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The development of nanoformulations with simple compositions that can exert targeted combination therapy still remains a great challenge in the area of precision cancer nanomedicine. Herein, we report the design of a multifunctional nanoplatform based on methotrexate (MTX)-loaded layered double hydroxide (LDH) coated with chlorin e6 (Ce6)-modified MCF-7 cell membranes (CM M ) for combined chemo/sonodynamic therapy of breast cancer. LDH nanoparticles were in situ loaded with MTX via coprecipitation, and coated with CM M that were finally functionalized with phospholipid-modified Ce6. The created nanoformulation of LDH-MTX@CM M -Ce6 displays good colloidal stability under physiological conditions and can release MTX in a pH-dependent manner. We show that the formulation can homologously target breast cancer cells, and induce their significant apoptosis through arresting the cell cycle via cooperative MTX-based chemotherapy and ultrasound (US)-activated sonodynamic therapy. The assistance of US can not only trigger sonosensitizer Ce6 to produce reactive oxygen species, but also enhance the cellular uptake of LDH-MTX@CM M -Ce6 via an acoustic cavitation effect. Upon intravenous injection and US irradiation, LDH-MTX@CM M -Ce6 displays an admirable antitumor performance towards a xenografted breast tumor mouse model. Furthermore, the modification of Ce6 on the CM M endows the LDH-based nanoplatform with fluorescence imaging capability. The developed LDH-based nanoformulation here provides a general intelligent cancer nanomedicine platform with simple composition and homologous targeting specificity for combined chemo/sonodynamic therapy and fluorescence imaging of tumors.

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

A methotrexate (MTX)-loaded layered double hydroxide (LDH) nanoparticle system was synthesized by intercalating MTX into the interlayer spaces of LDH. In vivo pharmacokinetic study demonstrated that the MTX-LDH hybrid had similar kinetic behaviors as free MTX, showing a rapid decline in the plasma MTX level, with characteristics of a biexponential function. However, the hybrid system remarkably suppressed tumor growth in human osteosarcoma-bearing mice compared to an equivalent amount of free MTX. Using MTX-LDH nanoparticles, a significantly high amount of MTX was delivered to target tumor tissue, whereas a low level was found in normal tissues. Moreover, LDH nanocarriers did not accumulate in any specific tissue nor cause acute toxicity up to the applied dose for the hybrid system. These results suggest that the MTX-LDH nanohybrid system has great potential as an anti-cancer drug with enhanced in vivo anti-tumor activity and bioavailability in target tumor tissue along with reduced side effects.

An anticancer drug, methotrexate (MTX), has been successfully hybridized with layered double hydroxide (LDH) through co-precipitation route to produce MTX-LDH nanohybrids (MTX-LDH). According to the X-ray diffraction and FT-IR spectroscopy, it was confirmed that MTX molecules are stabilized in the interlayer space of LDHs by electrostatic interaction, maintaining their functional groups and structural integrity. According to the drug release study, the total amount of released MTX from the LDH lattice was determined to be larger under a simulated intracellular lysosomal condition (pH = 4.5) than simulated body fluid one (pH = 7.4). It is, therefore, expected that the MTX molecules in MTX-LDH can be effectively released in lysosomes, since the MTX release could be accelerated via ion-exchange reaction and dissolution of LDH in an acidic lysosomal condition. We also examined the anticancer efficacy of MTX-LDH in human breast adenocarcinoma MCF-7 cells. The cellular uptake of MTX was considerably higher in MTX-LDH-treated cells than in free MTX-treated cells, giving a lower IC50 value for the former than the latter. All the results demonstrated that the MTX-LDH nanohybrid allows the efficient drug delivery in cells, and thus enhances drug efficacy.

Folic acid derivatives such as folinic acid and methotrexate (MTX) have been successfully hybridized with layered double hydroxide (LDH) by ion-exchange reaction. The X-ray diffraction patterns and spectroscopic analyses indicate that these molecules intercalated into the hydroxide interlayer space are stabilized in the tilted longitudinal monolayer mode by electrostatic interaction. No significant changes in their structural and functional properties are found in the hybrids. The cellular uptake test of MTX-LDH hybrid is carried out in the fibroblast (human tendon) and SaOS-2 cell line (Osteosarcoma, human) by in vitro MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide) assay. The initial proliferation of SaOS-2 cell is more strongly suppressed by treatment with MTX-LDH hybrid than with MTX alone. This study clearly shows that LDH not only plays a role as a biocompatible-delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency.