Synthesis of New Water Soluble ß-Cyclodextrin@Curcumin Conjugates and In Vitro Safety Evaluation in Primary Cultures of Rat Cortical Neurons.

Self-aggregation of Curcumin (Cur) in aqueous biological environment decreases its bioavailability and in vivo therapeutic efficacy, which hampers its clinical use as candidate for reducing risk of neurodegenerative diseases. Here, we focused on the design of new Cur- ß-Cyclodextrin nanoconjugates to improve the solubility and reduce cell toxicity of Cur. In this study, we described the synthesis, structural characterization, photophysical properties and neuron cell toxicity of two new water soluble ß-CD/Cur nanoconjugates as new strategy for reducing risks of neurodegenerative diseases. Cur was coupled to one or two ß-CD molecules via triazole rings using CuAAC click chemistry strategy to yield ß-CD@Cur and (ß-CD)2@Cur nanoconjugates, respectively. The synthesized nanoconjugates were found to be able to self-assemble in aqueous condition and form nano-aggregates of an average diameter size of around 35 and 120 nm for ß-CD@Cur and (ß-CD)2@Cur, respectively. The photophysical properties, water solubility and cell toxicity on rat embryonic cortical neurons of the designed nanoconjugates were investigated and compared to that of Cur alone. The findings revealed that both new nanoconjugates displayed better water solubility and in vitro biocompatibility than Cur alone, thus making it possible to envisage their use as future nano-systems for the prevention or risk reduction of neurodegenerative diseases.

Effect of Cetuximab-Conjugated Gold Nanoparticles on the Cytotoxicity and Phenotypic Evolution of Colorectal Cancer Cells.

Epidermal growth factor receptor (EGFR) is estimated to be overexpressed in 60~80% of colorectal cancer (CRC), which is associated with a poor prognosis. Anti-EGFR targeted monoclonal antibodies (cetuximab and panitumumab) have played an important role in the treatment of metastatic CRC. However, the therapeutic response of anti-EGFR monoclonal antibodies is limited due to multiple resistance mechanisms. With the discovery of new functions for gold nanoparticles (AuNPs), we hypothesize that cetuximab-conjugated AuNPs (cetuximab-AuNPs) will not only improve the cytotoxicity for cancer cells, but also introduce expression change of the related biomarkers on cancer cell surface. In this contribution, we investigated the size-dependent cytotoxicity of cetuximab-AuNPs to CRC cell line (HT-29), while also monitored the expression of cell surface biomarkers in response to treatment with cetuximab and cetuximab-AuNPs. AuNPs with the size of 60 nm showed the highest impact for cell cytotoxicity, which was tested by cell counting kit-8 (CCK-8) assay. Three cell surface biomarkers including epithelial cell adhesion molecule (EpCAM), melanoma cell adhesion molecule (MCAM), and human epidermal growth factor receptor-3 (HER-3) were found to be expressed at higher heterogeneity when cetuximab was conjugated to AuNPs. Both surface-enhanced Raman scattering/spectroscopy (SERS) and flow cytometry demonstrated the correlation of cell surface biomarkers in response to the drug treatment. We thus believe this study provides powerful potential for drug-conjugated AuNPs to enhance cancer prognosis and therapy.

Antibacterial activity of antimicrobial peptide-conjugated nanofibrous membranes.

Antimicrobial peptides (AMPs) are considered as novel potential alternatives to antibiotics against increasing number of multi drug resistant (MDR) pathogens. Although AMPs have shown strong antimicrobial activity against gram-negative or gram-positive microorganisms, AMP conjugated biomaterials that are effective against MDR microorganisms are yet to be developed. Herein, the potential use of (RWRWRWRW)-NH2 (AMP-1) and KRFRIRVRV-NH2 (AMP-2) peptide conjugated electrospun polylactic-co-glycolic-acid (PLGA) nanofibers (NFs) fabricated and their antimicrobial effect by themselves and in their dual combination (1:1) were evaluated on P. aeruginosa and methicillin-resistant S. aureus (MRSA). Those AMP conjugated NFs did not inhibit proliferation of keratinocytes. These results suggest that AMP conjugated NF, which has multiple biological activities, would be a promising candidate as a wound dressing material.

