Folate Ligand Research Articles

Synthesis, spectroscopic, structural and morphological characterizations of magnesium(II), calcium(II), strontium(II) and barium(II) folate complexes

This article aimed to synthesis and characterizations of metal folic acid as a vitamin B9 drug (H2FO) complexes. Using this bi-dentate ligand, complexes of magnesium(II), calcium(II), strontium(II) and barium(II) with general formula [M2(FO)(H2O)6(Cl)2].2H2O have been synthesized. The synthesized folate complexes were characterized by number of techniques using elemental analysis, molar conductance, (FTIR, Raman laser, 1HNMR & electronic) spectroscopy and particle size analysis using X-ray powder diffraction (XRD) spectra. The elemental analysis results suggest the stoichiometry to be 2 : 1 (M : L). All the synthesized complexes are non-electrolytic nature as confirmed by molar conductance measurements. Infrared spectral data indicate the coordination between the folate ligand and the central metal ion via the folate anion which acts as a dicarboxylate ligand with the metal ion coordinated to both the α and β carboxylate groups of the glutamic acid moiety. Spectral studies suggest six-coordination geometry for all complexes.

Mediating the Fate of Cancer Cell Uptake: Dual-Targeted Magnetic Nanovectors with Biotin and Folate Surface Ligands.

Recognition of folate and biotin surface receptors by dual-functionalized nanoparticles (NPs) is key for site-selective receptor-mediated transport of anticancer drugs to cancer cells. We present here dopamine-capped iron oxide nanoprobes (Fe3O4, 10 ± 2 nm) containing two surface-grafted biologically relevant ligands, namely, folic acid (FA) and biotin (BT). The covalent attachment of both FA and BT on Fe3O4 nanoparticles was achieved by following carbodiimide coupling and click-chemistry protocols. The dual-function Fe3O4 probes were delivered into E-G7 and human HeLa cancer cell lines and tested toward their cellular uptake by immunofluorescence and flow cytometry analysis. Owing to receptor-mediated endocytosis, enhanced accumulation of nanoprobes in cancer cells was successfully monitored by confocal laser microscopy. When compared to dual-function probes, single-functionalized nanoparticles possessing either FA or BT ligands showed significantly reduced uptake in the tested cell lines, underlining the superior interaction potential of dual-purpose probes. A time-dependent receptor-mediated endocytosis of FA-Fe3O4-BT nanovectors was demonstrated by flow cytometry analysis, whereas the unfunctionalized NPs did not show any specificity in terms of uptake. Besides their specific uptake, the surface-functionalized nanoparticles exhibited promising cytotoxicity profiles by demonstrating good viability of more than 95% with analogous cancer cell lines. Our results demonstrate that dual and/or multivariate conjugation of receptor-specific ligands on NPs is highly effective in molecular recognition of surface biomarkers that enhances their potential in anticancer treatment for pretargeting-radio strategies based on biotin/avidin interactions.

Cellular Analysis and Chemotherapeutic Potential of a Bi-Functionalized Halloysite Nanotube.

The surface of halloysite nanotubes (HNTs) was bifunctionalized with two ligands—folic acid and a fluorochrome. In tandem, this combination should selectively target cancer cells and provide a means for imaging the nanoparticle. Modified bi-functionalized HNTs (bi-HNTs) were then doped with the anti-cancer drug methotrexate. bi-HNTs were characterized and subjected to in vitro tests to assess cellular growth and changes in cellular behavior in three cell lines—colon cancer, osteosarcoma, and a pre-osteoblast cell line (MC3T3-E1). Cell viability, proliferation, and cell uptake efficiency were assessed. The bi-HNTs showed cytocompatibility at a wide range of concentrations. Compared with regular-sized HNTs, reduced HNTs (~6 microns) were taken up by cells in more significant amounts, but increased cytotoxicity lead to apoptosis. Multi-photon images confirmed the intracellular location of bi-HNTs, and the method of cell entry was mainly through caveolae-mediated endocytosis. The bi-HNTs showed a high drug loading efficiency with methotrexate and a prolonged period of release. Most importantly, bi-HNTs were designed as a drug carrier to target cancer cells specifically, and imaging data shows that non-cancerous cells were unaffected after exposure to MTX-doped bi-HNTs. All data provide support for our nanoparticle design as a mechanism to selectively target cancer cells and significantly reduce the side-effects caused by off-targeting of anti-cancer drugs.

