and superb properties for cutaneous application is urgently needed. A promising solution to address these current challenges may turn to a new class of crystalline porous materials known as metal-organic frameworks (MOFs).16Zhou H.C. Kitagawa S. Metal–organic frameworks (MOFs).Chem. Soc. Rev. 2014; 43: 5415-5418Crossref PubMed Google Scholar, 17Maurin G. Serre C. Cooper A. Férey G. The new age of MOFs and of their porous-related solids.Chem. Soc. Rev. 2017; 46: 3104-3107Crossref PubMed Google Scholar, 18Cui Y. Li B. He H. Zhou W. Chen B. Qian G. Metal–organic frameworks as platforms for functional materials.Acc. Chem. Res. 2016; 49: 483-493Crossref PubMed Scopus (1124) Google Scholar MOFs feature high and tunable porosity, good physical stability and machinability, and facile post-synthetic modification.19Furukawa H. Cordova K.E. O’Keeffe M. Yaghi O.M. The chemistry and applications of metal-organic frameworks.Science. 2013; 341: 1230444Crossref PubMed Scopus (7521) Google Scholar,20Burrows A.D. Frost C.G. Mahon M.F. Richardson C. Post-synthetic modification of tagged metal–organic frameworks.Angew. Chem. Int. Ed. Engl. 2008; 47: 8482-8486Crossref PubMed Scopus (237) Google Scholar They have exhibited excellent performance in various fields such as catalysis,21García-García P. Müller M. Corma A. MOF catalysis in relation to their homogeneous counterparts and conventional solid catalysts.Chem. Sci. 2014; 5: 2979-3007Crossref Scopus (251) Google Scholar,22Jiao L. Wang Y. Jiang H.L. Xu Q. Metal–organic frameworks as platforms for catalytic applications.Adv. Mater. 2018; 30: 1703663Crossref PubMed Scopus (696) Google Scholar gas adsorption,23Li H. Wang K. Sun Y. Lollar C.T. Li J. Zhou H.C. Recent advances in gas storage and separation using metal–organic frameworks.Mater. Today. 2018; 21: 108-121Crossref Scopus (694) Google Scholar, 24Li J.R. Yu J. Lu W. Sun L.B. Sculley J. Balbuena P.B. et al.Porous materials with pre-designed single-molecule traps for CO2 selective adsorption.Nat. Commun. 2013; 4: 1538Crossref PubMed Scopus (408) Google Scholar, 25Xiang S. He Y. Zhang Z. Wu H. Zhou W. Krishna R. Chen B. Microporous metal-organic framework with potential for carbon dioxide capture at ambient conditions.Nat. Commun. 2012; 3: 954Crossref PubMed Scopus (594) Google Scholar separation,26Rodenas T. Luz I. Prieto G. Seoane B. Miro H. Corma A. Kapteijn F. Llabrés I Xamena F.X. Gascon J. Metal–organic framework nanosheets in polymer composite materials for gas separation.Nat. Mater. 2015; 14: 48-55Crossref PubMed Scopus (1314) Google Scholar,27Xiang S.C. Zhang Z. Zhao C.G. Hong K. Zhao X. Ding D.R. Xie M.H. Wu C.D. Das M.C. Gill R. et al.Rationally tuned micropores within enantiopure metal-organic frameworks for highly selective separation of acetylene and ethylene.Nat. Commun. 2011; 2: 204Crossref PubMed Scopus (409) Google Scholar sensors,28Liu X. Qi W. Wang Y. Su R. He Z. A facile strategy for enzyme immobilization with highly stable hierarchically porous metal–organic frameworks.Nanoscale. 2017; 9: 17561-17570Crossref PubMed Google Scholar and functional devices.29Ma H. Liu J. Ali M.M. Mahmood M.A.I. Labanieh L. Lu M. Iqbal S.M. Zhang Q. Zhao W. Wan Y. Nucleic acid aptamers in cancer research, diagnosis and therapy.Chem. Soc. Rev. 2015; 44: 1240-1256Crossref PubMed Google Scholar More importantly, the high structural diversity endows great amenability to design MOFs as multifunctional materials for biomedical exploration.30Chen Y. Lykourinou V. Vetromile C. Hoang T. Ming L.J. Larsen R.W. Ma S. How can proteins enter the interior of a MOF? Investigation of cytochrome c translocation into a MOF consisting of mesoporous cages with microporous windows.J. Am. Chem. Soc. 2012; 134: 13188-13191Crossref PubMed Scopus (251) Google Scholar, 31Wang Z. Hu S. Yang J. Liang A. Li Y. Zhuang Q. Gu J. Nanoscale Zr-based MOFs with tailorable size and introduced mesopore for protein delivery.Adv. Funct. Mater. 2018; 28: 1707356Crossref Scopus (65) Google Scholar, 32Horcajada P. Gref R. Baati T. Allan P.K. Maurin G. Couvreur P. Férey G. Morris R.E. Serre C. Metal-organic frameworks in biomedicine.Chem. Rev. 2012; 112: 1232-1268Crossref PubMed Scopus (2982) Google Scholar However, their applications in cosmetic and dermatological fields have been rarely reported. The development of MOFs for cutaneous application is a campaign of great significance, which will pave a new avenue for the improvement and reformation of materials used in this field. Herein, for the first time, we comprehensively screened MOFs library for cutaneous treatment by developing a unique and efficient assay package, and constructed versatile MOF platforms with multifunctionalities to serve for the related application and production (Scheme 1). A MOF library composed of thirteen representative MOFs (ZIF-11(Zn),33Park K.S. Ni Z. Côté A.P. Choi J.Y. Huang R. Uribe-Romo F.J. Chae H.K. O’Keeffe M. Yaghi O.M. Exceptional chemical and thermal stability of zeolitic imidazolate frameworks.Proc Natl. Acad. Sci. U.S.A. 2006; 103: 10186-10191Crossref PubMed Scopus (4455) Google Scholar MIL-101(Fe),34Férey G. Mellot-Draznieks C. Serre C. Millange F. Dutour J. Surblé S. Margiolaki I. A chromium terephthalate-based solid with unusually large pore volumes and surface area.Science. 2005; 309: 2040-2042Crossref PubMed Scopus (3823) Google Scholar MIL-101-NH2(Fe),35Bauer S. Serre C. Devic T. Horcajada P. Marrot J. Férey G. Stock N. High-throughput assisted rationalization of the formation of metal organic frameworks in the iron (III) aminoterephthalate solvothermal system.Inorg. Chem. 2008; 47: 7568-7576Crossref PubMed Scopus (367) Google Scholar MIL-101-CH3(Fe), MIL-101-NO2(Fe), MIL-101-Br(Fe), MIL-100(Fe),36Férey G. Serre C. Mellot-Draznieks C. Millange F. Surblé S. Dutour J. Margiolaki I. A hybrid solid with giant pores prepared by a combination of targeted chemistry, simulation, and powder diffraction.Angew. Chem. Int. Ed. Engl. 2004; 43: 6296-6301Crossref PubMed Scopus (703) Google Scholar HKUST-1(Cu),37Chui S.S.Y. Lo S.M.F. Charmant J.P. Orpen A.G. Williams I.D. A chemically functionalizable nanoporous material.Science. 1999; 283: 1148-1150Crossref PubMed Scopus (4709) Google Scholar MOF-808(Zr),38Liang W. Chevreau H. Ragon F. Southon P.D. Peterson V.K. D'Alessandro D.M. Tuning pore size in a zirconium–tricarboxylate metal–organic framework.CrystEngComm. 2014; 16: 6530-6533Crossref Google Scholar MIL-53(Al),39Serre C. Millange F. Thouvenot C. Noguès M. Marsolier G. Louër D. Férey G. Very large breathing effect in the first nanoporous chromium (III)-based solids: MIL-53 or CrIII (OH)·x [O2C- C6H4-CO2] x [HO2C-C6H4-CO2H]x·x H2Oy.J. Am. Chem. Soc. 2002; 124: 13519-13526Crossref PubMed Scopus (1466) Google Scholar UiO-66(Zr),40Cavka J.H. Jakobsen S. Olsbye U. Guillou N. Lamberti C. Bordiga S. Lillerud K.P. A new zirconium inorganic building brick forming metal organic frameworks with exceptional stability.J. Am. Chem. Soc. 2008; 130: 13850-13851Crossref PubMed Scopus (3865) Google Scholar PCN-333(Al),41Feng D. Liu T.F. Su J. Bosch M. Wei Z. Wan W. Yuan D. Chen Y.P. Wang X. Wang K. et al.Stable metal-organic frameworks containing single-molecule traps for enzyme encapsulation.Nat. Commun. 2015; 6: 5979Crossref PubMed Scopus (390) Google Scholar and PCN-333(Fe)41Feng D. Liu T.F. Su J. Bosch M. Wei Z. Wan W. Yuan D. Chen Y.P. Wang X. Wang K. et al.Stable metal-organic frameworks containing single-molecule traps for enzyme encapsulation.Nat. Commun. 