A Novel Folic Acid Receptor-Targeted Drug Delivery System Based on Curcumin-Loaded ß-Cyclodextrin Nanoparticles for Cancer Treatment.

PURPOSE: A novel folate receptor-targeted ß-cyclodextrin (ß-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA). METHODS: Folate-conjugated ß-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied. RESULTS: The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity. CONCLUSION: These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.

The Interplay between Fe3O4 Superparamagnetic Nanoparticles, Sodium Butyrate, and Folic Acid for Intracellular Transport.

Combined treatments which use nanoparticles and drugs could be a synergistic strategy for the treatment of a variety of cancers to overcome drug resistance, low efficacy, and high-dose-induced systemic toxicity. In this study, the effects on human colon adenocarcinoma cells of surface modified Fe3O4 magnetic nanoparticles (MNPs) in combination with sodium butyrate (NaBu), added as a free formulation, were examined demonstrating that the co-delivery produced a cytotoxic effect on malignant cells. Two different MNP coatings were investigated: a simple polyethylene glycol (PEG) layer and a mixed folic acid (FA) and PEG layer. Our results demonstrated that MNPs with FA (FA-PEG@MNPs) have a better cellular uptake than the ones without FA (PEG@MNPs), probably due to the presence of folate that acts as an activator of folate receptors (FRs) expression. However, in the presence of NaBu, the difference between the two types of MNPs was reduced. These similar behaviors for both MNPs likely occurred because of the differentiation induced by butyrate that increases the uptake of ferromagnetic nanoparticles. Moreover, we observed a strong decrease of cell viability in a NaBu dose-dependent manner. Taking into account these results, the cooperation of multifunctional MNPs with NaBu, taking into consideration the particular cancer-cell properties, can be a valuable tool for future cancer treatment.

Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent.

Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

Supramolecular magnetonanohybrids for multimodal targeted therapy of triple-negative breast cancer cells.

Despite the undeniable advances in recent decades, cancer remains one of the deadliest diseases of the current millennium, where the triple-negative breast cancer (TNBC) is very aggressive, extremely metastatic, and resistant to conventional chemotherapy. The nanotheranostic approach focusing on targeting membrane receptors often expressed at abnormal levels by cancer cells can be a strategic weapon for fighting malignant tumors. Herein, we introduced a novel "all-in-one nanosoldier" made of colloidal hybrid nanostructures, which were designed for simultaneously targeting, imaging, and killing TNBC cells. These nanohybrids comprised four distinct components: (a) superparamagnetic iron oxide nanoparticles, as bi-functional nanomaterials for inducing ferroptosis via inorganic nanozyme-mediated catalysis and magnetotherapy by hyperthermia treatment; (b) carboxymethyl cellulose biopolymer, as a water-soluble capping macromolecule; (c) folic acid, as the membranotopic vector for targeting folate receptors; (d) and doxorubicin (DOX) drug for chemotherapy. The results demonstrated that this novel strategy was highly effective for targeting and killing TNBC cells in vitro, expressing high levels of folate membrane-receptors. The results evidenced that three integrated mechanisms triggered the deaths of the cancer cells in vitro: (a) ferroptosis, by magnetite nanoparticles inducing a Fenton-like reaction; (b) magneto-hyperthermia effect by generating heat under an alternate magnetic field; and (c) chemotherapy, through the DOX intracellular release causing DNA dysfunction. This "all-in-one nanosoldier" strategy offers a vast realm of prospective alternatives for attacking cancer cells, combining multimodal therapy and the delivery of therapeutic agents to diseased sites and preserving healthy cells, which is one of the most critical clinical challenges faced in fighting drug-resistant breast cancers.

Folic acid-modified celastrol nanoparticles: synthesis, characterization, anticancer activity in 2D and 3D breast cancer models.