Antitumor Activity of a Novel Double-Targeted System for Folate Receptor-Mediated Delivery of Mitomycin C.

In this study, we designed, formulated, and investigated the potential antitumor activity of a folate receptor (FR)-mediated double-targeted drug delivery system. The system comprised of the FR ligand folic acid (FA), glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly, GFLG), which can be specifically cleaved by cathepsin B, and the anticancer drug mitomycin C (MMC). The antitumor effect of FA-GFLG-MMC was compared to that of MMC. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that FA-GFLG-MMC has a significantly higher inhibitory effect on HeLa, SiHa, and PC9 cells (high FR expression) than that on 16HBE and A549 cells (low FR expression). Furthermore, FA-GFLG-MMC inhibited cancer cell proliferation in a dose-dependent manner. Free MMC was toxic to both cancer and normal cells. Apoptosis of the HeLa, SiHa, and PC9 cells was higher than that of the A549 cells; however, the apoptotic effect on 16HBE cells was minimal. Proapoptotic protein bcl-2-associated X-protein (BAX) and antiapoptotic protein BCL-2 play critical roles in cellular defense and apoptotic signal transduction. BAX/BCL-2 ratio is used to determine the intensity of an apoptotic signal and assess whether a cell will survive or undergo apoptosis. BAX and BCL-2 expression in cells treated with 5 μM FA-GFLG-MMC was studied by Western blotting. FA-GFLG-MMC increased the BAX/BCL-2 ratio in HeLa, SiHa, and PC9 cells. The results show that FA-GFLG-MMC can effectively inhibit tumor cell proliferation by inducing apoptosis. Therefore, the system developed can enhance the delivery of anticancer drugs to cancer cells and thereby reduce their toxic effects on normal cells.

Dandelion-Inspired Hierarchical Upconversion Nanoplatform for Synergistic Chemo-Photodynamic Therapy In Vitro.

Herein, inspired by the structure of a dandelion, we develop a fresh preparation of an upconversion nanoplatform (UCNPs@C60-DOX-FA). The target part folic acid (FA) modified with β-CD-NH2 can enhance dispersibility and afford the nanoplatform to arrive at the tumor and enter cancer cells easily. After the mouse breast cancer (4T1) cell incubation with the nanoplatform, the abundant glutathione (GSH) in cells cuts the -S-S- bonds like scissors, just as dandelion encountering wind, and the drug doxorubicin (DOX) flows into the nucleus for chemotherapy. Meanwhile, the photodynamic therapy (PDT) effect is enhanced with the decrease content of GSH, which promotes the reactive oxygen species to accumulation. The synergistic chemotherapy and PDT are outstanding in killing 4T1 cells. The rest part UCNPs@C60 possesses excellent biocompatibility and low cytotoxicity. As for cancer diagnosis, UCNPs can be used as a visual imaging agent. Benefited by the delicate structure, all of the functional parts of the nanoplatform go and coordinate well. On account of an FA ligand and the -S-S- bond, the nanoplatform works very well in 4T1 cells while it is able to avoid damage to normal cells since the FA receptors and GSH have overexpression in the 4T1 cells. Thus, this work shows an accessible strategy to design a dandelion-like hierarchical nanoplatform for potential bioimaging-guided synergistic chemo-photodynamic therapy.

Eyeball-Like Yolk-Shell Bimetallic Nanoparticles for Synergistic Photodynamic-Photothermal Therapy.

Noble metal-based nanomaterials offer great potential as cargoes for multifunctional cancer treatment. In this research, Au eyeball-like nanoparticles (NPs) with open-mouthed Pd shells were synthesized and their surface was functionalized with cell-targeting ligand folic acid (FA) and photodynamic agent Chlorin e6 (Ce6). Due to the broad near-infrared (NIR) absorption band of eyeball-like bimetallic Au and Pd, the photothermal therapy effects of this nanomaterial were studied in MCF-7 cancer cells. The anchored Ce6 not only addressed the hypoxia issue of tumor cells but also exhibited remarkable photodynamic efficacy upon irradiation. Results showed that the obtained Au@Pd-PEG-FA-Ce6 (APPFC) NPs were selectively accumulated at the tumor site and induced cell apoptosis effectively due to the target specificity and synergistic phototherapy effect. The high specificity, desirable biosafety, fast delivery, and drug functionalization demonstrated eyeball-like Au@Pd NPs are promising candidate for multifunctional therapy of breast cancer.

Dual charged folate labelled chitosan nanogels with enhanced mucoadhesion capacity for targeted drug delivery

Nanometric gel particles (CsSH/PEGBCOOH) were successfully synthesized through water in oil (W/O) emulsion by the covalent cross–linking between the primary amines of thiolated chitosan (CsSH) and the dicarboxylic poly(ethylene glycol) (PEG) derivative as cross–linker (PEGBCOOH). Thus, the amidation reaction led to the formation of stable nanosized networks positively or negatively charged by the ionization of either amines or thiol moieties depending on the surrounding pH. This double response, which has not been studied before, was markedly observed and quantified during the characterization of the nanogels, concluding the high impact that could suppose these promising nanoparticles in the biomedical field. Besides, the presence of thiol groups in the nanogels was demonstrated to greatly improve the nanoparticle–mucus interactions, highlighting the potential of this novel strategy in the field of nanotechnology. Finally, nanogels were further labelled with folate ligand as an example of a simple and easy functionalization route via thiol–Michael addition (MA) reaction for future studies of tumour targeting therapies of these nanocarriers. Therefore, the synthesized chitosan–based labelled nanogels presented an adaptable character to the environmental conditions due to their dual pH response and mucoadhesion capacity, making them great candidates as nanocarriers for biomedical applications.

Selection of superior targeting ligands using PEGylated PLGA nanoparticles for delivery of curcumin in the treatment of triple-negative breast cancer cells

Many chemotherapeutic drugs are unable to achieve their potency because of their hydrophobic nature [e. g. curcumin (Cur)], coupled to its inability to reach the target site, lower circulation time and low half-lifetime. To overcome these, PLGA nanoparticles were synthesized, loaded with curcumin, coated with polyethylene glycol (PEG) and conjugated with different targeting moieties - either folic acid (FA), or hyaluronic acid (HA), or transferrin (Tf) - in the quest to find the best possible targeting agent. TEM images confirm uniform coating of PEG over the PLGA nanoparticle surface, with a size increment from 85 nm (for only PLGA) to ~124 nm (for PLGA-Cur-PEG-ligand nanoparticles), subsequent to PEG coating and attachment of targeting moieties. Cell viability experiments at 80 μM drug concentration on MDA-MB-231 cells confirmed that, viability gradually decreased from 92% to 41%, 32%, 39%, 19% and 8% for free Cur in PBS, to PLGA-Cur, PLGA-Cur-PEG, PLGA-Cur-PEG-Tf, PLGA-Cur-PEG-HA and PLGA-Cur-PEG-FA, respectively. Confocal microscopy and flow cytometry established a higher percentage of curcumin internalization in cells, leading to enhanced cancer cell killing with targeted nanoparticles. Therefore, HA and FA ligands are better targeting moieties, to treat highly aggressive and metastatic MDA-MB-231 breast cancer cells using PLGA nanoparticles.