2015; 6: 5979Crossref PubMed Scopus (390) Google Scholar was chosen due to their high water stability, low cost, easy fabrication, and high surface area. An efficient pre-evaluation was first conducted to screen the MOF library, including biocompatibility and absorbability tests. Further property investigations, such as antibacterial activity, control release, and penetration promoting were then performed to further explore their potentials for practical cutaneous applications (Scheme 1). All studied MOF samples were prepared according to the procedures reported in the literature or modified procedures. Powder X-ray diffraction (PXRD), Fourier transform infrared spectrometer (FT-IR), scanning electron microscope (SEM), thermogravimetric analysis (TGA) (Figures S1–S4) data confirmed that all MOFs possessed high crystallinity and the expected structures, as reported in the literature. Biocompatibility is the foremost factor in biomedical and cosmetic applications, especially for the susceptible population. Therefore, the biocompatibility of selected MOFs was first evaluated. The cytotoxicity assay was conducted on human dermal fibroblasts (HDF) (Figure S5A), 3T3 (Figure S5B), and Hela (Figure S5C) cell lines. The 50% cytotoxic con1 centration (CC50) values of MOFs are listed in Table 1. The cytotoxicity of MOF was inversely proportional to CC50 value. MIL-101(Fe) and PCN-333(Fe) were used as representatives to perform the cytotoxicity experiments with longer exposure times with cells. The results showed that there was no significant difference in cytotoxicity after incubation for 24 h compared with that of 4 h (Figures S5D–S5F). Among all the tested MOFs, Zn-based MOFs exhibited the highest cytotoxicity (ZIF-11(Zn): CC50 (HDF) = 60 ± 20 μg/mL; CC50 (Hela) = 20 ± 9 μg/mL; CC50 (3T3) = 60 ± 15 μg/mL), followed by Cu-based MOF (HKUST-1(Cu): CC50 (HDF) = 1,140 ± 340 μg/mL; CC50 (Hela) = 620 ± 210 μg/mL; CC50 (3T3) = 560 ± 160 μg/mL). The low cytotoxicity for most tested MOFs could be attributed to their relatively large particles, which prohibited cell -uptake and guaranteed their safety for cutaneous application. Overall, Fe-, Zr-, and Al-based MOFs possessed low cytotoxicity and excellent biocompatibilities, which suggest their potentials to serve as excellent transdermal matrixes.Table 1The CC50 (μg/mL) Values for Different MOFsHDF3T3HelaZIF-11(Zn)60 ± 2060 ± 1520 ± 9HKUST-1(Cu)1,140 ± 340560 ± 160620 ± 210PCN-333(Fe)7,230 ± 6904,660 ± 2204,430 ± 1,140PCN-333(Al)6,610 ± 6503,820 ± 6703,840 ± 740MIL-101(Fe)>7,2004,920 ± 4106,030 ± 60MIL-101-NH2(Fe)>7,2005,790± 4205,930 ± 390MIL-101-NO2(Fe)>7,200>7,200>6,400MIL-101-CH3(Fe)>7,200>8,400>7,200MIL-101-Br (Fe)>7,200>9,000>8,400MIL-100(Fe)>7,200>9,600>7,200MOF-808(Zr)>6,400>7,200>7,200UiO-66(Zr)>7,200>7,200>6,400MIL-53(Al)>6,4003,690 ± 4505,160 ± 920 Open table in a new tab Furthermore, hemolysis behavior for blood cells and the skin irritation test were conducted on all MOFs to further investigate their biocompatibilities. Briefly, different concentrations of MOFs were co-cultured with red blood cells (RBC) for 1, 2, and 4 h at 37°C. After centrifugation, the absorbance of the supernatant at 540 nm was measured on a microplate reader. Figures 1 and S6 show the hemolytic behavior of Fe-, Al-, Zr-, and Zn- based MOFs, which are all much lower than the clinical safety standard (5%). The hemolytic data of HKUST-1 was not successfully obtained due to its structure decomposition resulted from relatively poor water stability.42Álvarez J.R. Sánchez-González E. Pérez E. Schneider-Revueltas E. Martínez A. Tejeda-Cruz A. et al.Structure stability of HKUST-1 towards water and ethanol and their effect on its CO2 capture properties.Dalton Trans. 