Effects of folate-chicory acid liposome on macrophage polarization and TLR4/NF-κB signaling pathway in ulcerative colitis mouse.

BACKGROUND: Chichoric acid (CA) is a major active ingredient found in chicory and Echinacea. As a derivative of caffeic acid, it has various pharmacological effects. PURPOSE: Due to the unclear etiology and disease mechanisms, effective treatment methods for ulcerative colitis (UC) are currently lacking. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and dextran sulfate sodium (DSS)-induced mouse UC models. METHODS: Folate-chicory acid liposome was prepared using the double emulsion ultrasonic method with the aim of targeting folate receptors specifically expressed on macrophages. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and DSS -induced mouse UC models. Furthermore, the effects of the liposomes on macrophage polarization and their underlying mechanisms in UC were explored. RESULTS: The average particle size of folate-chicory acid liposome was 120.4 ± 0.46 nm, with an encapsulation efficiency of 77.32 ± 3.19 %. The folate-chicory acid liposome could alleviate macrophage apoptosis induced by LPS, decrease the expression of inflammatory factors in macrophages, enhance the expression of anti-inflammatory factors, inhibit macrophage polarization towards the M1 phenotype, and mitigate cellular inflammation in vetro. In vivo test, folate-chicory acid liposome could attenuate clinical symptoms, increased colon length, reduced DAI scores, CMDI scores, and alleviated the severity of colonic histopathological damage in UC mice. Furthermore, it inhibited the polarization of macrophages towards the M1 phenotype in the colon and downregulated the TLR4/NF-κB signaling pathway, thereby ameliorating UC in mice. CONCLUSION: Folate-chicory acid liposome exhibited a uniform particle size distribution and high encapsulation efficiency. It effectively treated UC mice by inhibiting the polarization of macrophages towards the M1 phenotype in the colon and downregulating the TLR4/NF-κB signaling pathway.

Preoperative predictors of successful tumour localization by intraoperative molecular imaging with pafolacianine in lung cancer to create predictive nomogram.

OBJECTIVES: Intraoperative molecular imaging (IMI) uses cancer-targeted fluorescent probe to locate nodules. Pafolacianine is a Food and Drug Administration-approved fluorescent probe for lung cancer. However, it has a 8-12% false negative rate for localization. Our goal is to define preoperative predictors of tumour localization by IMI. METHODS: We performed a retrospective review of patients who underwent IMI using pafolacianine for lung lesions from June 2015 to August 2019. Candidate predictors including sex, age, body mass index, smoking history, tumour size, distance of tumour from surface, use of neoadjuvant therapy and positron emission tomography avidity were included. The outcome was fluorescence in vivo and comprehensively included those who were true or false positives negatives. Multiple imputation was used to handle the missing data. The final model was evaluated using the area under the receiver operating characteristic curve. RESULTS: Three hundred nine patients were included in our study. The mean age was 64 (standard deviation 13) and 68% had a smoking history. The mean distance of the tumours from the pleural surface was 0.4 cm (standard deviation 0.6). Smoking in pack-years and distance from pleura had an odds ratio of 0.99 [95% confidence interval: 0.98-0.99; P = 0.03] and 0.46 [95% confidence interval: 0.27-0.78; P = 0.004], respectively. The final model had an area under the receiver operating characteristic curve of 0.68 and was used to create a nomogram that gives a probability of fluorescence in vivo. CONCLUSIONS: Primary tumours that are deeper from the pleural surface, especially in patients with a higher pack-years, are associated with a decreased likelihood of intraoperative localization. We identified a nomogram to predict the likelihood of tumour localization with IMI with pafolacianine.

Enhanced ROS-Boosted Phototherapy against Pancreatic Cancer via Nrf2-Mediated Stress-Defense Pathway Suppression and Ferroptosis Induction.