Hyaluronic acid tethered pH-responsive alloy-drug nanoconjugates for multimodal therapy of glioblastoma: An intranasal route approach.

In the present investigation, FePt alloy nanoparticles were synthesized with controlled size and elemental composition followed by surface modification using (3-Aminopropyl) triethoxysilane (APTES). Lenalidomide was covalently bound to FePt-NH2 by pH sensitive hydrazone bonding. Hyaluronic acid was conjugated to amino groups of APTES while lactoferrin (Lf) was directly conjugated to excess carboxylic group present on hyaluronic acid (HA) to form surface modified pH sensitive alloy-drug nanoconjugates (SPANs). The multifunctional nanoconjugates were characterized and evaluated using extensive in vitro and in vivo techniques. The nanoconjugates demonstrated excellent heating ability on exposure to alternating magnetic field and near-infrared laser irradiation. The acidic microenvironment of lysozome triggered release of LND from SPANs. Owing to leaching of Fe and Pt contents, SPANs demonstrated ability to generate reactive oxygen species (ROS) in U87MG cell line which further enhanced therapeutic effect of SPANs. Significant difference in cell viability suppression was observed in in vitro photothermal, chemo-photothermal and chemo-magnetophotothermal killing of cancer cells using SPANs in U87MG cell lines. Significant difference in heating ability and cell cytotoxicity of SPANs in comparison to alternative magnetic field and NIR irradiation was observed for DUAL-mode exposure of SPANs. The results of cellular internalization study showed efficient internalization of SPANs inside U87MG cells. The in vivo results (both qualitative and quantitative) confirmed enhanced uptake of SPANs in brain after intranasal administration with enhanced nasal and mucus penetration owing to presence of Lf. No significant interaction was observed with ECM and mucin due to presence of carboxyl group on SPANs.

Green synthesis of multifunctional PEG-carboxylate π back-bonded gold nanoconjugates for breast cancer treatment.

BACKGROUND: Surface functionalization of gold nanoparticles (AuNPs) has emerged as a promising field of research with enormous biomedical applications. The folate (FA)-attached polymer-gold nanoconjugates play vital role in targeting the cancer cells. METHODS: AuNPs were synthesized by using di- or tri-carboxylate-polyethylene glycol (PEG) polymers, including citrate-PEG (CPEG), malate-PEG (MAP), and tartrate-PEG (TAP), as a reducing and stabilizing agent. After synthesis of polymer-AuNPs, the freely available hydroxyl and carboxylate groups of CPEG, MAP, and TAP were used to attach a cancer cell-targeting agent, FA, via a 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy succinimide coupling reaction to obtain FA-CPEG-AuNP, FA-MAP-AuNP, and FA-TAP-AuNP nanocon-jugates, respectively. The 5-fluorouracil (5FU) was attached to π back-bonded carbonyl oxygens of the nanoconjugates, and the in vitro drug release profile was studied by high pressure liquid chromatography. Biocompatibility profiles of the FA-CPEG-AuNP, FA-MAP-AuNP, and FA-TAP-AuNP nanoconjugates were investigated using adult human dermal fibroblasts. Anti-breast cancer activity of 5FU-loaded nanoconjugates was investigated using MCF-7 breast cancer cells. RESULTS: X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy analyses confirmed that AuNPs attached to CPEG, MAP, or TAP via the formation of π back bonding between AuNPs and the ester carbonyl group. The π back-bonded nanoconjugates exhibited sustained release of 5FU up to 27 days. FA-MAP-AuNPs exhibited an IC50 at 5 µg/mL, while FA-CPEG-AuNPs and FA-TAP-AuNPs showed the IC50 at 100 µg/mL toward MCF-7 cancer cells. CONCLUSION: The developed polymer π back-bonded multifunctional gold nanoconjugates could be used as a potential drug delivery system for targeting MCF-7 cancer cells.