Accurate Targeting and Controllable Release of Hybrid Liposome Containing a Stretchable Copolymer

AbstractDeveloping an intelligent drug delivery/release system, which can transport drugs to the target tissues precisely and release drugs timely, is an important challenge in chemotherapy. A multistage sensitive drug delivery system is designed by inserting a folate (FA) modified lipid and a pH/temperature dual‐sensitive amphiphilic copolymer into a liposome bilayer. The stretchable copolymer plays a role in protection on FA ligand for more accurate targeting. Then, the stretch ability of the copolymer in the liposome bilayer is verified by using the Langmuir–Blodgett film technique. The interaction between the 1,2‐dipalmitoyl‐sn‐glycerol‐3‐phosphocholine (DPPC) monolayer and hybrid liposomes is found to increase, indicating the FA ligand is exposed due to the copolymer shrinking with increasing temperature. Fluorescence polarization measurements demonstrate that the insertion of the copolymer improves the stability of the liposome and offers pH‐controllability for drug release. As a result, the drug leakage of the hybrid liposome is restrained significantly at pH 7.4, while at an acidic pH, the drug release is accelerated. The designed pH/temperature dual‐sensitive copolymer is expected to provide more precise targeting and environmentally controlled drug release to drug delivery systems based on liposomes.

Ditelluride-Bridged PEG-PCL Copolymer as Folic Acid-Targeted and Redox-Responsive Nanoparticles for Enhanced Cancer Therapy.

The development of the nanosized delivery systems with targeting navigation and efficient cargo release for cancer therapy has attracted great attention in recent years. Herein, a folic acid (FA) modified PEGylated polycaprolactone containing ditelluride linkage was synthesized through a facile coupling reaction. The hydrophobic doxorubicin (DOX) can be encapsulated into the polymeric micelles, and such nanoparticles (F-TeNPDOX) exhibited redox-responsive drug release under abundant glutathione (GSH) condition due to the degradation of ditelluride bonds. In addition, flow cytometric analyses showed that the FA ligands on F-TeNPDOX could facilitate their cellular uptake in 4T1 breast cancer cells. Therefore, F-TeNPDOX led to the promoted drug accumulation and enhanced growth inhibition on 4T1 tumor in vivo. The obtained results suggest F-TeNPDOX excellent potential as nanocarriers for anticancer drug delivery.

A Fluorescent Probe for Rapid, High-Contrast Visualization of Folate-Receptor-Expressing Tumors In Vivo.

Folate receptors (FRs) are membrane proteins involved in folic acid uptake, and the alpha isoform (FR-α) is overexpressed in ovarian and endometrial cancer cells. For fluorescence imaging of FRs in vivo, the near-infrared (NIR) region (650-900 nm), in which tissue penetration is high and autofluorescence is low, is optimal, but existing NIR fluorescent probes targeting FR-α show high non-specific tissue adsorption, and require prolonged washout to visualize tumors. We have designed and synthesized a new NIR fluorescent probe, FolateSiR-1, utilizing a Si-rhodamine fluorophore having a carboxy group at the benzene moiety, coupled to a folate ligand moiety through a negatively charged tripeptide linker. This probe exhibits very low background fluorescence and afforded a tumor-to-background ratio (TBR) of up to 83 in FR-expressing tumor-bearing mice within 30 min. Thus, FolateSiR-1 has the potential to contribute to the research in the field of biology and the clinical medicine.

A Fluorescent Probe for Rapid, High‐Contrast Visualization of Folate‐Receptor‐Expressing Tumors In Vivo

AbstractFolate receptors (FRs) are membrane proteins involved in folic acid uptake, and the alpha isoform (FR‐α) is overexpressed in ovarian and endometrial cancer cells. For fluorescence imaging of FRs in vivo, the near‐infrared (NIR) region (650–900 nm), in which tissue penetration is high and autofluorescence is low, is optimal, but existing NIR fluorescent probes targeting FR‐α show high non‐specific tissue adsorption, and require prolonged washout to visualize tumors. We have designed and synthesized a new NIR fluorescent probe, FolateSiR‐1, utilizing a Si‐rhodamine fluorophore having a carboxy group at the benzene moiety, coupled to a folate ligand moiety through a negatively charged tripeptide linker. This probe exhibits very low background fluorescence and afforded a tumor‐to‐background ratio (TBR) of up to 83 in FR‐expressing tumor‐bearing mice within 30 min. Thus, FolateSiR‐1 has the potential to contribute to the research in the field of biology and the clinical medicine.