Celastrol is used in traditional Chinese medicine for treating cancers. However, its low water solubility and poor tumour selection represent major pitfalls for clinical application. In the present study, gold nanoparticle (AuNP) firstly was conjugated with PVP-co-2-dimethylaminoethyl methacrylate (Polymer) and celastrol then modified by folic acid. The as-prepared folate receptor-targeted celastrol AuNP (FCA) was characterized using attenuated total reflection Fourier transform infrared spectroscopy, UV-Vis spectrometry, transmission electron microscope, and inductively coupled plasma mass spectrometry. The physical properties of FCA were also determined in solubility, drug encapsulation and in vitro drug release. Its anticancer activities were assessed in the 2D and 3D breast cancer models. The results showed that FCA was synthesized successfully with good solubility, high encapsulation efficiency and loading content. FCA showed the optimal cumulative release at pH 5.0 and high cellular uptake and exhibited significant inhibition on breast cancer cells. FCA also induced more significant apoptosis either in 2D and 3D breast cancer model than the celastrol AuNP and celastrol alone. These findings demonstrate that FCA improves water solubility of celastrol and enhances its anticancer activities against breast cancer. FCA might be a potential candidate of anticancer drug for breast cancer in the future if further development.

Albumin-functionalized CuFeS2/photosensitizer nanohybrid for single-laser-induced folate receptor-targeted photothermal and photodynamic therapy.

Multimodal therapy is an emerging medical intervention to overcome the current limitation in cancer therapy combining treatment modalities with different mechanisms of action to eradicate tumors. This study demonstrates a targeted multifunctional bovine serum albumin (BSA)-functionalized CuFeS2/chlorin e6 (Ce6) for synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) effects. The CuFeS2 nanocrystals were synthesized through a simple heating-up approach and transferred into an aqueous phase using BSA in an ultrasonic-assisted microemulsion method. The as-prepared CuFeS2@BSA nanoparticles further conjugated with folic acid (FA) followed by attachment of Ce6 to form the Ce6:CuFeS2@BSA-FA nanohybrid with improved solubility and strong near-infrared (NIR) absorbance and fluorescence. It is the first report to fabricate the targeted Ce6:CuFeS2@BSA-FA hybrid and evaluates their synergistic PTT/PDT effect using a single laser. The Ce6:CuFeS2@BSA-FA hybrid showed lower toxicity in vitro (HeLa and HepG2 cells) and in vivo (zebrafish embryos), while they are selectively recognized and internalized by HeLa cells that over-express folate receptors. Compared to each modality applied separately, the combined single-laser-induced PTT and PDT treatment showed the enhanced generation of heat and reactive oxygen species (ROS) with synergistic cancer killing under 671 nm laser irradiation (10 min, 1 W/cm2). As a biocompatible targeted nanoprobe, the multifunctional nanohybrid holds promise in combined PDT/PTT synergistic therapy to achieve better efficacy.

Plug-and-Play Continuous Gas Flow Assembly of Cysteine-Inserted AuCu Nanobimetals for Folate-Receptor-Targeted Chemo-Phototherapy.

Conjugatable nanobimetals exhibiting broadband light absorption for use as phototherapeutic platforms were assembled via a plug-and-play continuous gas flow route. Electrically produced AuCu nanobunches (NBs) under nitrogen gas flow were directly injected into cysteine (cys) solution through gas pressurization to mechanically spray the solution (AuCu into cys droplets). The sprayed droplets were then exposed to 185 nm UV light (higher photon energy [6.2 eV] than the work functions of Au [5.1 eV] and Cu [4.7 eV]) to initiate photoionization of AuCu NBs for subsequent electrostatic reaction with the SH- group of cys to form cys-inserted AuCu (AuCu-cys) platforms in a single-pass gas stream. These platforms exhibited broadband light absorption spectra because of hybridized interparticle plasmonic coupling and could be conjugated to folic acid (FA) when dispersed in FA solution to form highly dispersible, biocompatible, and cancer-targetable AuCu-cys-FA. This material was suitable for use in targeted phototherapy of folate-receptor (FR)-rich cancers via FR-mediated endocytosis, and loading doxorubicin (DOX) into AuCu-cys-FA (i.e., AuCu-cys-DOXFA) facilitated chemo-phototherapy because of photoresponsive anticancer drug release upon induction of hyperthermia.

GSH and enzyme responsive nanospheres based on self-assembly of green tea polyphenols and BSA used for target cancer chemotherapy.

Developing safe and effective stimuli-responsive nanocarriers is very important for tumor chemotherapy. In this work, bovine serum albumin (BSA) and green tea polyphenol (TP) were used to prepare glutathione (GSH) and enzyme (trypsin) responsive nanocarriers for doxorubicin (DOX). These nanocarriers were further modified with folate, briefly named as DOX@BSA-TP-FA NSs. The diameter of nanocarriers was about 220 nm. The DOX loading efficiency and loading amount were 86.4% and 23.5 wt%, respectively. The cellular uptake, apoptosis, and GSH and trypsin responsive release properties of these nanocarriers were investigated.

