2020-03-14 11:22:00
Debabrata Maiti, Jing Zhong, Zheng Zhang, Hailin Zhou, Saisai Xion, Ziliang Dong, Sarvendra Kumar, Zhuang Liu, and Kai Yang
Compared to chemotherapy and surgery, radiotherapy (RT) using X-rays, gamma rays or an electron beam is still broadly applied for cancer treatment in clinical applications.1 Numerous RT clinical trials have revealed that using high dose X-rays could kill most of the cancer cells, but also cause side effects to the patients. Optical therapy including photodynamic therapy (PDT)3,4 and photothermal therapy (PTT)5,6 have been developed for the last two decades to decrease the side effects. However, the weak penetration of light limits the therapeutic efficiency of optical therapy of tumors in deeper tissue.7 Therefore, X-rays with high deep penetration are widely used compared with NIR light. However, the side effects of RT are unavoidable. Certainly, they have been partially alleviated by advanced nanobiotechnology. During X-ray radiation therapy (X-RT), radiosensitizers produce Compton or photoelectrons which strike adjacent water or biomolecules to generate reactive oxygen species (ROS), breaking indirectly DNA strands.8 Owning to insufficient biomolecules near to the radiosensitizers, loss of Compton or photoelectrons is another drawback of X-RT along with the prime problem of side effects. Addressing the issue to minimize the side effects and to overcome the limitations of X-RT and PDT, the use of X-rays for X-ray inducible PDT (X-RDT) has become a promising technique for the treatment of malignant tumors in the last decade.9–11 X-RDT is an energy transduction process. The scintillator nanoparticles (SNPs) could convert the high energy X-rays into light to stimulate photosensitizers (PS) for generation of toxic reactive oxygen species (ROS) which irreversibly damage cancer cells.12–14 Nanomedicine containing ScNPs such as nanoparticles with high Z-elements or metal nanoclusters have been observed to be an effective methodology to enhance PDT efficacy under X-ray irradiation.15,16 In this paradigm, ScNPs combined with porphyrin or organic dye as photosensitizers are glaringly investigated in vitro and in vivo to kill cancer cells or to destroy solid tumors.17,18 Amusingly, low dose treatment is the major advantage of X-RDT, but it still faces a lack of radiosensitivity. In order to accomplish splendid therapeutic efficacy, Lin and co-workers have successfully designed a hafnium (Hf)–Ru based nanoscale metal-organic framework (MOF) for mitochondrial-targeted X-ray induced radiation and radio dynamic therapy (X-RT-RDT) under low dose X-ray irradiation.19 In the Hf–Ru based MOF, Hf could act as an X-ray scintillator, and transfer high energy X-rays into Qlight for the Ru-complex photosensitizer to produce singlet oxygen (1O2). Additionally, Hf as an X-ray radiosensitizer was capable of generating hydroxyl radicals from adjacent water molecules resulting in enhancement of RT efficacy. However, high quantum yield and long lifetime of the photosensitizers are the imperative properties for superior RDT efficacy.20 Recently, the Chen group has well designed a metal-doped silicate nanosensitizer conjugated with an effective photosensitizer, rose Bengal (RB) as a new X-PDT agent which exhibited a significant inhibitory effect on tumor progression under low dose X-ray irradiation.21 In order to improve X-RT, radiosensitizers (RS) have been immensely used for X-ray irradiated auger therapy (AT) in which low energy auger electrons disrupt directly DNA strands.22–24 The main attracting advantage of X-ray irradiated auger therapy (AT) is the continues generation of auger electrons upon single dose X-ray irradiation, which is unlike the frequent use of X-rays in conventional RT.25
Hence, to address the effective efficacy for both X-RT by Auger electrons and X-RDT by producing 1O2, X-ray inducible radiation and radio dynamic therapy (X-RRDT) could build a revolution in the entire discipline of cancer treatment. Several recent studies have reported the significant radiosensitizing and scintillating properties of octahedral molybdenum clusters under X-ray irradiation. Herein, we established the largest strawberry-shaped polyoxomolybdate nanoclusters (POMo NCs) which exhibited radiosensitizing features by producing auger electrons and scintillating properties upon X-ray irradiation. To date, investigations on POMo NCs as an X-RT agent and POMo NCs-photosensitizer based X-RDT agents for tumor destruction have not yet been studied. Meanwhile, rose Bengal (RB) as a photosensitizer is massively used in light-induced PDT due to the generation of abundant 1O2 with high quantum yield.28–30 Therefore, the design of nanoformulations composed of POMo NCs as an X-ray radiosensitizer and X-ray scintillator with RB as a photosensitizer could be an advanced technique for X-RRDT to combat cancer.