Folate conjugation improved uptake and targeting of porous hydroxyapatite nanoparticles containing epirubicin to cancer cells

As hydroxyapatite (HAp) with the hexagonal crystal structure is biocompatible and bioactive. In the present study, HAp nanoparticles were synthesized and functionalized with polyethylene glycol and folic acid. The anticancer drug, epirubicin, was loaded to the folic acid-conjugated polyethylene glycol-coated HAp (FA-PEG-HAp) nanoparticles. The prepared nanoparticles were used for in vitro and in vivo experiments. Particle size analyzer showed that the hydrodynamic size of PEG-HAp and FA-PEG-HAp nanoparticles was 150.3 ± 1.5 nm and 217.2 ± 14.9 nm, respectively. The release behavior of epirubicin from nanoparticles showed an increase in the rate of release in acidic pH. The released drug in acidic pH was 2.5 fold more than pH 7.4. The results of in vitro study indicated an increase in cellular uptake of nanoparticles due to folate ligand. In vivo treatment with both PEG-HAp and FA-PEG-HAp nanoparticles had notably higher inhibition efficacy towards tumor growth than free epirubicin. In conclusion, folate conjugation provided higher uptake and better targeting of hydroxyapatite nanoparticles to cancer cells.

Nanotoxicological study of downconversion Y2 O3 :Eu3+ luminescent nanoparticles functionalized with folic acid for cancer cells bioimaging.

Luminescent lanthanide downconversion nanoparticles (DCNPs) provide a combination of high luminescence intensity, sharp emission peaks with narrow bandwidth and a large Stokes' shift, leading to high-performance biomedical applications mainly for imaging. The purpose of this study is to present a nanotoxicological study of DCNPs Y2 O3 codoped with Eu3+ and functionalized with folic acid (FA). These assessments include cytotoxicity, genotoxicity, hemocompatibility, and in vitro inflammatory studies. We demonstrated by flow cytometry and confocal microscope the internalization of FA-DCNPs in breast cancer and melanoma cells. They were synthesized by sol-gel method and coated with a thin silica shell to make them biocompatible; also they were functionalized with amino groups and FA ligands that bind to the folate receptors (FR) located on the surface of the cancer cells studied. This functionalization enables the DCNPs to be internalized into the cancer cells via endocytosis by the conjugation FA-FR. The DCNPs were characterized with transmission electron microscope, Fourier transform infrared spectroscopy and photoluminescence. The nanotoxicological assessments demonstrated that both nanoparticles (bare and functionalized) are no cytotoxic and no genotoxic at the tested concentrations (0.01-20 μg/mL) in three cell lines (breast, skin cancer, and osteoblasts). Also they are hemocompatible and do not exert nitric oxide production in vitro by macrophages. The FA-DCNPs were clearly localized into the cell cytoplasm with bright red luminescence. Thus, herein we present a complete nanotoxicological study of FA-DCNPs Y2 O3 codoped with Eu3+ and we conclude that these nanoparticles are biocompatible and can be further used for cancer cells bioimaging.

Gd-/CuS-Loaded Functional Nanogels for MR/PA Imaging-Guided Tumor-Targeted Photothermal Therapy.

The second near-infrared (NIR-II, 1000-1700 nm) light-based diagnosis and therapy have received extensive attention for neoplastic disease treatments because of the fact that light in the NIR-II window possesses less photon scattering along with deeper tissue penetration than that in the NIR-I (700-950 nm) window. Herein, we present a Gd- and copper sulfide (CuS)-integrated nanogel (NG) platform for magnetic resonance (MR)/photoacoustic (PA) imaging-guided tumor-targeted photothermal therapy (PTT). In our approach, we prepared cross-linked polyethylenimine (PEI) NGs via an inverse emulsion method, modified the PEI NGs with Gd chelates, targeting ligand folic acid (FA) through a polyethylene glycol (PEG) spacer and 1,3-propanesultone, and finally loaded CuS nanoparticles (NPs) within the functional NGs. The as-synthesized Gd/CuS@PEI-FA-PS NGs with a mean size of 85 nm exhibit a good water dispersibility and protein resistance property, admirable r1 relaxivity (11.66 mM-1 s-1), excellent NIR-II absorption feature, high photothermal conversion efficiency (26.7%), and FA-mediated targeting specificity to cancer cells overexpressing FA receptor (FAR). With these properties along with the good cytocompatibility, the developed Gd/CuS@PEI-FA-PS NGs enable MR/PA dual-mode imaging-guided targeted PTT of FAR-overexpressing tumors under the irradiation of an NIR-II (1064 nm) laser. The designed Gd/CuS@PEI-FA-PS NGs may be used as a promising theranostic agent for MR/PA dual-mode imaging-guided PTT of other FAR-expressing tumors.