In situ oxygen generation is the most common strategy to boost reactive oxygen species (ROS) for enhancing the efficacy of phototherapy in cancer, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, hyperoxidation or hyperthermia often triggers stress-defense pathways and promotes tumor cell survival, thus severely limiting the therapeutic efficacy. To overcome the tumor hypoxia and thermal resistance existing in phototherapy, we constructed a self-synergistic nanoplatform for tumors by incorporating brusatol, a nuclear factor erythroid 2-related factor (Nrf2) inhibitor, into the silica nanonetwork. It was then sequentially decorated with MnO2 and the photosensitizer chlorin e6 (Ce6) and then coated with poly(ethylene glycol)-folate (PEG-FA)-functionalized polydopamine (PDA) (designated as brusatol/silica@MnO2/Ce6@PDA-PEG-FA). As an oxygen generator, MnO2 can promote ROS production, which not only directly enhances Ce6-mediated PDT but also strengthens PDA-mediated PTT by attacking heat shock proteins (HSPs). Particularly, brusatol could efficiently inhibit the activation of Nrf2 defense pathway under hyperoxidation and hyperthermia and cause glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) inactivation, thereby inducing ferroptosis and ultimately enhancing the phototherapeutic effects. By exploiting these features, brusatol/silica@MnO2/Ce6@PDA-PEG-FA exhibited excellent antitumor efficacy with enhanced PDT and PTT both in in vitro and in vivo studies. Overall, our work highlights a promising strategy against hypoxia- and hyperthermia-associated resistance in phototherapy via suppressing stress-defense system and inducing ferroptosis.

Synthesis of biocompatible nanocrystalline cellulose against folate receptors as a novel carrier for targeted delivery of doxorubicin.

We designed amine-functionalized nanocrystalline cellulose grafted folic acid/magnetic nanoparticles (AF-NCC/Fe3O4 NPs) against folate receptors for targeted delivery of doxorubicin (DOX). Toxicity is a major side effect of DOX, damaging vital organs such as the heart, kidney, and liver; for example, it causes dilated cardiomyopathy and hepatotoxicity. Accordingly, we aimed to reduce this adverse effect and increase the targeted delivery of DOX to the right point of cancer cells by using the unique features of cancer cells. The characterizations were approved in each step using Fourier transform infrared (FTIR), scanning electron microscope (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), zeta potential, and dynamic light scattering (DLS) analysis techniques. Encapsulation efficacy of AF-NCC/Fe3O4 NPs was 99.6%; drug release investigations showed excellent stability in physiological conditions (pH âˆ¼ 7.4) and a high release rate in the low pH condition of cancer environments (pH âˆ¼ 5.0). The hemolysis assay and Masson's trichrome and hematoxylin and eosin (H&E) staining results showed that the nanocarrier was entirely biocompatible. In vitro cell viability study approved that the designed nanocarrier increased the therapeutic effects of DOX on Saos-2 cells. The cellular internalization results displayed a high percentage of uptake within 2 h. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was applied for the evaluation of tumor protein p53 (p53), p21, and Bcl-2-associated X protein (Bax). DOX exerted its effects through DNA damage and oxidative stress that led to p53 upregulation, and p53 inhibited cell cycle progression. This arrest initiated apoptosis and inhibited cell migration. In summary, encapsulating DOX in AF-NCC/Fe3O4 NPs dramatically decreases the toxic effects of this chemotherapeutic agent on vital organs, especially on the heart. This smart nanocarrier increases the delivery of DOX using acid folic on its surface and also enhances the DOX release in the acidic environment of cancer cells. DOX exerts its therapeutic effects by the initiation of apoptosis and inhibition of migration.

Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras.

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform for the targeted delivery of IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells with the potential to ameliorate toxicity.

Efficient Design to Monitor the Site-specific Sustained Release of a Non-Emissive Anticancer Drug.

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

A multiple environment-sensitive prodrug nanomicelle strategy based on chitosan graftomer for enhanced tumor therapy of gambogic acid.