In this work, we successfully synthesized POMo NCs and RB loaded PEG functionalized chitosan (CS) nanoformulations (PEGylated POM@CS–RB) as X-ray radiosensitizers and X-ray scintillators. Hollow structured CS for RB loading in their cavity to a large extent and simultaneously their cationic surface charge assisted to hold anionic POMo NCs firmly. Importantly, the remarkable radiosensitizing properties of the POMo NCs expedited X-ray induced RT as strongly evidenced by g-H2AX assay. Moreover, X-ray inducible excellent RDT efficacy by POMo NCs arose from their incredible scintillating properties in which the transduced energy stimulated RB to generate cytotoxic 1O2 as confirmed from the SOSG assay kit study extra and intracellularly. However, the mutual consequence of RT and RDT from POMo@CS–RB leading to the damage of DNA which in turn resulted in the killing of cancer cells was successfully evidenced by both g-H2AX and live/dead cell co-staining assay. For instance, robust NIR absorbance of POMo NCs at 860 nm resulted in photoacoustic imaging (PA) guided X-ray inducible radiation and radio dynamic therapy (X-RRDT) in vivo. Finally, an in vivo study revealed the effective outcome in regression of the tumor growth without triggering side effects in major normal organs as demonstrated by hematoxylin and eosin (H&E) staining. However, the continuous production of auger electrons from POMo NCs under single-dose X-ray irradiation could be advantageous for low dose treatment. Additionally, the low dose treatment might protect the other normal organs from serious damage. Hence, our projected nanomaterials, PEGylated POMo@CS–RB could be successfully applied for clinical trials as X-RRDT agents for cancer treatment in the future.
Results and discussion
The detailed synthesis procedure for the formation of POMo nanoparticles (NPs), POMo NCs and hollow chitosan as well as the designing of PEGylated POMo@CS–RB have been discussed in the methods section. In brief, POMo nanoclusters (NCs) were obtained by the reduction of phosphomolybdic acid in a mild alkaline medium followed by cryodesiccation. POMo NCs were added to freshly prepared CS solution and then stirred for 24 h under dark conditions. After the removal of unloaded POMo, the yellowish blue solution was collected, yielding POMo loaded CS (POMo@CS) nano-formulation. Next, POMo@CS–RB was prepared by adding an RB solution in the POMo@CS solution. Polyethylene glycol (PEG) was used to modify the POMo@CS–RB nanoformulation to make it biocompatible. The overall design of PEGylated POMo@CS–RB and the plausible mechanism of auspicious mutual radiosensitization with scintillating properties for X-RRDT have been schematically demonstrated in Fig. 1. In short, upon X-ray irradiation, POMo NCs could constantly generate auger electrons to break DNA, improving RT efficacy. Meanwhile, POMo NCs could also transfer high energy X-rays into visible light to stimulate RB for the production of 1O2 which damaged DNA indirectly.