Folate receptor-targeted liposomal nanocomplex for effective synergistic photothermal-chemotherapy of breast cancer in vivo.

An effective nanoparticle-based drug delivery platform holds great promise for non-invasive cancer therapy. This study explores the breast tumor regression in vivo by synergistic photothermal-chemotherapy based on liposomal nanocomplex (folic acid-gold nanorods-anticancer drug-liposome). The proposed liposomal nanocomplex can enhance the tumor targeting by functionalizing folic acid (FA) molecules on the surface of liposome that encapsulates both gold nanorods (AuNRs) and the doxorubicin (DOX) to combine the photothermal therapy and the chemotherapy, respectively. Herein, 7-nm gold nanorods were fabricated and co-encapsulated with DOX into nanoliposomes functionalized with FA, with an average diameter of 154 nm, for active targeting to the cancer cells. The experimental results showed that the FA targeting liposomes had better cellular uptake than the non-targeting liposomes (AuNRs-DOX-LPs). Especially, upon 5 min exposure to near infrared (NIR) irradiation (808 nm) triggered DOX release could be achieved to 46.38% in 60 min at pH 5.5. In addition, in vitro cell proliferation assays indicated that, with synergistic photothermal-chemotherapy, the targeting liposomes could significantly enhance the toxicity towards the cancer cells with the IC50 value of 1.90 ± 0.12 µg mL-1. Furthermore, in vivo experiments on the breast tumor-bearing mice showed that the targeting liposomes could effectively inhibit the growth of the tumors using the combined strategy.

pH/Redox-Triggered Photothermal Treatment for Cancer Therapy Based on a Dual-Responsive Cationic Polymer Dot.

In the present study, a pH/redox-responsive cationic polymer dot (CD) was successfully prepared for a near-infrared (NIR)-mediated, simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. Carbonized disulfide cross-linked branched polyethyleneimine (bPEI) was conjugated with folic acid (FA) as a targeting moiety and partially formed an ionic complex with anionic indocyanine green (ICG) to afford a bPEI-based CD (ICG-CD). This was responsive to mild reductive (glutathione, GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites. The ICG-CD internalized readily into the cytoplasm of cancer cells by a FA receptor and cationic-mediated endocytosis in the off state, whereas if ICG-CD met intracellular GSH at high concentrations, GSH contributed partially to the recovery of fluorescence and was then internalized into acidic endosomes to induce complete restoration of fluorescence. This tumor-sensitive degradability of the CD not only facilitated ICG release in the tumor location but also allowed controllable photothermal therapy effects of nanoparticles under NIR irradiation, which resulted in improved cancer therapy. Taken together, the results indicate great potential in tumor targeting, intracellular imaging, and controllable therapeutic delivery through a fluorescence off/on assay under the pH/redox conditions of cancer cells.

Folate-receptor-targeted laser-activable poly(lactide-co-glycolic acid) nanoparticles loaded with paclitaxel/indocyanine green for photoacoustic/ultrasound imaging and chemo/photothermal therapy.

BACKGROUND: Cancer is one of the most serious threats to human health. Precision medicine is an innovative approach to treatment, as part of which theranostic nanomedicine has been studied extensively. However, the required biocompatibility and substantial cost for the approval of nanomedicines hinder their clinical translation. PURPOSE: We designed a novel type of theranostic nanoparticle (NP) folate-receptor-targeted laser-activatable poly(lactide-co-glycolic acid) (PLGA) NPs loaded with paclitaxel (Ptx)/indo-cyanine green (ICG)-folic acid-polyethylene glycol (PEG)-PLGA-Ptx@ICG-perfluorohexane (Pfh)- using safe and approved materials and drugs, which would facilitate clinical translation. With laser irradiation, highly efficient photothermal therapy can be achieved. Additionally, targeted NPs can be activated by near-infrared laser irradiation at a specific region, which leads to the sharp release of Ptx at areas of high folate-receptor expression and ensures a higher Ptx concentration within the tumor region, thereby leading to chemo/photothermal synergistic antitumor efficacy. Meanwhile, the NPs can be used as a dual-modality contrast agent for photoacoustic and ultrasound imaging. MATERIALS AND METHODS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were prepared by sonification method and characterized for physicochemical properties. Cytotoxicity and in vivo biocompatibility were evaluated respectively by CCK8 assay and blood analysis. NPs as dual-modality contrast agents were evaluated by photoacoustic/ultrasound imaging system in vitro and in vivo. In vitro anticancer effect and in vivo anticancer therapy was evaluated by CCK8 assay and MDA-MB231 tumor-bearing mice model. RESULTS: FA-PEG-PLGA-Ptx@ICG-Pfh NPs were in the size of 308±5.82 nm with negative zeta potential and showed excellent photothermal effect. The NPs could be triggered sharp release of Ptx by laser irradiation, and showed the good biocompatibility in vitro and in vivo. Through photoacoustic/ultrasound imaging, the NPs showed an excellent ability as dual-modality contrast agents in vitro and in vivo. FA-PEG-PLGA-Ptx@ICG-Pfh NPs with laser irradiation showed the best anticancer efficacy in vitro and in vivo. CONCLUSION: Such a biocompatible and novel theranostic NP is expected to integrate dual-modality imaging with improved therapeutic efficacy and provide a promising paradigm for cancer therapy.