Liposomes co-delivery system of doxorubicin and astragaloside IV co-modified by folate ligand and octa-arginine polypeptide for anti-breast cancer.

Doxorubicin (DOX) is one of the core drugs in triple-negative breast cancer (TNBC) chemotherapy, but its resistance has severely limited its clinical application. Our previous study found that astragaloside IV (AS-IV) has a good reversal effect on doxorubicin resistance. In order to encapsulate DOX and AS-IV simultaneously, a new liposome-targeted co-delivery system co-modified by the folate ligand (FA) and octa-arginine polypeptide (R8) (FA-R8-LPs, for short) was prepared. In this co-delivery system, R8 not only served as a bond connecting the FA to the liposome, but also played the role of cell penetrating peptides (CPPs). This design effectively increased the tumor targeting and cellular uptake capacity of liposomes. The results of the cytotoxicity test indicated that FA-R8-LPs significantly inhibited the proliferation of the DOX resistant cell line MDA-MB-231/DOX in vitro. In nude mice tumor models inoculated with MDA-MB-231/DOX cells, FA-R8-LPs significantly inhibited tumor growth, and overcame doxorubicin resistance, exhibiting excellent antitumor effects. This study demonstrates that liposome-targeted co-delivery systems based on FA and R8 double modifying may provide a new and effective strategy for the treatment of TNBC, which is of great significance for drug combination.

RNA Nanotechnology to Solubilize Hydrophobic Antitumor Drug for Targeted Delivery.

Small‐molecule drugs are used extensively in clinics for cancer treatment; however, many antitumor chemical drugs dissolve poorly in aqueous solution. Their poor solubility and nonselective delivery in vivo often cause severe side effects. Here, the application of RNA nanotechnology to enhance the solubility of hydrophobic drugs, using camptothecin (CPT) for proof‐of‐concept in targeted delivery for cancer treatment is reported. Multiple CPT prodrug molecules are conjugated to RNA oligos via a click reaction, and the resulting CPT‐RNA conjugates efficiently self‐assemble into thermodynamically stable RNA three‐way junction (3WJ) nanoparticles. The RNA 3WJ is covalently linked with seven hydrophobic CPT prodrug molecules through cleavable ester bonds and a folic acid ligand for specific tumor targeting while remaining soluble in aqueous solutions without detectable aggregation at therapeutic dose. This CPT‐RNA nanoparticle exhibits efficient and specific cell binding and internalization, leading to cell apoptosis. Tumor growth is effectively inhibited by CPT‐RNA nanoparticles; the targeted delivery, strengthened by tumor ligand, further enhances tumor suppression. Compared with the traditional formulation, solubilization of CPT in aqueous buffer using RNA nanoparticles as a carrier is found to be safe and efficacious, demonstrating that RNA nanoparticles are a promising platform for the solubilization and the delivery of hydrophobic antitumor drugs.

Core‐Shell Functionalized Zirconium‐Pemetrexed Coordination Nanoparticles as Carriers with a High Drug Content

AbstractSelected drug molecules with Lewis base functions can be assembled into coordinative nanoparticles (NPs) by linking them with suitable metal ions. Such nanomaterials exhibit a high material economy due to high drug contents and minor amounts of inactive additives. The antifolate pemetrexed (PMX) which is used for the treatment of lung cancers contains two carboxy functions that are able to undergo coordinative binding of metal ions. This study presents the development of a multilayer PMX NP system where each layer serves a distinct purpose. The metal‐drug NP core is assembled in a bottom‐up approach by coordinative interactions between zirconium (IV) ions and PMX molecules. Since the NP core is generated from drug molecules as essential units, it features a very high drug content of almost 80%. The NP core is stabilized against serum with a shell of a polymerized oligoamine‐modified trimethoxysilane derivative (TMSP). As external layer, a polyglutamate‐block‐polysarcosine‐N3 (pGlu‐b‐pSar) coating mediates efficient colloidal stabilization and enables introduction of targeting functionalities by click chemistry. Attaching folate or transferrin ligands to the polymer layer enhances NP uptake into target receptor positive KB and L1210 cells. This study illustrates the development and characterization of metal‐drug coordination NPs with high drug content and variable external functionalizations.