X-ray diffraction (XRD) patterns of POMo NCs were matched well with the previously reported articles31 (ESI,† Fig. S1). An interesting investigation on structural analysis by macro model-2 (MM-2) study revealed that strawberry-shaped POMo NCs composed of 652 Mo atoms with an overall size of 5.9 nm were structurally formed which was nicely corroborated by transmission electron microscope (TEM) images. To the best of our knowledge, this was the largest POMo cluster containing 163 Mo (Mo)3 units of three edge-sharing MoO6 octahedra and connecting to the central PO4 octahedron (Fig. 2a). This structure was formed following the kegging structure of PMo12O40.32 As shown in Fig. 2b and c, the crucially optimized strawberry structured POMo NC is shown by both stick-ball and space fill style, respectively. On controlled reduction of Mo(VI) to Mo(V), both oxidation states (VI/V) of Mo in POMo NCs persisted as determined by X-ray photoelectron spectroscopic (XPS) analysis (Fig. 2d). The full XPS spectrum of POMo NCs is presented in the ESI,† Fig. S2. Additionally, the intense peak at 670 nm was attributed to the metal to metal charge transfer between Mo(VI) and Mo(V), further assuring their simultaneous presence in the cluster (ESI,† Fig. S3). However, the sharp peak at 862 nm was ascribed to the charge transfer from oxygen to Mo(V), resulting in blue color. The monodispersed POMo NCs with an average size of 6 nm (histogram inset) were uniformly distributed on CS as shown by TEM images (Fig. 2e and f). Moreover, a uniform hollow structure in the CS was clearly observed by TEM images. The surface-modified POMo loaded CS (PEGylated POMo@CS) exhibited an average size of 80 nm (histogram inset, Fig. 2b), whereas, dynamic light scattering (DLS) measurement showed a Z-average of 106 nm with polydispersity index of 0.134 T 0.02 (ESI,† Fig. S4). Good distributions of molybdenum (Mo) and oxygen were successfully analyzed by TEM elemental mapping (Fig. 2c). The high Brauner Emmett Teller (BET) surface area and the Barret Joyner Halenda (BJH) pore size of PEGylated POMo@CS were measured to be B97 m2 g—1 and B50 nm, respectively, further ensuring the formation of hollow structured CS (ESI,† Fig. S5).
As expected, during RB loading, a large amount of RB was effectively loaded into the cavity of hollow CS. The successful loading of various concentrations of RB was examined from the characteristic UV-visible-NIR absorbance of RB at 530 nm (ESI,† Fig. S6a). The loading efficiency (POMo@CS: RB, w/w) was enhanced with increasing the concentration of RB and the utmost RB loading efficiency was calculated to be 68% (ESI,† Fig. S6b). The loaded RB in the POMo@CS–RB nanoformulation was very stable in different solutions including deionized water and phosphate buffer solution (PBS). Only less than 10% of RB could be released from the POMo@CS–RB nanoformulation (ESI,† Fig. S6c). Additionally, we also tested the stability of the POMo@CS–RB nanoformulation in different pH (pH 7.4 and 6.5) solutions. It was found that the size of the POMo@CS–RB nanoformulation exhibited no obvious change in different pH solutions, indicating good stability of the nanoformulation (ESI,† Fig. S7). Such a high amount of RB loading was due to the incorporation of dye molecules inside the cavity of hollow CS. However, the fine and firm orientation of the POMo NCs onto the CS was well explained from surface charge analysis as measured by zeta potential (ESI,† Fig. S8). The zeta potential of chitosan nanoparticles and POMo NCs was measured to be +31 and —9 mV, respectively. Therefore, the adequate distribution of anionic charged POMo NCs onto cationic CS was possible due to the effective ionic interaction between them. Nevertheless, after RB loading, the positive surface charge of POMo@CS was decreased by 2 mV, further confirming RB loading in the cavity of hollow CS. Furthermore, the positive surface charge of +18 mV for POMo@CS was abruptly reduced to +6 mV after PEG modification. Almost neutral surface charge of PEGylated POMo@CS would enhance its mobility through the bloodstream during the animal experiment.