Laboratory assessment of folate (vitamin B9) status.

Folate (vitamin B9) plays a crucial role in fundamental cellular processes, including nucleic acid biosynthesis, methyl group biogenesis and amino acid metabolism. The detection and correction of folate deficiency prevents megaloblastic anaemia and reduces the risk of neural tube defects. Coexisting deficiencies of folate and vitamin B12 are associated with cognitive decline, depression and neuropathy. Folate deficiency and excess has also been implicated in some cancers. Excessive exposure to folic acid, a synthetic compound used in supplements and fortified foods, has also been linked to adverse health effects. Of at least three distinct laboratory markers of folate status, it is the total abundance of folate in serum/plasma that is used by the majority of laboratories. The analysis of folate in red cells is also commonly performed. Since the folate content of red cells is fixed during erythropoiesis, this marker is indicative of folate status over the preceding ~4 months. Poor stability, variation in polyglutamate chain length and unreliable extraction from red cells are factors that make the analysis of folate challenging. The clinical use of measuring specific folate species has also been explored. 5-Methyltetrahydrofolate, the main form of folate found in blood, is essential for the vitamin B12-dependent methionine synthase mediated remethylation of homocysteine to methionine. As such, homocysteine measurement reflects cellular folate and vitamin B12 use. When interpreting homocysteine results, age, sex and pregnancy, specific reference ranges should be applied. The evaluation of folate status using combined markers of abundance and cellular use has been adopted by some laboratories. In the presence of discordance between laboratory results and strong clinical features of deficiency, treatment should not be delayed. High folate status should be followed up with the assessment of vitamin B12 status, a review of previous results and reassessment of folic acid supplementation regime.

Preparation of Folic Acid-Targeted Temperature-Sensitive Magnetoliposomes and their Antitumor Effects In Vitro and In Vivo.

BACKGROUND: Ovarian cancer is a common gynecologic malignancy with poor prognosis, requiring innovative new therapeutic strategies. Temperature-controlled drug delivery to cancer cells represents a novel, promising, targeted treatment approach. OBJECTIVE: We prepared folate receptor-targeted thermosensitive liposomes wrapped with the HSP90 inhibitor 17-AAG and superparamagnetic material (17-AAG/MTSLs-FA), and tested the efficacy of these targeted magnetoliposomes in vitro and in vivo. METHODS: Magnetic thermosensitive liposomes wrapped with 17-AAG were coprecipitated with Fe3O4 magnetic nanoparticles and prepared by a rotary evaporation method. Experiments were conducted with SKOV3 human ovarian cancer cells and MCF7 human breast carcinoma cells to evaluate the anti-tumor effects. RESULTS: 17-AAG/MTSLs-FA prepared in this study met the basic requirements for therapeutic application. The preparation method is relatively simple and the raw materials are readily available. The product exhibited strong magnetism, high encapsulation efficiencies, and satisfactory performance. The liposomes combined with hyperthermia significantly inhibited the proliferation of SKOV3 cells and induced apoptosis. Experiments using a mouse subcutaneous model as well as an ascites tumor xenograft model indicated that 17-AAG/MTSLs-FA was stable in vivo and effectively targeted tumor tissues expressing the folate receptor. CONCLUSIONS: Folic acid-conjugated 17-AAG magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating can achieve a synergistic anti-tumor effect of chemotherapy and heat treatment, potentially offering a new method for ovarian cancer treatment.