2017; 46: 9192-9200Crossref PubMed Google Scholar,43DeCoste J.B. Peterson G.W. Schindler B.J. Killops K.L. Browe M.A. Mahle J.J. The effect of water adsorption on the structure of the carboxylate containing metal–organic frameworks Cu-BTC, Mg-MOF-74, and UiO-66.J. Mater. Chem. A. 2013; 1: 11922-11932Crossref Scopus (346) Google Scholar Among them, Fe-based MOFs exhibited the lowest hemolytic rate, which was lower than 3.0% even at a high concentration of 2.0 mg/mL and incubated for 4 h. These results implied the excellent biocompatibility of Fe-based MOFs.44Grall R. Hidalgo T. Delic J. Garcia-Marquez A. Chevillard S. Horcajada P. In vitro biocompatibility of mesoporous metal (III; Fe, Al, Cr) trimesate MOF nanocarriers.J. Mater. Chem. 2015; 3: 8279-8292Crossref Google Scholar The skin irritation tests showed that the mice skin presented no erythema or edema after treating with all tested MOFs, indicating low allergenicity of the tested MOFs (Figures 1 and S7). These results, together with the cytotoxicity and hemolysis tests, implied that those MOFs exhibited good biocompatibilities, especially the Fe-based MOFs offer a higher potential to be applied in cosmetics and cutaneous treatment. Absorbability is also a crucial factor for cutaneous applications. Excess accumulation of skin secretions will enact various pathological reactions, such as seborrheic dermatitis45Paulino L.C. New perspectives on dandruff and seborrheic dermatitis: lessons we learned from bacterial and fungal skin microbiota.Eur. J. Dermatol. 2017; 27: 4-7Crossref PubMed Scopus (15) Google Scholar and hircismus.46Shokry E. de Oliveira A.E. Avelino M.A.G. de Deus M.M. Filho N.R.A. Earwax: A neglected body secretion or a step ahead in clinical diagnosis? A pilot study.J. Proteomics. 2017; 159: 92-101Crossref PubMed Scopus (13) Google Scholar Additionally, the surplus sebum will affect drug delivery and transdermal process, while sebum elimination will facilitate the penetration and delivery of drugs/active compounds for therapeutic or cosmetic purposes. Therefore, the adsorption capacity of MOFs for two main dermatic secretions (triglycerides and oleic acid) were studied and compared with traditional porous materials used in cutaneous therapy or cosmetics. After encapsulation of glycerol triacetate and oleic acid, MOFs were characterized by PXRD, N2 porosimetry, TGA, and FT-IR (Figures S8–S11), which demonstrated the successful adsorption of sebum by MOFs. The adsorption amounts of glycerol triacetate and oleic acid are summarized in Figures 2 and S12. The results indicated that all the tested MOFs possessed an excellent sorption capability for glycerol triacetate and oleic acid: 1.0 mg PCN-333(Fe) could adsorb 6.1 mg glycerol triacetate; 1.0 mg PCN-333(Fe) could adsorb 3.5 mg oleic acid, that was significantly higher than traditional porous materials (e.g., 1.0 mg active carbon can absorb 1.3 mg glycerol triacetate and 1.2 mg oleic acid). The prominent adsorption capacity of MOFs can be ascribed to the high porosity and strong interactions between organic linkers in MOFs and lipophilic molecules. In addition, the adsorption amount of oleic acid is lower than glycerol triacetate, which is probably due to the larger molecular dimension of oleic acid (glycerol triacetate: 3.2 Å × 4.8 Å × 9.6 Å, oleic acid: 3.1 Å × 8.7 Å × 16.6 Å). Notably, PCN-333(Fe) with a large pore size (42 Å and 55 Å) and high surface area (BET: 2,770 m2/g) displayed the highest glycerol triacetate and oleic acid uptake capacity among all studied MOFs. We