Stabilization of polydopamine modified silver nanoparticles bound trypsin: Insights on protein hydrolysis.

This study presents an effective method to enhance the proteolytic activity of trypsin by designing a nanobioconjugate of trypsin and polydopamine coated silver nanoparticles (Ag-PDA). Ag-PDA nanocomposite was synthesized and trypsin was covalently attached to this matrix. A multifold enhancement in enzyme activity was observed after conjugation, with an effectiveness factor of η = 5.62. Conjugated trypsin was more stable to extremes of pH and temperature as compared to normal unconjugated version. Unconjugated trypsin retained only 41% of activity after 60 days of storage at 4 °C, whereas the conjugated enzyme preserved 91% of activity. Immobilized trypsin conserved 83% of activity even after its ten repeated uses. It was found that conjugated trypsin required lower incubation periods for complete hydrolysis of casein, BSA & ovalbumin as compared to free enzyme. Contrary to this, even long hours of incubation with free trypsin were unable to completely digest these proteins. The current observations suggest that Ag-PDA conjugated trypsin could be more suitable for efficient hydrolysis of various proteins under industrial environments.

Improving Plasma Stability and Bioavailability In Vivo of Gemcitabine Via Nanoparticles of mPEG-PLG-GEM Complexed with Calcium Phosphate.

PURPOSE: Despite being widely used for the treatment of several solid tumors, Gemcitabine (GEM) exhibits several suboptimal pharmacokinetic properties. Therefore, the design of nanoparticle delivery systems is a promising strategy to enhance GEM pharmacokinetic properties. METHODS: In this work, the polymeric material methoxy poly(ethylene glycol)-block-poly(L-glutamic acid)-graft-gemcitabine (mPEG-b-PLG-g-GEM) was synthesized through the covalent conjugation of GEM with the carboxylic group of methoxy poly(ethylene glycol)-block-poly (L-glutamic acid) (mPEG-b-PLG) (mPEG113, Mn = 5000). mPEG-PLG-GEM/CaP nanoparticles were prepared through the simple mixing of calcium and phosphate/mPEG-PLG-GEM solutions. mPEG-PLG-GEM was embedded in the calcium phophate (CaP) backbone via electrostatic interactions. RESULTS: After incubation in plasma at 37°C for 24 h, gemcitabine was degraded by 24.6% for the mPEG-PLG-GEM, 14.7% for the mPEG-PLG-GEM/CaP nanoparticles, and 90% for the free gemcitabine solution. It was observed that mPEG-PLG-GEM and mPEG-PLG-GEM/CaP improved the area-under-curve (AUC) values by 5.26-fold and 6.33-fold compared to free drug, respectively. CONCLUSION: The amide bond linked gemcitabine polymers was able to protect GEM from cytidine deaminase degradation in vivo, and the skeleton formed by the calcium phosphate enhanced the stability and prolonged the half-life of GEM. Importantly, mPEG-PLG-GEM/CaP nanoparticles elevated the GEM plasma concentration in an animal model.

Novel electrochemical sensing platform for ultrasensitive detection of cardiac troponin I based on aptamer-MoS2 nanoconjugates.