In order to evaluate the scintillating characteristics of POMo NCs upon X-ray irradiation, a photoluminescence (PL) study was assertively conducted (Fig. 2h). Bare POMo NCs exhibited no optical features. However, the RB showed a single strong broad emission centered at 566 nm upon excitation at 490 nm before and after X-ray treatment. A similar result was observed for RB loaded POMo@CS before X-ray irradiation. Interestingly, miniature observation revealed that two more peaks at 522 and 602 nm for RB loaded POMo@CS nanoparticles were intensified after X-ray treatment, while the most common peak of RB was at 566 nm at the same excitation energy. Here, we called these two peaks as phantom peaks because these appeared only for X-ray treated RB loaded POMo@CS. The appearance of the two phantom peaks could be explained as the occurrence of several redox reactions among the various reduced and oxidized states of RB which were produced at the excited triplet state of RB.33 It assumed that POMo NCs could act as an energy transducer. Upon X-ray irradiation, POMo NCs could transfer incident high energy into visible light which could stimulate the RB in sequence to create its excited state. Since RB is a prominent photosensitizer to generate colossal 1O2 from molecular oxygen at its triplet excited state, it could be possible for a plentiful generation of 1O2 upon falling X-rays on RB loaded POMo NCs. The feasibility for the generation of singlet oxygen by POMo, RB or POMo@CS–RB was assessed by a single oxygen sensor green (SOSG) indicator. By measuring the fluorescence signal of SOSG, 1O2 is easily be detected in both extra and intracellular circumstances.34 However, in our experiment, 100 mM of SOSG was added to deionized water or an aqueous solution of RB or water-dispersed POMo or POMo@CS–RB at an RB and Mo concentration of 50 and 100 mg mL—1, respectively, and then irradiated with X-rays at 2 Gy. As shown in Fig. 2i, strong fluorescence intensity of SOSG for POMo@CS–RB treated solution was detected, while almost no response from other nanomaterials was observed. It could only be possible if POMo nanoclusters exhibited scintillating features under high energy electromagnetic radiation. Hence it was anticipated that upon X-ray irradiation, POMo nanoclusters might transfer the high energy into visible light which in turn activated RB to produce 1O2. Meanwhile, the same experiment was conducted at different X-ray doses in the range between 0 and 10 Gy and the production of singlet oxygen was quantified by measuring the fluorescence intensity of SOSG. With increasing X-ray doses, the fluorescence intensity of SOSG was sharply amplified for POMo@CS–RB, while negligible intensity was perceived for the rest of the tested samples (Fig. 2j). Furthermore, in order to determine whether hydroxyl radicals (●OH) as ROS were generated upon X-ray irradiation at a low dose, we carried out the p-aminophenyl fluorescein (APF) assay. AFP could react with ●OH resulting in a strong fluorescence at 515 nm at an excitation wavelength of 490 nm.35,36 No prominent peak (data not shown) suggested that the excited triplet state of RB has proceeded importantly via the type II pathway.
In aid of the therapeutic performance of the synthesized X-RRDT nanoformulation, it is necessary to check its activity towards cells and the ability to localize to the site of the disease. Therefore, to image the intracellular distribution of the PEGylated POMo@CS–RB nanoformulation, we performed fluorescence imaging on 4T1 cells by using confocal laser scanning microscopy (CLSM) after incubation of the nanomaterial for 12 h at 37 1C. The cell nucleus was stained with 40,6-diamidino-2-phenyl indole (DAPI) (blue) and the green fluorescence of the fluorescein isothiocyanate (FITC) conjugated POMo@CS–RB nanoformulation was observed in all the cells. The strong green fluorescence was spotted around the cell nucleus and preferentially distributed across the cytoplasm (Fig. 3a). The good internalization of the nanomaterials by the cells depended on endocytosis.
Henceforth, in vitro toxicity of the bare RB, PEGylated POMo@CS and POMo@CS–RB nanoformulations towards 4T1 cells with and without X-ray irradiation was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay. The control nanoparticles without X-ray treatment caused no toxicity to cells. The cells were viable virtually up to 95% at a high concentration of both POMo (500 mg mL—1) and RB (200 mg mL—1) (ESI,† Fig. S9). Therefore, the results of the cell viability suggested that all nanoformulations were biocompatible to the 4T1 cells. In disparity, upon 2 Gy of
X-ray irradiation, the PEGylated POMo@CS nanoparticles caused a minute toxicity to the cells at low concentration of POMo NCs and cell viability was gradually dropped with increasing the concentration of POMo (Fig. 3d). This result specified that POMo NCs could perform as a fabulous X-ray radiosensitizer via X-ray inducible RT. However, RB induced no toxicity to the cell upon X-ray treatment. Importantly, at a very low concentration of both POMo and RB, the PEGylated POMo@CS–RB nanoformulation manifested a substantial death of 4T1 cells under a very low dose of X-ray irradiation (2 Gy) via X-ray inducible radiation and radio dynamic therapy (X-RRDT).