High prevalence of serum folate receptor autoantibodies in children with autism spectrum disorders.

BACKGROUND: Supplementation of folic acid by pregnant mothers is thought to lower the risk of autism spectrum disorders (ASDs) in the offspring. Folic acid is taken up by cells via receptors with high affinity for folate and reduced folic acid derivatives. However, this is blocked by the presence of folate receptor autoantibodies (FRAA). Cerebral FRAA have been detected with high frequency in children with ASDs, suggesting the existence of a link between folic acid uptake and disease aetiology. METHODS: We investigated the frequency of FRAA in serum samples from 40 children with ASDs and 42 gender- and age-matched children with typical development (TD). Serum FRAA concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: We found a significant difference in the frequency of serum FRAA in the two study cohorts. Serum FRAA were present in 77.5% (31/40) of children with ASDs compared with 54.8% (23/42) of TD children (p = 0.03746, Fischer's exact test). Thus, serum FRAA are more prevalent in children with ASDs than in TD children. CONCLUSIONS: Our data suggest that children with ASDs may have defects in folic acid absorption that play a role in the onset of ASDs.

pH-responsive selenium nanoparticles stabilized by folate-chitosan delivering doxorubicin for overcoming drug-resistant cancer cells.

Herein, we first report pH-responsive SeNPs stabilized with modified folic acid-N-trimethyl chitosan (TMC-FA) as nanocarriers for delivery of doxorubicin (DOX) to overcome drug-resistant cancer cells, which could enhance the activity of DOX by approximately 10-fold for a reduced IC50 value compared to free DOX. When nanoparticles were taken up by cells, the DOX-loaded SeNPs@TMC-FA demonstrated a faster release rate under acidic conditions. The cumulative release amount of DOX at pH 5.3 was 54.1% within 2h and 95.5% at 6h, whereas the release rate at pH 7.4 was 12.3% in 2h and 42.2% for 6h; release was not completed at the end of the study, 72h. Mechanistic studies suggested that DOX-SeNPs@TMC-FA induced cell death through the apoptosis pathway by involvement of caspase-3 and PARP proteins. The results demonstrated that pH-responsive SeNPs@TMC-FA, as targeted nanocarriers, promoted the efficacy of DOX and overcame drug resistance in NCI/ADR-RES cells.

ATP mediated rolling circle amplification and opening DNA-gate for drug delivery to cell.

Here, we have developed a facile fluorometric system for the detection of adenosine triphosphate (ATP) by a rolling circle amplification (RCA) based on proximity ligation mediated amplification, and simultaneously achieved the release of the anticancer drug doxorubicin (DOX) through the mesoporous silicon system. Once the ATP molecule is present, the linker DNA will be released from the graphene oxide (GO) surface and hybridized to the template DNA of the GO surface joining with ligation enzyme. RCA reaction is followed by the addition of the phi29 DNA polymerase. The product of RCA reaction contains a base fragment complementary to the signal DNA, allowing the fluorescent oligonucleotide probe to be released from the GO surface and fluorescence is recovered. The strong fluorescence signal realized the sensitive detection of ATP. Gate DNA were modified to the surface of the mesoporous silica (MSN) by electrostatic attraction to encapsulate DOX. After the above-mentioned RCA process, its result that long DNA chain containing a base fragment complementary to gate DNA, would be hybridized to the gate DNA strand on the surface of MSN, which opened the MSN hole and released the drug DOX into cell for HeLa cell therapy. And the specificity to folate receptor overexpressed on cell surface was satisfactory which would be beneficial for cancer therapy.

Folate-PEG-NOTA-Al18F: A New Folate Based Radiotracer for PET Imaging of Folate Receptor-Positive Tumors.