A novel multiple environment-sensitive polymeric prodrug of gambogic acid (GA) based on chitosan graftomer was fabricated for cancer treatment. Folic acid-chitosan conjugates was complexed with thermosensitive amine terminated poly-N-isopropylacrylamide (NH2-PNIPAM) to develop FA-CSPN. Gambogic acid was conjugated with the graftomer via esterification to achieve high drug-loading capacity and controlled drug release. The resulting amphiphilic prodrug, O-(gambogic acid)-N-(folic acid)-N'-(NH2-PNIPAM) chitosan graftomer (GFCP), could self-assemble into micelles. As expected, the micelles were stable and biocompatible, featuring pH-, esterase- and temperature-dependent manner of drug release. Moreover, the anticancer effect studies of GFCP micelles were performed using a tumor-bearing mouse model and cellular assays (tumor cell uptake assay, cytotoxicity and tumor-sphere penetration). Collectively, GFCP micelles show both potential in vivo and in vitro in improving the anticancer effectiveness of GA owing to high loading capacity, targeted tumor accumulation, and multiple tumor microenvironmental responsiveness.

Novel Multifunctional Stimuli-Responsive Nanoparticles for Synergetic Chemo-Photothermal Therapy of Tumors.

In this study, a novel class of multifunctional responsive nanoparticles is designed and fabricated as drug nanocarriers for synergetic chemo-photothermal therapy of tumors. The proposed nanoparticles are composed of a thermo-/pH-responsive poly(N-isopropylacrylamide-co-acrylic acid) (PNA) nanogel core, a polydopamine (PDA) layer for photothermal conversion, and an outer folic acid (FA) layer as a targeting agent for the folate receptors on tumor cells. The fabricated nanoparticles show good biocompatibility and outstanding photothermal conversion efficiency. The proposed nanoparticles loaded with doxorubicin (DOX) drug molecules are stable under physiological conditions with low leakage of drugs, while rapidly release drugs in environments with low pH conditions and at high temperature. The experimental results show that the drug release process is mainly governed by Fickian diffusion. In vitro cell experimental results demonstrate that the PNA-DOX@PDA-FA nanoparticles can be phagocytized by 4T1 tumor cells and release drugs in tumor cell acidic environments, and confirm that the combined chemo and photothermal therapeutic efficacy of PNA-DOX@PDA-FA nanoparticles is higher than the photothermal therapeutic efficacy or the chemotherapeutic efficacy alone. The proposed multifunctional responsive nanoparticles in this study provide a novel class of drug nanocarriers as a promising tool for synergetic chemo-photothermal therapy of tumors.

Sonochemical preparation of folate-decorated reductive-responsive carboxymethylcellulose-based nanocapsules for targeted drug delivery.

In this study, a biocompatible folate-decorated reductive-responsive carboxymethylcellulose-based nanocapsules (FA-RCNCs) were designed and prepared via sonochemical method for targeted delivery and controlled release of hydrophobic drugs. The shell of FA-RCNCs was cross-linked by disulfide bonds formed from hydrosulfuryl groups on the thiolated carboxymethylcellulose (TCMC) and encapsulated hydrophobic drug dispersed in the oil phase into nanocapsules. Moreover, the size and morphology of drug loaded FA-RCNCs were characterized by DLS, SEM and CLSM which indicated that the synthesized nanocapsules have suitable size range and excellent stability for circulating in the bloodstream. The drug release rate of FA-RCNCs could be controlled by adjusting their sizes and shell thickness, which could be dominated by the concentration of TCMC and sonochemical conditions. Furthermore, the obtained FA-RCNCs could be ingested into Hela cells via folate-receptor (FR)-mediated endocytosis and quickly release drugs under reductive environment, which demonstrated that FA-RCNCs could become potential hydrophobic drugs carries for cancer therapy.

Folic Acid-Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting.