further investigated the influences of different structural features of MOFs on their adsorption capacities. The results demonstrated that MIL-101(Fe) variants with substituent groups, such as -NH2, -NO2, -CH3, and -Br on terephthalate ligands, possessed higher adsorption ability compared with pristine MIL-101(Fe) (Figures 2 and S12), which could be attributed to two factors: (1) the water repellent groups ( -Br, - NO2, and -CH3) can enhance MOFs’ adsorption affinity to hydrophobic sebum; and (2) The -NH2 group could form hydrogen bonding interaction with the functional groups in sebum molecules, such as the carbonyl group.47Hansch C. Leo A. Unger S.H. Kim K.H. Nikaitani D. Lien E.J. Aromatic substituent constants for structure-activity correlations.J. Med. Chem. 1973; 16: 1207-1216Crossref PubMed Scopus (1368) Google Scholar,48Seo P.W. Bhadra B.N. Ahmed I. Khan N.A. Jhung S.H. Adsorptive removal of pharmaceuticals and personal care products from water with functionalized metal-organic frameworks: remarkable adsorbents with hydrogen-bonding abilities.Sci. Rep. 2016; 6: 34462Crossref PubMed Scopus (133) Google Scholar The results also implied that different metal centers present no significant influence on the adsorption capacity of MOFs (e.g., PCN-333(Fe) versus PCN-333(Al)). It is preferable that materials used for cutaneous treatment can keep the skin’s moisture while eliminating the excess sebum or lipid (oil).49Musthaq S. Mazuy A. Jakus J. The microbiome in dermatology.Clin. Dermatol. 2018; 36: 390-398Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Therefore, the selective adsorption capacity of MOFs toward water/triglycerides were investigated using MIL-101(Fe) and PCN-333(Fe) as representatives. These two MOFs were added to a mixture of triglycerides and water, respectively. After the removal of PCN-333(Fe), the ratio of lipid/water decreased from 1: 1 to nearly 1: 4 (Figure 2) (triglycerides were stained with Sudan Ⅳ for easy comparison), which means 80% of triglycerides were effectively removed by PCN-333(Fe), while only 20% water was adsorbed. The performance of MIL-101(Fe) was similar to PCN-333(Fe), which selectively adsorbed lipid over water. In addition, the water adsorption capacity of MOFs was carried out as a comparison. The results showed that the adsorption capacity of water was far less than that of oil (Figure S13). The results indicated that MIL-101(Fe) and PCN-333(Fe) possessed highly selective lipid adsorption capability, which can eliminate harmful skin secretion effectively without resulting in skin roughness. The permeation of drug/active compounds through the skin (particularly stratum corneum) is a critical factor in their bioavailability. Therefore, we selected Fe-based MOFs (PCN-333 and MIL-101 series MOFs) as representatives to study their ability to promote the penetration of active molecules into the skin. The fluorescent rhodamine B (RhB) was used as the model molecule. The mice skin was treated with a mixture of pure MOFs and RhB-loaded MOFs for 12 h. The penetration depth of RhB was tracked with a confocal laser scanning microscope (CSLM), and the ability of MOFs to promote the penetration of RhB into the skin is directly proportional to the penetration depth and the fluorescence intensity of RhB. The results (Figure S14) revealed that the fluorescence intensity of experimental groups (skin treated with MIL-101 series) was much higher than those of the control groups, which means more RhB can penetrate skin after the treatment with MOFs. In addition, RhB in these experimental groups penetrated deeper area of skin than those in the control groups. It is notable that MIL-101(Fe) series