Dextran-based Nanoparticles Research Articles

Dextran-based nanoparticles with 5-FU-conjugated polymethacrylate segments for drug delivery: Synthesis of amphiphilic graft copolymers by mechanochemical solid-state polymerization and characterization

Dextran (Dx) is a biodegradable and biocompatible polysaccharide, thus promising as a drug delivery carrier for tumor therapy. Herein, we applied mechanical energy to a high molecular weight Dx to control its molecular weight and simultaneously generate mechanoradicals. The solid-state polymerization of methacrylate- or methacrylamide derivatives initiated with Dx mechanoradicals showed polymer conversion of >95%, yielding Dx-based graft copolymers with molecular weights of approximately 30,000 g mol−1. The Dx-based graft copolymers with hydrophobic segments formed nanoparticles with a particle size of 25–35 nm in an aqueous solution. The anti-pancreatic tumor drug 5-fluorouracil (5-FU) was covalently conjugated onto the hydrophobic segments of the amphiphilic Dx, and the nanoparticles were also prepared. The drug release profile from 5-FU-conjugated nanoparticles corresponded well to the Korsmeyer-Peppas model applied to drug release from matrix substrates, and was also immensely predicted by the Logistic and Gompertz curves. The 5-FU-conjugated nanoparticles showed cytotoxicity against the pancreatic adenocarcinoma cell lines (BxPC-3) that were not significantly inferior to the 5-FU positive group. Furthermore, the fluorescein-labeled nanoparticles internalized into BxPC-3 within 6 h and actively migrated into the cytosol. These results suggest that Dx-based graft copolymers with hydrophobic segments might be used to enhance therapeutic activity.

Nanoparticle-Encapsulated Epirubicin Efficacy in the Inhibition of Growth of Orthotopic Ovarian Patient-Derived Xenograft in Immunocompromised Mice.

Epirubicin hydrochloride (EPI) is an anticancer drug widely used in the treatment of many solid tumors, including ovarian cancer. Because of its anatomical location, ovarian cancer shows symptoms when it is already in an advanced stage and is thus more difficult to treat. Epirubicin hydrochloride kills cancer cells effectively, but its dose escalation is limited by its severe toxicity. By encapsulating epirubicin in dextran-based nanoparticles (POLEPI), we expected to deliver higher and thus clinically more effective doses directly to tumors, where epirubicin would be released and retained longer in the tumor. The antitumor activity of POLEPI compared to EPI was first tested ex vivo in a series of ovarian cancer patient-derived tumor xenografts (PDX). The most promising PDX was then implanted orthotopically into immunocompromised mice, and tumor growth was monitored via magnetic resonance imaging (MRI). Although we succeeded in suppressing the growth of ovarian cancer derived from a patient, in a mouse model by 70% compared to 40% via EPI in 5 days after only one injection, we could not eliminate serious side effects, and the study was terminated prematurely for humane reasons.

Hydrogel microspheres containing dextran-based nanoparticles as novel anticancer drug delivery system

Hydrogel microspheres containing dextran-based nanoparticles as novel anticancer drug delivery system

Bidirectional Uptake, Transfer, and Transport of Dextran-Based Nanoparticles in Plants for Multidimensional Enhancement of Pesticide Utilization.

The development of effective multifunctional nano-delivery approaches for pesticide absorption remains a challenge. Here, a dextran-based pesticide delivery system (MBD) is constructed to deliver tebuconazole for multidimensionally enhancing its effective utilization on tomato plants. Spherical MBD nanoparticles are obtained through two-step esterification of dextran, followed by tebuconazole loading using the Michael addition reaction. Confocal laser scanning microscopy shows that fluorescein isothiocyanate-labeled MBD nanoparticles can be bidirectionally transported in tomato plants and a modified quick, easy, cheap, effective, rugged, and safe-HPLC approach demonstrates the capacity to carry tebuconazole to plant tissues after 24 h of root uptake and foliar spray, respectively. Additionally, MBD nanoparticles could increase the retention of tebuconazole on tomato leaves by up to nearly 2.1 times compared with the tebuconazole technical material by measuring the tebuconazole content retained on the leaves. In vitro antifungal and pot experiments show that MBD nanoparticles improve the inhibitory effect of tebuconazole against botrytis cinerea by 58.4% and the protection against tomato gray molds by 74.9% compared with commercial suspensions. Furthermore, the MBD nanoparticles do not affect the healthy growth of tomato plants. These results underline the potential for the delivery system to provide a strategy for multidimensional enhancement of pesticide efficacy.