Drug-target interaction, cellular internalization, and target engagement should be addressed to design a lead with high chances of success in further optimization stages. Accordingly, we have designed conjugates of folic acid with anticancer peptides able to bind human thymidylate synthase (hTS) and enter cancer cells through folate receptor α (FRα) highly expressed by several cancer cells. Mechanistic analyses and molecular modeling simulations have shown that these conjugates bind the hTS monomer-monomer interface with affinities over 20 times larger than the enzyme active site. When tested on several cancer cell models, these conjugates exhibited FRα selectivity at nanomolar concentrations. A similar selectivity was observed when the conjugates were delivered in synergistic or additive combinations with anticancer agents. At variance with 5-fluorouracil and other anticancer drugs that target the hTS catalytic pocket, these conjugates do not induce overexpression of this protein and can thus help combating drug resistance associated with high hTS levels.

The 1316T>C missenses mutation in MTHFR contributes to MTHFR deficiency by targeting MTHFR to proteasome degradation.

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.

Preparation and characterization of lutein loaded folate conjugated polymeric nanoparticles.

AIM: To prepare and characterise lutein-loaded polylactide-co-glycolide-polyethylene glycol-folate (PLGA-PEG-FOLATE) nanoparticles and evaluate enhanced uptake in SK-N-BE(2) cells. METHODS: Nanoparticles were prepared using O/W emulsion solvent evaporation and characterised using DLS, SEM, DSC, FTIR and in-vitro release. Lutein-uptake in SK-N-BE(2) cells was determined using flow-cytometry, confocal-microscopy and HPLC. Control was lutein PLGA nanoparticles. RESULTS: The size of lutein-loaded PLGA and PLGA-PEG-FOLATE nanoparticles were 189.6 ± 18.79 nm and 188.0 ± 4.06 nm, respectively. Lutein entrapment was ∼61%(w/w) and ∼73%(w/w) for PLGA and PLGA-PEG-FOLATE nanoparticles, respectively. DSC and FTIR confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies showed ∼1.6 and ∼2-fold enhanced uptake of lutein from PLGA-PEG-FOLATE nanoparticles compared to PLGA nanoparticles and lutein, respectively. Cumulative release of lutein was higher in PLGA nanoparticles (100% (w/w) within 24 h) compared to PLGA-PEG-FOLATE nanoparticles (∼80% (w/w) in 48 h). CONCLUSION: Lutein-loaded PLGA-PEG-FOLATE nanoparticles could be a potential treatment for hypoxic ischaemic encephalopathy.

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.

Water-Soluble closo-Docecaborate-Containing Pteroyl Derivatives Targeting Folate Receptor-Positive Tumors for Boron Neutron Capture Therapy.

Water-soluble pteroyl-closo-dodecaborate conjugates (PBCs 1-4), were developed as folate receptor (FRα) targeting boron carriers for boron neutron capture therapy (BNCT). PBCs 1-4 had adequately low cytotoxicity with IC50 values in the range of 1~3 mM toward selected human cancer cells, low enough to use as BNCT boron agents. PBCs 1-3 showed significant cell uptake by FRα positive cells, especially U87MG glioblastoma cells, although the accumulation of PBC 4 was low compared with PBCs 1-3 and L-4-boronophenylalanine (L-BPA). The cellular uptake of PBC 1 and PBC 3 by HeLa cells was arrested by increasing the concentration of folate in the medium, indicating that the major uptake mechanisms of PBC 1-3 are primarily through FRα receptor-mediated endocytosis.

Ultrasound-targeted microbubble destruction augmented synergistic therapy of rheumatoid arthritis via targeted liposomes.