Application of silicon dioxide nanoparticles modified with tumor-targeting ligands for cellular delivery of nucleoside triphosphate analogues

A key advantage of amino-modified SiO2 nanoparticles for delivery of phosphorylated nucleosides is a broad possibility for functionalization. It can be modified with ligands currently investigated in targeted drug delivery. To improve the efficacy for intracellular delivery, SiO2 nanoparticles were functionalized with tumor-targeting ligands folic acid, biotin or 5-fluorouracil. Studies of accumulation of these conjugates in HCT116 colon carcinoma cells revealed that the uptake of modified conjugates was significantly bigger compared to unmodified nanoparticles, with the biotinylated conjugate as the preferred compound. The nanocomposites of biotin modified SiO2 and 2′,3′-dideoxyuridine triphosphate showed a pronounced antiproliferative potency relative to the unmodified nanocomposites. Thus, multi-functionalization of SiO2 nanoparticle based conjugates has a major potential for delivery of nucleoside triphosphate analogues, therefore tentatively enhancing their bioactivity.

Mixed Lanthanide Oxide Nanoparticles Coated with Alginate-Polydopamine as Multifunctional Nanovehicles for Dual Modality: Targeted Imaging and Chemotherapy.

Integrating anticancer drugs and diagnostic agents in a polymer nanosystem is an emerging and promising strategy for improving cancer treatment. However, the development of multifunctional nanoparticles (NPs) for an "all-in-one" platform characterized by specific targeting, therapeutic efficiency, and imaging feedback remains an unmet clinical need. In this study, pH-responsive mixed-lanthanide-based multifunctional NPs were fabricated based on simple metal-ligand interactions for simultaneous cancer cell imaging and drug delivery. We investigated two new systems of alginate-polydopamine complexed with either terbium/europium or dysprosium/erbium oxide NPs (Tb/Eu@AlgPDA or Dy/Er@AlgPDA NPs). Tb/Eu@AlgPDA NPs were then functionalized with the tumor-targeting ligand folic acid (FA) and loaded with the anticancer drug doxorubicin (DOX) to form FA-Tb/Eu@AlgPDA-DOX NPs. Using such systems, the mussel-inspired property of PDA was introduced to improve tumor targetability and penetration, in addition to active targeting (via FA-folate receptor interactions). Determining the photoluminescence efficiency showed that the Tb/Eu@AlgPDA system was superior to the Dy/Er@AlgPDA system, presenting intense and sharp emission peaks on the fluorescence spectra. In addition, compared to Dy/Er@AlgPDA NPs (82.4%), Tb/Eu@AlgPDA NPs exhibited negligible cytotoxicity with >93.3% HeLa cell viability found in MTT assays at NP concentrations of up to 0.50 mg/mL and high biocompatibility when incubated with zebrafish (Danio rerio) embryos and larvae. The FA-Tb/Eu@AlgPDA-DOX system exhibited a pH-responsive and sustained drug-release pattern. In a spheroid model of HeLa cells, the FA-Tb/Eu@AlgPDA-DOX system showed a better penetration efficiency and spheroid growth-inhibitory effect than free DOX. After incubation with zebrafish embryos, the FA-Tb/Eu@AlgPDA-DOX system also showed improved antitumor efficacies versus the other experimental groups in HeLa tumor cell xenografted zebrafish. Therefore, our results suggested that FA-Tb/Eu@AlgPDA-DOX NPs are promising multifunctional nanocarriers with therapeutic capacity for tumor targeting and penetration.