Cardiac troponin I (cTnI) is a specific and sensitive biomarker for the early diagnosis of acute myocardial infarction and for the subsequent clinical treatments. In this work, novel electrochemical sensing platform for sensing of cTnI based on aptamer-MoS2 nanoconjugates was proposed. For comparison, core-shell Au@SiO2@Au nanoparticles were also used for sensing of cTnI. The sensing schemes and electrochemical responses of the proposed sensors were investigated by electrochemical impedance spectroscopy (EIS) in 5.0 mM K3[Fe(CN)6]/K4[Fe(CN)6] (1:1) solution containing 0.1 M KCl, respectively. Results showed that the aptamer-Au@SiO2@Au based aptasensor shows a linear rage of 10 pM-10.0 µM with the detection limits of 1.23 pM For the aptamer-MoS2 nanosheets based aptasensor, the linear range for cTnI detection was from 10 pM to 1.0 µM with a lower detection limit of 0.95 pM Meanwhile, both the sensors were successfully applied for detection of cTnI in human blood samples. The two kinds of aptsensors have been successfully used for detecting of cTnI in human blood serums. Moreover, no negligible signal changes could be observed in the presence of non-targets of CK-MB and Myo, suggesting the good potential for clinic diagnosis.

Chitosan binding onto the epigallocatechin-loaded ferritin nanocage enhances its transport across Caco-2 cells.

The effect of chitosan decoration on the transport of epigallocatechin (EGC)-encapsulated ferritin cage across the Caco-2 cells was investigated. After the encapsulation of EGC in apo-red bean (adzuki) ferritin (apoRBF), the EGC-loaded apoRBF nanoparticle (ER) was fabricated with an encapsulation ratio of 11.6% (w/w). The results indicated that different chitosan molecules (with molecular weights of 980, 4600, 46 000, and 210 000 Da) could attach onto the apoRBF via electrostatic interactions to form ER-chitosan complexes (ERCs) (ERCs980, ERCs4600, ERCs46000, and ERCs210000). ERCs980 and ERCs4600 retained the typical shell-like morphology of ferritin with a size distribution of 12 nm and showed weak negative zeta-potentials at pH 6.7, while ERCs46000 and ERCs210000 significantly aggregated. Furthermore, the transport of EGC in ERCs980 and ERCs4600 across the Caco-2 cells was enhanced by the transferrin receptor 1 (TfR-1)-mediated absorption pathway, demonstrating that chitosan molecules with low molecular weights of 980 and 4600 Da were beneficial to the absorption of EGC based on the ferritin cage. This study will facilitate the application of ferritin-chitosan materials for fabricating the core-shell platform for encapsulation and bioavailability enhancement of bioactive molecules.

Antifungal efficacy of Au@ carbon dots nanoconjugates against opportunistic fungal pathogen, Candida albicans.

In the current study, we have investigated the toxicological effect of a novel hydrophilic nanoconjugate gold@carbon dot (Au@CD) and carbon dots (CDs) on the opportunistic fungal pathogen, Candida albicans. A homogenous experimental analysis was conducted for determining the toxicity of Au@CDs nanoconjugates of five different sizes ranging from 22 ±â€¯2 to 35 ±â€¯3 nm prepared using the carbon dots of mean hydrodynamic radius 12 ±â€¯1 nm. The smallest size of nanoconjugate was synthesized using 0.3 mg ml-1 HAuCl4 precursor. Our study for the first time, conclusively establishes the size-dependent toxicity effect of these characterized nanoconjugates against the abovementioned fungal pathogen. The MIC80 value of smaller sized Au@CDs nanoconjugates, S1-S3 samples were 250, 500 and 500 µg ml-1, respectively, while nanoconjugates of Rh diameter greater than 30 nm (S4 and S5 samples) did not show any toxicity. The results thus demonstrate that alteration in composition (carbon vs Au@CDs) exhibits a profound effect on the susceptibility of Candida albicans cells. While a size-dependent toxicity was observed for the nanoconjugates, CDs were found to be quite toxic owing to their small size which facilitated their entry into the cells and challenged the biocompatibility of carbon allotropes.

Bioengineered II-VI semiconductor quantum dot-carboxymethylcellulose nanoconjugates as multifunctional fluorescent nanoprobes for bioimaging live cells.