Rheumatoid arthritis (RA) can lead to joint destruction and deformity, which is a significant cause of the loss of the young and middle-aged labor force. However, the treatment of RA is still filled with challenges. Though dexamethasone, one of the glucocorticoids, is commonly used in the treatment of RA, its clinical use is limited because of the required high-dose and long-term use, unsatisfactory therapeutic effects, and various side-effects. Ultrasound-targeted microbubble destruction (UTMD) can augment the ultrasonic cavitation effects and trigger drug release from targeted nanocarriers in the synovial cavity, which makes it a more effective synergistic treatment strategy for RA. In this work, we aim to utilize the UTMD effect to augment the synergistic therapy of RA by using polyethylene glycol (PEG)-modified folate (FA)-conjugated liposomes (LPs) loaded with dexamethasone sodium phosphate (DexSP) (DexSP@LPs-PEG-FA). The UTMD-mediated DexSP@LPs-PEG-FA for targeted delivery of DexSP including a synergistic ultrasonic cavitation effect and drug therapy were investigated through in vitro RAW264.7 cell experiments and in vivo collagen-induced arthritis SD rat model animal experiments. The results show the DexSP release from targeted liposomes was improved under the UTMD effect. Likewise, the folate-conjugated liposomes displayed targeting association to RAW264.7 cells. Together with the application of ultrasound and microbubbles, liposomes-delivered DexSP potently reduced joints swelling, bone erosion, and inflammation in both joints and serum with a low dose. These results demonstrated that UTMD-mediated folate-conjugated liposomes are not only a promising method for targeted synergistic treatment of RA but also may show high potential for serving as nanomedicines for many other biomedical fields.

Isolation, Characterization and Preliminary Cytotoxic and Antifungal Evaluations of Novel Lancifoliate Isolated from Methanol Extract of Conocarpus lancifolius.

BACKGROUND: Combretaceae is a large family comprising of 500 species and 20 genera distributed in subtropical and tropical regions of the world. Conocarpus genus is an ornamental tree native to coastal and riverine areas of East Africa and is also planted as an ornamental plant in different areas of Pakistan. This genus has proved medicinal value as a cytotoxic, antibacterial, antiprotozoal, anti-leishmanial, antifungal and antidiabetic agent. OBJECTIVE: The current study was designed to screen the selected pharmacological attributes of sulphur containing novel compound isolated from Conocarpus lancifolius using a series of in vitro and molecular docking models. MATERIALS AND METHODS: After collection and authentication of plant material, methanolic extract was prepared from which various secondary metabolites were qualitatively examined. The compound was isolated using open column chromatography and the structure was established with spectroscopic techniques such as UV-visible, infrared spectroscopy, proton nuclear magnetic resonance (1H-NMR), 13C NMR (BB, DEPT-135, 90), twodimensional correlation techniques (HMBC, HSQC) and mass spectrometry (HRMS) respectively. C. lancifolius extract and isolated compound were studied for cytotoxic and antifungal potentials using in vitro Sulforhodamine B (SRB) and disc diffusion methods, respectively. Molecular docking studies were conducted to check the interaction of the isolated compound with major oncogenic proteins. RESULTS: Qualitative phytochemical screening revealed the presence of saponins, steroids, flavonoids, anthraquinones, and cardiac glycosides while alkaloids were absent in C. lancifolius extract. Isolated compound was characterized as lancifoliate, which showed cytotoxic activity towards a variety of cancer cell lines including murine lymphocytic leukemia (P-388, IC50 = 2.65µg/ml), human colon cancer (Col-2, IC50 = 0.84µg/ml), human breast cancer (MCF-7, IC50 = 0.72µg/ml) while no cytotoxic activity was observed towards human lung cancer (Lu-1), rat normal glioma cells (ASK, IC50 = 11.6µg/ml) and human embryonic kidney cells (Kek293, IC50 = 6.74µg/ml) respectively. Minimum Inhibitory Concentration (MIC) of Lancifoliate towards Aspergillus fumigatus, Aspergillus nigar (skin sample), Aspergillus flavus (pleural fluid) and Candida albicans (urine and blood samples) was found to be 54.5, 44.8, 43.5, 22.4 and 20.2µg/ml respectively. Moreover, docking results are in strong agreement with our experimental finding, which has identified lancifoliate to be a more potent antiproliferative agent than previously known compound ellipticine. CONCLUSION: C. lancifolius extract and lancifoliate possess potent cytotoxic and antifungal properties and thus has potential to be further studied. To the best of our knowledge, this is the first study that highlights isolation, identification and pharmacological activities of lancifoliate from Conocarpus lancifolius.

Study on the optical and biological properties in vitro of IR808-PEG-FA.