The hollow structure of CS could provide a novel nano- platform to load RB with a high content. In aid of the massive generation of extracellular 1O2, we hypothesized that POMo NCs might relay energy in the form of visible light to stimulate RB to produce 1O2 upon X-ray irradiation. To validate the effect in the detection of the ample generation of intracellular 1O2, singlet oxygen sensor green (SOSG) was used to detect 1O2. The cells incubated with PEGylated POMo@CS–RB nanoparticles and irradiated by X-rays exhibited strong green fluorescence signal. While minimal fluorescence signals were visualized for the other X-ray treated nanomaterials such as PBS, RB or PEGylated POMo@CS (Fig. 3b). Meanwhile, the fluorescence intensity of SOSG was detected by flow cytometry analysis. For X-ray treated PEGylated POMo@CS–RB nanoparticles, obtaining superior fluorescence intensity with diminished cell count confirmed that colossally generated 1O2 caused the death of the cells probably via X-ray inducible radio dynamic therapy (X-RDT) (Fig. 3c). However, for X-ray treated RB or PEGylated POMo@CS, no specious change was perceived in both the fluorescence intensities of SOSG and in cell count from X-ray irradiated PBS. Therefore, from in vitro data (Fig. 3d), we could speculate indirectly that the POMo@CS–RB nanoformulation could transfer the high energy into visible light which in turn stimulated the RB to produce 1O2 for killing cancer cells.
Encouraged by the radiosensitization effect of POMo NCs, we performed a DNA strands break immunofluorescence staining assay using phosphorylated g-H2AX, a sensitive protein biomarker to detect DNA damage induced by ionizing radiation. Upon X-ray irradiation at a dose of 2 Gy, red fluorescence of g-H2AX was alleged for both POMo and RB loaded POMo NCs, indicating the breakages of DNA double strands in the nuclei of the cells (Fig. 4a). POMo@CS–RB under X-ray irradiation would generate abundant ROS and decrease DNA damage repairability in the cytoplasm. Therefore, the POMo@CS–RB nanoformulation could significantly induce DNA damage. The results further confirmed that POMo nanoclusters could act as X-ray radiosensitizers which triggered DNA damage via X-ray inducible radiation therapy (X-RT). Furthermore, strong red fluorescence was more intensified from the nuclei for POMo@CS–RB treated cells. In addition, no indication of fluorescence signal in PBS or RB treated cells at the same X-ray irradiation dose reversely supported the radiosensitization effect of POMo nanoclusters.
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HalfenproxCatalog No.:AA01FNWI CAS No.:111872-58-3 MDL No.: MF:C24H23BrF2O3 MW:477.3384 |
Butanenitrile,4-[(dimethylamino)dimethylsilyl]-Catalog No.:AA007DDT CAS No.:111873-32-6 MDL No.:MFCD05663912 MF:C8H18N2Si MW:170.3274 |
8-iodocubane-1-carboxylic acidCatalog No.:AA01EIKG CAS No.:111873-46-2 MDL No.:MFCD30723376 MF:C9H7IO2 MW:274.0552 |
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[4-(2-carboxyethyl)-2-thiazolyl]thio]methyl]-8-oxo-, [6R-[6a,7b(Z)]]-Catalog No.:AA01CBP1 CAS No.:111874-09-0 MDL No.: MF:C20H20N6O7S4 MW:584.6688 |
3-amino-1,2,3,4-tetrahydro-1,8-naphthyridin-2-one dihydrochlorideCatalog No.:AA01BHSS CAS No.:1118751-87-3 MDL No.:MFCD26405780 MF:C8H11Cl2N3O MW:236.0984 |