Colloidal semiconductor quantum dots (QDs) are light-emitting ultra-small nanoparticles, which have emerged as a new class of nanoprobes with unique optical properties for bioimaging and biomedical diagnostic. However, to be used for most biomedical applications the biocompatibility and water-solubility are mandatory that can achieved through surface modification forming QD-nanoconjugates. In this study, semiconductor II-VI quantum dots of type MX (M=Cd, Pb, Zn, X=S) were directly synthesized in aqueous media and at room temperature using carboxymethylcellulose sodium salt (CMC) behaving simultaneously as stabilizing and surface biofunctional ligand. These nanoconjugates were extensively characterized using UV-visible spectroscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, dynamic light scattering and zeta potential. The results demonstrated that the biopolymer was effective on nucleating and stabilizing the colloidal nanocrystals of CdS, ZnS, and PbS with the average diameter ranging from 2.0 to 5.0nm depending on the composition of the semiconductor core, which showed quantum-size confinement effect. These QD/polysaccharide conjugates showed luminescent activity from UV-visible to near-infrared range of the spectra under violet laser excitation. Moreover, the bioassays performed proved that these novel nanoconjugates were biocompatible and behaved as composition-dependent fluorescent nanoprobes for in vitro live cell bioimaging with very promising perspectives to be used in numerous biomedical applications and nanomedicine.

Brain-Eating Amoebae: Silver Nanoparticle Conjugation Enhanced Efficacy of Anti-Amoebic Drugs against Naegleria fowleri.

The overall aim of this study was to determine whether conjugation with silver nanoparticles enhances effects of available drugs against primary amoebic meningoencephalitis due to Naegleria fowleri. Amphotericin B, Nystatin, and Fluconazole were conjugated with silver nanoparticles, and synthesis was confirmed using UV-visible spectrophotometry. Atomic force microscopy determined their size in range of 20-100 nm. To determine amoebicidal effects, N. fowleri were incubated with drugs-conjugated silver nanoparticles, silver nanoparticles alone, and drugs alone. The findings revealed that silver nanoparticles conjugation significantly enhanced antiamoebic effects of Nystatin and Amphotericin B but not Fluconazole at micromolar concentrations, compared with the drugs alone. For the first time, our findings showed that silver nanoparticle conjugation enhances efficacy of antiamoebic drugs against N. fowleri. Given the rarity of the disease and challenges in developing new drugs, it is hoped that modifying existing drugs to enhance their antiamoebic effects is a useful avenue that holds promise in improving the treatment of brain-eating amoebae infection due to N. fowleri.

Use of Biocompatible Sorafenib-gold Nanoconjugates for Reversal of Drug Resistance in Human Hepatoblatoma Cells.

The present study identifies the potential of highly biocompatible SF-GNP nano-conjugate to enhance the chemotherapeutic response to combat drug resistance in cancer cells. We developed a stable colloidal suspension of sorafenib-gold nanoconjugate (SF-GNP) of <10 nm size in aqueous medium for reverting the cancer drug resistance in SF-resistant HepG2 cells in a 3D ex-vivo model system. In-vivo biocompatibility assay of SF-GNPs showed absence of systemic toxicological effects including hematological, biochemical and histological parameters. More importantly, the histopathological analysis of vital organs such as liver, brain, lung, kidney and heart showed very least or no sign of inflammation, cell infiltration, necrosis, tissue disorganization or fibrotic reactions after intra-peritoneal administration of SF-GNP nanoconjugates in animals. However, SF-GNP nanoconjugates significantly reduced (>80%) the percentage cell survival and the size and number of SF resistant solid tumor colonies of HepG2 cells in 3D model system. The exposure of SF-GNP nanoconjugate to SF resistant HepG2 cell colonies also provided evidence for anti-proliferative effect and reversal of drug resistance by elucidating the molecular regulatory mechanisms of extracellular matrix factor (CD147), tumor growth factor (TGF-ß), hepatoma upregulated protein (hURP) and drug transporter (ABCG-2).