MOFs, especially MIL-101-CH3(Fe) and MIL-101(Fe), showed excellent ability to promote skin permeability (Figures 3 and 4). The results revealed that the ability to promote skin penetration by materials was related to their ability to adsorb sebum as well as their releasing capacity (Figure S15). A major barrier of drug penetration is the stratum corneum, which is composed of keratinocytes and lipids. Therefore, the superior adsorption capacities of MOFs can greatly facilitate skin penetration by removal of the sebum, lipid, or other wastes on the surface of the skin and expose the stratum corneum to increase its contact area with drug molecules for better penetration. The drug-releasing ability is another key factor in promoting skin penetration. For instance, MIL-101(Fe) possessed the best release performance among the tested MOFs, hence leading to good delivery performance (Figures 3 and 4). The outstanding skin-penetration promotion effect makes MOFs preeminent candidates as highly efficient transdermal matrix.Figure 4The Comparison Results of Permeability Promoting Capacity of MIL-101(Fe) Series MOFs.Show full captionMFIExp/MFICon = Mean fluorescence intensity of experimental group/Mean fluorescence intensity of the control group.View Large Image Figure ViewerDownload Hi-res image Download (PPT) MFIExp/MFICon = Mean fluorescence intensity of experimental group/Mean fluorescence intensity of the control group. Microbes are mainly responsible for infections during cutaneous treatment or the rot of transdermal patches/cutaneous agents. Microorganisms that inhabit the skin can cause various skin diseases (e.g., dermatitis and skin ulcer).50Nakatsuji T. Chen T.H. Narala S. Chun K.A. Two A.M. Yun T. et al.Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis.Sci. Transl. Med. 2017; 9: eaah4680Crossref PubMed Scopus (442) Google Scholar,51Lei X. Liu B. Huang Z. Wu J. A clinical study of photodynamic therapy for chronic skin ulcers in lower limbs infected with Pseudomonas aeruginosa.Arch. Dermatol. Res. 2015; 307: 49-55Crossref PubMed Scopus (49) Google Scholar Therefore, antibiotics or preservatives are often introduced in cosmetics or transdermal patches, which may lead to unexpected resistance, toxicity, or irritation. Herein, we investigated the antimicrobial activities of the selected MOFs to evaluate if they can inherently inhibit the growth of undesirable microbes without extra additives. Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa) were used to determine the antibacterial capability of MOFs. The minimum inhibition concentration (MIC) values of MOFs are summarized in Table 2. Among all the studied MOFs, ZIF-11(Zn), HKUST-1(Cu), PCN-333(Fe), MIL-101(Fe), and MIL-101-NH2(Fe) exhibited distinguished antimicrobial activities, especially for Gram-positive bacteria. The influence of particle sizes (Figures S23–S25) toward the antimicrobial performance of MOFs was then investigated, represented by PCN-333(Fe) and ZIF-11(Zn). The results showed that the antibacterial activity of PCN-333(Fe) and ZIF-11(Zn) with small particle sizes were higher than that with large particle sizes (Table S1). Moreover, we further investigated the solubilization speed of MOFs of different sizes through the ICP-OES (inductively coupled plasma-optical emission spectrometry) test. The results revealed that only a trace amount (<0.15%) of metal ions were exuded from MOFs after 24 h, and MOFs with a smaller size exuded more metal ions (Table S2). Therefore, it can be assumed that both the contacting possibility with bacteria and the dissolution speed of MOF particles account for the difference in antibacterial activity. Gram-positive bacteria remain an important cause of nosocomial wound infections,52Grice E.A. Segre J.A. The skin microbiome.Nat. Rev. Microbiol. 