The folate receptor (FR) has been established as a promising target for imaging and therapy of cancer (FR-α), inflammation, and autoimmune diseases (FR-ß). Several folate based PET radiotracers have been reported in the literature, but an 18F-labeled folate-PET imaging agent with optimal properties for clinical translation is still lacking. In the present study, we report the design and preclinical evaluation of folate-PEG12-NOTA-Al18F (1), a new folate-PET agent with improved potential for clinical applications. Radiochemical synthesis of 1 was achieved via a one-pot labeling process by heating folate-PEG12-NOTA in the presence of in situ prepared Al18F for 15 min at 105 °C, followed by HPLC purification. Specific binding of 1 to FR was evaluated on homogenates of KB (FR-positive) and A549 (FR-deficient) tumor xenografts in the presence and absence of excess folate. In vivo tumor imaging with folate-PEG12-NOTA-Al18F was compared to imaging with 99mTc-EC20 using nu/nu mice bearing either KB or A549 tumor xenografts. Specific accumulation of 1 in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folate. Radiosynthesis of 1 was accomplished within ∼35 min, affording pure radiotracer 1 in 8.4 ± 1.3% (decay corrected) radiochemical yield with ∼100% radiochemical purity after HPLC purification and a specific activity of 35.8 ± 15.3 GBq/mmol. Further in vitro and in vivo examination of 1 demonstrated highly specific FR-mediated uptake in FR+ tumor, with Kd of ∼0.4 nM (KB), and reduced accumulation in liver. Given its facile preparation and improved properties, the new radiotracer, folate-PEG12-NOTA-Al18F (1), constitutes a promising tool for identification and classification of patients with FR overexpressing cancers.

Multifunctional folate receptor-targeting and pH-responsive nanocarriers loaded with methotrexate for treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive cartilage and bone destruction. Activated macrophages that overexpress folic acid (FA) receptors play an important role in RA, due to their abundance in inflamed synovial membrane and joints. In an effort to deliver drugs to the inflamed tissues, multifunctional FA receptor-targeting and pH-responsive nanocarriers were developed. They were composed of lipids, polyethylene glycol (PEG)-poly(lactic-co-glycolic acid) (PLGA) forming a hydrophilic shell, FA around the hydrophilic shell as a targeting ligand, and poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) and PLGA as a hydrophobic core. PCADK also acts as a pH-responsive material. Methotrexate (Mtx) was encapsulated in the nanoparticles, which exhibited pH-responsive release in vitro. Cellular uptake and cytotoxicity experiments revealed that FA-PEG-PLGA/PCADK-lipid nanoparticles loaded with Mtx (FA-PPLNPs) exhibited superior cellular uptake and higher cytotoxicity to activated macrophages than PPLNPs/Mtx. The therapeutic effect of FA-PPLNPs/Mtx in RA was confirmed in an adjuvant-induced arthritis rat model. These results suggest that the multifunctional folate receptor-targeting and pH-responsive nanocarriers are promising for the treatment of RA.

Theranostic Nanoparticles Loaded with Imaging Probes and Rubrocurcumin for Combined Cancer Therapy by Folate Receptor Targeting.

The combination of different therapeutic modalities is a promising option to combat the recurrence of tumors. In this study, polylactic and polyglycolic acid nanoparticles were used for the simultaneous delivery of a boron-curcumin complex (RbCur) and an amphiphilic gadolinium complex into tumor cells with the aim of performing boron and gadolinium neutron capture therapy (NCT) in conjunction with the additional antiproliferative effects of curcumin. Furthermore, the use of Gd complexes allows magnetic resonance imaging (MRI) assessment of the amount of B and Gd internalized by tumor cells. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were targeted to ovarian cancer (IGROV-1) cells through folate receptors, by including in the formulation a PEGylated phospholipid functionalized with the folate moiety. NCT was performed on IGROV-1 cells internalizing 6.4 and 78.6 µg g-1 of 10 B and 157 Gd, respectively. The synergic action of neutron treatment and curcumin cytotoxicity was shown to result in a significant therapeutic improvement.

Biomimetic membrane-conjugated graphene nanoarchitecture for light-manipulating combined cancer treatment in vitro.

We report that through facile lipid self-assembly, biomimetic membrane-conjugated mesoporous silica-coated graphene oxide is constructed as targeting nanocarrier toward efficient combination of photothermal therapy and chemotherapy. Impressively, the simple surface modification with folate-contained lipid bilayer allows the graphene-based nanoarchitecture above to be selectively internalized by tumor cells overexpressing relevant receptors. Compared to pure drug, 7-fold doxorubicin is delivered into tumor cells by the nanoarchitecture. After cellular internalization, upon near infrared light illumination, graphene oxide in the nanoarchitecture can convert light energy into heat to kill cancer cells partially. Simultaneously, hyperthermia will drive rapid release of doxorubicin from the nanoarchitecture above to further cause the death of more cancer cells. Thus, integrated cancer treatment with higher efficacy is achieved in vitro compared to that of individual therapy.