Effect of GNP functionalisation and multiple N-methylation of ß-amyloid residue (32-37) on Gram-positive bacterium.

In the previous report, the authors showed the gold nanoparticle (GNP) functionalised multiple N-methylated fragments of the residue (32-37) of beta (ß)-amyloid protein (1-42), CGGIGLMVG and CGGGGGIGLMVG toward disruption of ß-amyloid (1-42), the predominant component of senile plaques. Herein the in vitro antimicrobial activities of both normal and multiple N-methylated sequences of CGGIGLMVG and CGGGGGIGLMVG were screened and it was found that all the eight sequences including four (non-functionalised with GNP) to possess activity against both Gram-positive [Staphylococcus aureus (ATCC 43300) and Enterococcus faecalis (ATCC 5129)] and Gram-negative [Escherichia coli (ATCC 35218), Pseudomonas aeruginosa (ATCC 27853) and Klebsiella pneumoniae (ATCC 700603)] bacteria. Among them, N-methylated sequences CGGIGLMVG and CGGGGGIGLMVG shown remarkable activity against Gram-positive bacteria.

ZnO nanoparticles and their acarbose-capped nanohybrids as inhibitors for human salivary amylase.

The authors report a controlled synthesis of biocompatible ZnO and acarbose-capped nanohybrids, and examined the inhibition activities of these nanosystems with human salivary α-amylase (HSA) activity. XRD measurements reveal ZnO present in wurtzite phase with hexagonal structure. The average size of ZnO particles for the two studied nanosystems was estimated to lie between 10 to 12 nm using Scherrer equation. These particles depict the onset of absorption at about 320 nm and the band-gap emission at about 370 nm, which are fairly blue shifted as compared with the bulk ZnO and have been understood due to the size quantisation effect. The inhibitory action of thioglycerol capped ZnO nanoparticles (SP1) and acarbose drug (used for diabetes type II) capped ZnO (SP2) for HSA was observed to 61 and72%, respectively. The inhibition activity of the SP1 alone was found to be very similar to that of acarbose and the coating of these particles with drug (SP2) demonstrated an enhancement in inhibition activity of the enzyme by about 30%. From the inhibition studies, it is confirmed that these nanosystems showed better inhibition activity at physiological temperature and pH. These nanosystems are projected to have potential applications in diabetes type II control.

Shape-dependent enzyme-like activity of Co3O4 nanoparticles and their conjugation with his-tagged EGFR single-domain antibody.

In this study, Co3O4 nanopolyhedrons, nanocubes, nanoplates and nanorods were synthesized and characterized. Furthermore, the peroxidase- and catalase-like activities of these Co3O4 nanoparticles (NPs) were studied and influence of the exposed crystal planes was explored. According to their morphology and peroxidase-like activity, dimercaptosuccinic acid (DMSA) modified Co3O4 nanopolyhedrons synthesized via coprecipitation method (Co3O4 NHs) were selected as a proper candidate for the immunohistochemical (IHC) detection of epidermal growth factor receptor (EGFR) expression in non-small cell lung cancer (NSCLC) tissues. Bivalent cobalt ions were coupled to the carboxyls on the surface of the obtained Co3O4 NHs so as to chelate the hexahistidine residues (His-Tags) at the C-terminal of EGFR single-domain antibodies (EGFR sdAbs). Finally, the as-obtained EGFR sdAbs-binding Co3O4 NHs (Co3O4 nanoprobes) were successfully applied to the detection of EGFR expression in NSCLC tissues.

Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

(3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface of HACE-AMPB/MB NPs (in the aqueous milieu) may react with the sialic acid over-expressed in cancer cells and intramolecular B‒O bond can be formed. This phenylboronic acid-sialic acid interaction may provide additional tumor targeting and penetration potentials together with an enhanced permeability and retention (EPR) effect (passive tumor targeting) and HA-CD44 receptor interaction (active tumor targeting). Developed HACE-AMPB NP may be one of promising nanocarriers for the imaging and therapy of CD44 receptor-expressed cancers.