IR808, an IR780 derivative, is capable of fluorescently imaging and photodynamic therapy in vitro and in vivo. However, its application is greatly hampered by hydrophobicity, toxicity and nonspecific delivery to the targeting tissue and that causes accumulation in the liver and kidney. In order to overcome these limitations, we prepared IR808-PEG-FA from IR808, amino-terminated poly(ethylene glycol) (NH2 -PEG-NH2 , denoted as PEG) and folate (FA). PEG, an accepted hydrophilic medicinal agent, was introduced to improve hydrophobicity, and FA was used to increase targeting ability of the conjugate. The obtained product provides a good water solubility and stronger light intensity in near infrared (NIR)-imaging, and CCK-8 test demonstrated which had no appreciable toxicity. In addition, the cell uptake results indicated that IR808-PEG-FA was specifically targeted to positive tumors cells with folate receptor (FR) compared with IR808, and thus it may be used as a novel diagnostic agent or imaging-guided agent for cancer treatment. So this article provides a way to improve hydrophobicity, optical stability and targeting ability in the field of nano-probe for fluorochromes.

Folate-conjugated herpes simplex virus for retargeting to tumor cells.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-mediated oncolytic therapy is a promising cancer treatment modality. However, viral tropism is considered to be one of the major stumbling blocks to the development of HSV-1 as an anticancer agent. METHODS: The surface of oncolytic HSV-1 G207 was covalently modified with folate-poly (ethylene glycol) conjugate (FA-PEG). The specificities and tumor targeting efficiencies of modified or unmodified G207 particles were analyzed by a real-time polymerase chain reaction at the level of cell attachment and entry. Immune responses were assessed by an interleukin-6 release assay from RAW264.7 macrophages. Biodistribution and in vivo antitumoral activity after intravenous delivery was evaluated in BALB/c nude mice bearing subcutaneous KB xenograft tumors. RESULTS: FA-PEG-HSV exhibited enhanced targeting specificity for folate receptor over-expressing tumor cells and had lower immunogenicity than the unmodified HSV. In vivo, the FA-PEG-HSV group revealed an increased anti-tumor efficiency and tumor targeting specificity compared to the naked HSV. CONCLUSIONS: These results indicate that folate-conjugated HSV G207 presents a folate receptor-targeted oncolytic virus with a potential therapeutic value via retargeting to tumor cells.

A tumor-targeted, intracellular activatable and theranostic nanodiamond drug platform for strongly enhanced in vivo antitumor therapy.

Enhancing tumor homing and improving the efficacy of drugs are urgent needs for cancer treatment. Herein a novel targeted, intracellularly activatable fluorescence and cytotoxicity nanodiamond (ND) drug system (ND-PEG-HYD-FA/DOX, NPHF/D) was successfully prepared based on doxorubicin (DOX) and folate (FA) covalently bound to PEGylated NDs, in which the DOX was covalently coupled via an intracellularly hydrolyzable hydrazone bond that was stable in the physiological environment to ensure minimal drug release in circulation. Cell uptake studies demonstrated the selective internalization of NPHF/D by folate receptor (FR) mediated endocytosis in the order MCF-7 > HeLa > HepG2 ≫ CHO, using confocal laser scanning microscopy (CLSM) and flow cytometry. Interestingly, the DOX fluorescence of NPHF/D was significantly quenched, while the fluorescence recovery and cytotoxicity took place by low pH regulation in intracellular lysosomes, which made NPHF/D act as a fluorescence OFF-ON messenger for activatable imaging and cancer therapy. Of note, NPHF/D significantly inhibited the growth of tumors. Simultaneously, it was demonstrated that the introduction of FA and the cleavability of the hydrazone greatly enhanced the therapeutic performance of NPHF/D. In addition, toxicity studies in mice verified that the composites were devoid of any detected hepatotoxicity, cardiotoxicity, and nephrotoxicity using histopathology and blood biochemistry studies. Our work provides a novel strategy for cancer therapy, using ND-conjugated cancer drugs, and the exploration of theranostic drug-delivery systems.