3,5-Bis(bromomethyl)pyridine hydrobromideCatalog No.:AA01AM95 CAS No.:1118754-56-5 MDL No.:MFCD27996064 MF:C7H8Br3N MW:345.8571 |
N-(2-aminophenyl)pyrrolidine-1-carboxamideCatalog No.:AA019UQH CAS No.:1118786-84-7 MDL No.:MFCD11857948 MF:C11H15N3O MW:205.2563 |
tert-Butyl 2-azaspiro[3.3]hept-6-ylcarbamateCatalog No.:AA007DDD CAS No.:1118786-85-8 MDL No.:MFCD11858159 MF:C11H20N2O2 MW:212.2887 |
2-(Boc-amino)-6-oxospiro[3.3]heptaneCatalog No.:AA008U0I CAS No.:1118786-86-9 MDL No.:MFCD11858160 MF:C12H19NO3 MW:225.2842 |
3-(2-Aminoethyl)benzamideCatalog No.:AA0097XW CAS No.:1118786-88-1 MDL No.:MFCD11858180 MF:C9H12N2O MW:164.2044 |
4,6-Dimethoxypyrimidin-5-methylamineCatalog No.:AA0094GY CAS No.:1118786-90-5 MDL No.:MFCD11858183 MF:C7H11N3O2 MW:169.1811 |
2-Trifluoromethoxy-ethanesulfonyl chlorideCatalog No.:AA019C6Z CAS No.:1118786-91-6 MDL No.:MFCD11858188 MF:C3H4ClF3O3S MW:212.5753 |
7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chlorideCatalog No.:AA019UHV CAS No.:1118786-95-0 MDL No.:MFCD11857862 MF:C9H7ClFNO3S MW:263.6732 |
2-(3-methyl-4-nitrophenyl)-1,3,4-oxadiazoleCatalog No.:AA019LYB CAS No.:1118786-96-1 MDL No.:MFCD11833085 MF:C9H7N3O3 MW:205.1702 |
5-[(methylsulfanyl)methyl]furan-2-carbaldehydeCatalog No.:AA019UI3 CAS No.:1118786-97-2 MDL No.:MFCD11857865 MF:C7H8O2S MW:156.2022 |
2-([(2-Chlorophenyl)methyl]amino)propan-1-olCatalog No.:AA019UIF CAS No.:1118787-00-0 MDL No.:MFCD11840121 MF:C10H14ClNO MW:199.6773 |
5-carbamoyl-1H-pyrrole-3-carboxylic acidCatalog No.:AA019UIN CAS No.:1118787-01-1 MDL No.:MFCD11840126 MF:C6H6N2O3 MW:154.1234 |
2-(3-Aminophenyl)-6-ethyl-3,4-dihydropyrimidin-4-oneCatalog No.:AA018SBN CAS No.:1118787-02-2 MDL No.:MFCD11840130 MF:C12H13N3O MW:215.2511 |
(E)-N-[1-(5-Phenylthiophen-2-yl)ethylidene]hydroxylamineCatalog No.:AA019UKG CAS No.:1118787-04-4 MDL No.:MFCD11857877 MF:C12H11NOS MW:217.2868 |
N-(3-tert-Butyl-3-azabicyclo[3.2.1]octan-8-ylidene)hydroxylamineCatalog No.:AA01EJL2 CAS No.:1118787-09-9 MDL No.:MFCD13806385 MF:C11H20N2O MW:196.2893 |
4-chloro-5-nitro-1H-pyrrole-2-carboxylic acidCatalog No.:AA019UKT CAS No.:1118787-10-2 MDL No.:MFCD11840132 MF:C5H3ClN2O4 MW:190.5413 |
6-cyclopropyl-2-(methylsulfanyl)pyrimidine-4-carboxylic acidCatalog No.:AA019UL5 CAS No.:1118787-11-3 MDL No.:MFCD11857887 MF:C9H10N2O2S MW:210.2529 |
[4-methyl-6-oxo-2-(pyridin-3-yl)-1H-pyrimidin-5-yl]acetic acidCatalog No.:AA018SBR CAS No.:1118787-12-4 MDL No.:MFCD11839729 MF:C12H11N3O3 MW:245.2340 |
5-methyl-4-(pyrrolidine-1-sulfonyl)furan-2-carboxylic acidCatalog No.:AA019UM8 CAS No.:1118787-13-5 MDL No.:MFCD11857894 MF:C10H13NO5S MW:259.2789 |
3-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acidCatalog No.:AA00HC45 CAS No.:1118787-14-6 MDL No.:MFCD11857900 MF:C8H7N3O2 MW:177.1601 |
3-(3-methoxyphenyl)-2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)propanoic acidCatalog No.:AA019UNG CAS No.:1118787-15-7 MDL No.:MFCD11857906 MF:C12H14N4O3 MW:262.2646 |
3-(4-fluorophenyl)-2-(5-methyl-1,2,3,4-tetrazol-1-yl)propanoic acidCatalog No.:AA018SBI CAS No.:1118787-16-8 MDL No.:MFCD11857907 MF:C11H11FN4O2 MW:250.2290 |
3-(3-fluorophenyl)-2-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)propanoic acidCatalog No.:AA019UOA CAS No.:1118787-20-4 MDL No.:MFCD11857919 MF:C11H11FN4O2 MW:250.2290 |