2011; 9: 244-253Crossref PubMed Scopus (1570) Google Scholar,53Bunce C. Wheeler L. Reed G. Musser J. Barg N. Murine model of cutaneous infection with Gram-positive cocci.Infect. Immun. 1992; 60: 2636-2640Crossref PubMed Google Scholar and most of the superbacteria, such as MRSA (Methicillin-resistant S. aureus), VISA (vancomycin-intermediate S. aureus), and PNSP (Penicillin-nonsusceptible S. pneumonia) are Gram-positive bacteria. Thus, MOFs’ selective antimicrobial properties provide potential for the treatment of skin diseases caused by Gram-positive bacteria. In addition, using MOFs as the multifunctional transdermal matrix can avoid the addition of antibiotics or related additives, and decrease the risk of irritation or side effect.Table 2The MIC (mg/L) Values for Different MOFsStaphylococcus aureusEscherichia coliPseudomonas aeruginosaZIF-11(Zn)150180350HKUST-1(Cu)400>1,000>1,000PCN-333(Fe)300560450PCN-333(Al)>360>1,000>1,000MIL-101(Fe)300>630500MIL-101-NH2(Fe)280>620430MIL-101-NO2(Fe)>600>900>900MIL-101-CH3(Fe)>650>900>900MIL-101-Br(Fe)>700>900>900MIL-100(Fe)>360>630>620MOF-808(Zr)>810>1,000>1,000UiO-66(Zr)>720>1,000>1,000 Open table in a new tab The high porosity and abundant interaction sites of MOFs endow them with the potentials of high loading capacity and control-releasing property. In this study, the loading capacity of MOFs (MIL-101(Fe), PCN-333(Fe)) toward procyanidine and indomethacin (two widely used active additives in skin treatment) was evaluated. We used liposome and diatomite as the control because they are common materials used in cutaneous and cosmetic treatment. As shown in Figure 5, the loading capacity of MOFs was more prominent than that of diatomite. The highly efficient loading of active compounds was further confirmed by FT-IR (Figure S16) and N2 sorption tests (Figure S17). Meanwhile, no significant change in the PXRD patterns was observed after adsorption tests (Figure S16), indicating good stability of tested MOFs. In terms of procyanidine, the entrapment efficiency of PCN-333(Fe) and MIL-101(Fe) was 80% and 67%, and the loading capacity of PCN-333(Fe) and MIL-101(Fe) was 0.80 mg/mg and 0.67 mg/mg, respectively, which was much higher than diatomite (0.03 mg/mg) and liposome 2000 (trace). The higher loading amount of PCN-333(Fe) than MIL-101(Fe) may be correlated with the higher surface area and the larger window/pore size of PCN-333(Fe) (Table S3). The low loading capacity of diatomite can be attributed to the lack of organic groups to provide interactions with guest molecules as well as its low surface area (BET ∼23 m2/g).54Liu Z. Fan T. Zhou H. Zhang D. Gong X. Guo Q. et al.Synthesis of ZnFe2O4/SiO2 composites derived from a diatomite template.Bioinspir. Biomim. 2007; 2: 30-35Crossref PubMed Scopus (14) Google Scholar The influence of particle sizes of MOFs toward their adsorption capacities and rates was also investigated, and the result showed that MIL-101 with a smaller particle size was superior to that with a larger particle size (Figure S18). In order to evaluate the controlled release kinetics, we tracked the amounts of the released active compounds from MOFs at different time frames. As shown in Figure 5, PCN-333(Fe) completely released procyanidine and indomethacin after ∼120 and 130 h, respectively. For MIL-101(Fe), 72% of procyanidine and 60% of indomethacin could be released after ∼130 and 100 h. MIL-101(Fe)’s slow release mainly resulted from its small window sizes (∼12 Å and 15 Å)34Férey G. Mellot-Draznieks C. Serre C. Millange F. Dutour J. Surblé S. Margiolaki I. A chromium terephthalate-based solid with unusually large pore volumes and surface area.Science. 