Killing colon cancer cells through PCD pathways by a novel hyaluronic acid-modified shell-core nanoparticle loaded with RIP3 in combination with chloroquine.

Due to extensive apoptosis defects and multidrug resistance, there is great interest regarding non-apoptotic programmed cell death (PCD) pathways, such as lysosomal-mediated programmed cell death (LM-PCD), necroptosis and autophagy. Because there is an intricate effector network among these PCD pathways, it is expected that they may act synergistically in cancer therapy. In this study, chloroquine (CQ) was found to significantly upregulate receptor-interacting protein kinase 3 (RIP3) expression, and RIP3 were involved in CQ-related autophagy. Overexpressed-eGFP-RIP3 co-localized with the selective autophagy receptor p62. mRIP3 overexpression in combination with CQ markedly increased the inhibition rate relative to that observed in the CQ-treatment group. Several experiments, including Hoechst staining, transmission electron microscopy (TEM) observation, the high-mobility group box 1 (HMGB1) release assay, Annexin V/PI staining and immunoblotting of proteins included in PCD pathways, verified that mRIP3 overexpression in combination with CQ induced lysosomal membrane permeabilization (LMP) and necroptosis of cancer cells, leading to cancer cell death. For tumor-targeted delivery, hyaluronic acid (HA)-modified, lipid-coated PLGA nanoparticles loaded with mRIP3-pDNA were prepared and characterized using a particle sizer, differential scanning calorimetry (DSC) and TEM. The nanoparticles exhibited ideal biocompatibility and good tumor-targeting efficiency, and the tumor inhibition rate of HA-Lip-PEI-mRIP3-PLGA-NPs + CQ was 80.2% in the CT26 mouse model. In this study, we attempted to treat tumors by inducing several alternative PCD pathways to shed light on the combination therapy of alternative PCD inducers.

Trimethyl chitosan based conjugates for oral and intravenous delivery of paclitaxel.

Paclitaxel (PTX) conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as polymer-drug conjugates for oral and intravenous delivery of PTX. As amphiphilic conjugates, TMC-PTX and FA-TMC-PTX containing approximately 11wt% PTX could self-assemble into spherical nanoparticles with average sizes of 170 and 187nm, respectively. The conjugates presented a sustained release of PTX and the release rate was positively correlated with the pH value of medium ranging from 1.2 to 7.4. TMC-PTX and FA-TMC-PTX possessed enhanced mucoadhesion compared with trimethyl chitosan, and promoted ex vivo intestinal transport of PTX in comparison to PTX solution by 15.5 and 18.8 folds, respectively. Hemolysis assessment confirmed the safety of TMC-PTX and FA-TMC-PTX, and FA modification alleviated protein adsorption of the conjugates. Prolonged blood retention and increased PTX accumulation in the tumor were achieved for orally and intravenously administered conjugates. In H22 tumor-bearing mice, TMC-PTX delivered via oral or intravenous route showed superior tumor retardation and survival rate compared with intravenously injected PTX, and FA-TMC-PTX further enhanced the antitumor efficacy. Overall, the trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for cancer therapy. STATEMENT OF SIGNIFICANCE: In the current study, PTX conjugated trimethyl chitosan (TMC-PTX) and folic acid (FA) modified TMC-PTX (FA-TMC-PTX) were developed as the polymer-drug conjugates for oral and intravenous delivery of PTX. By exploiting advantages with respect to improved solubility of drugs, controlled release behavior of covalently linked drugs, and enhanced targeting effect towards tumors, improved tumor growth inhibition efficacy and prolonged survival time were achieved for TMC-PTX as compared with free PTX, and FA modification further enhanced the in vivo antitumor efficacy. Overall, the self-assembled nanoplatform of trimethyl chitosan based drug conjugates may have potential applications as a promising candidate for tumor therapy via different administration routes.