2005; 309: 2040-2042Crossref PubMed Scopus (3823) Google Scholar compared with PCN-333(Fe) (26 Å and 30 Å).41Feng D. Liu T.F. Su J. Bosch M. Wei Z. Wan W. Yuan D. Chen Y.P. Wang X. Wang K. et al.Stable metal-organic frameworks containing single-molecule traps for enzyme encapsulation.Nat. Commun. 2015; 6: 5979Crossref PubMed Scopus (390) Google Scholar The interactions between MOFs and guest compounds are responsible for the controlled release, which avoid the “burst release effect” related to side effects and provide better bioavailability of active substances. Overall, the high loading capacities and controlled releasing properties of MOFs make them a promising efficient matrix in cutaneous or cosmetics applications (e.g., sleeping masks, perfume, burn ointment). After a comprehensive evaluation, Fe-based MOFs, especially MIL-101(Fe), demonstrated the highest potential to serve as a multifunctional platform for cutaneous treatment. On the one hand, the good biocompatibility, high stability (Figures S19–S21; Table S3), and excellent absorbability guarantees them as reliable and efficient cutaneous applications. On the other hand, several superb features such as antimicrobial activity, control-releasing capability, and satisfactory promotion to penetration entitle them as a versatile platform to facilitate an enhanced bioavailability of active substances without extra additives (e.g., chemical enhancers, release liner, and preservatives). Moreover, the relatively low cost of reagents (e.g., terephthalate and Fe salts) and easy large-scale synthesis make MIL-101(Fe) the most promising material for applications, including fine chemicals, cosmetics, and transdermal matrix. The facile functionality of MOFs further promotes them as potential platforms that can be customized to meet specific requirements for distinct active molecules in dermatological preparations and cosmetics. Finally, to demonstrate the practical application of MOFs in cosmetics, a peeling cleaning facial mask was fabricated using Fe-based MOFs (Figure S22). The development of other MOF-based functional cosmetics and transdermal patch, and the formula optimization for commercial products is ongoing in our lab. In conclusion, for the first time, we developed a systematic assay package to efficiently evaluate MOFs for cutaneous and cosmetic applications, based on which we built versatile and facile MOFs platforms that exhibit excellent biocompatibilities, high sebum adsorption, selective adsorption capacity, antimicrobial activity, skin permeability promotion, and control-release property. These great properties make MOFs ideal candidates to serve as high-performance matrixes for cutaneous applications, such as dermatological preparations and cosmetics. Further analysis of the structure-activity relationship of MOFs guided an in-depth understanding of the principles for the rational design of high-performance functional materials for cutaneous treatment. The results revealed that metal irons have a direct effect on the biocompatibilities of corresponding MOFs, while the ligands, especially their functional groups, are closely related to MOFs functionality and performance, such as selective adsorption and promotion of skin penetration. This study will pave a new avenue for the design, synthesis, and application of multifunctional biomedical materials. More importantly, the comprehensive MOFs screening system developed in this study can be broadly applied for material evaluation in cutaneous and cosmetic treatment and provide valuable guidance for the rational design of advanced biomedical materials.