Neutralization of ionic interactions by dextran-based single-chain nanoparticles improves tobramycin diffusion into a mature biofilm

The extracellular matrix protects biofilm cells by reducing diffusion of antimicrobials. Tobramycin is an antibiotic used extensively to treat P. aeruginosa biofilms, but it is sequestered in the biofilm periphery by the extracellular negative charge matrix and loses its efficacy significantly. Dispersal of the biofilm extracellular matrix with enzymes such as DNase I is another promising therapy that enhances antibiotic diffusion into the biofilm. Here, we combine the charge neutralization of tobramycin provided by dextran-based single-chain polymer nanoparticles (SCPNs) together with DNase I to break the biofilm matrix. Our study demonstrates that the SCPNs improve the activity of tobramycin and DNase I by neutralizing the ionic interactions that keep this antibiotic in the biofilm periphery. Moreover, the detailed effects and interactions of nanoformulations with extracellular matrix components were revealed through time-lapse imaging of the P. aeruginosa biofilms by laser scanning confocal microscopy with specific labeling of the different biofilm components.

Pickering emulsions stabilized by biodegradable dextran-based nanoparticles featuring enzyme responsiveness and co-encapsulation of actives

In this study, Pickering emulsions of dodecane and medium chain triglyceride (MCT) oils were stabilized by simply alkylated-dextran nanoparticles. Our findings show that very little of these bio-friendly nanoparticles is necessary to stabilize Pickering emulsions while providing a high time stability (more than a year at 37 °C). As dextran is known to be cleavable by dextranase enzyme, hydrolysis of the nanoparticles in the presence of dextranase could be achieved. This allowed performing on-demand destabilization of Pickering emulsions. Furthermore, two different fluorescent probes were loaded into the stabilizing particles and the oil droplets respectively, providing a proof of concept for co-encapsulation of actives in advanced delivery applications. Additionally, to a conventional fluorescence probe, quinine, an antimalarial drug was also encapsulated into the nanoparticles.

Spatio-temporal control over destabilization of Pickering emulsions stabilized by light-sensitive dextran-based nanoparticles

The implementation of light-sensitive Pickering emulsions with spatio-temporal responsiveness in advanced applications like drug-delivery, colloidal or reaction engineering would open new avenues. However, curiously, light-sensitive Pickering emulsions are barely studied in the literature and their biocompatibility and/or degradability scarcely addressed. Thus, their development remains a major challenge. As an original strategy, we synthesized light-sensitive nanoparticles based on biocompatible Poly(NitroBenzylAcrylate) grafted dextran (Dex-g-PNBA) to stabilize O/W Pickering emulsions. The produced emulsions were stable in time and could undergo time and space-controlled destabilization under light stimulus. Irradiation time and alkaline pH-control of the aqueous phase were proved to be the actual key drivers of destabilization. As the nanoparticles themselves were photolyzed under light stimulus, possible harmful effects linked to accumulation of nanomaterials should be avoided. In addition to UV light (365 nm), visible light (405 nm) was successfully used for the spatio-temporal destabilization of the emulsions, offering perspectives for life science applications.

Macrophage imaging and subset analysis using single-cell RNA sequencing.

Macrophages have been associated with drug response and resistance in diverse settings, thus raising the possibility of using macrophage imaging as a companion diagnostic to inform personalized patient treatment strategies. Nanoparticle-based contrast agents are especially promising because they efficiently deliver fluorescent, magnetic, and/or radionuclide labels by leveraging the intrinsic capacity of macrophages to accumulate nanomaterials in their role as professional phagocytes. Unfortunately, current clinical imaging modalities are limited in their ability to quantify broad molecular programs that may explain (a) which particular cell subsets a given imaging agent is actually labeling, and (b) what mechanistic role those cells play in promoting drug response or resistance. Highly multiplexed single-cell approaches including single-cell RNA sequencing (scRNAseq) have emerged as resources to help answer these questions. In this review, we query recently published scRNAseq datasets to support companion macrophage imaging, with particular focus on using dextran-based nanoparticles to predict the action of anti-cancer nanotherapies and monoclonal antibodies.

Dextran-Based Nanoparticles to Formulate pH-Responsive Pickering Emulsions: A Fully Degradable Vector at a Day Scale.

Biosourced Pickering emulsion stabilizers with stimuli responsiveness are mostly designed for recycling and do not offer fast degradability as required for drug-delivery applications. Herein, dextran-a hydrophilic and biofriendly polysaccharide obtainable from biomass recovery-was used for the first time as a brick material for the formulation of (bio)degradable pH-sensitive Pickering emulsions. It was first modified with hydrophobic acetal moieties to provide pH-sensitive acetalated dextran. Under acidic conditions, it degrades into three biocompatible (macro)molecules: dextran, ethanol, and acetone. Nanoparticles of acetalated dextran were obtained using the nanoprecipitation process and could be similarly fully hydrolyzed under acidic conditions within 6 h. Then, O/W Pickering emulsions of dodecane (model oil) and medium-chain triglyceride (biocompatible oil) were successfully stabilized using these nanoparticles. pH-induced destabilization of these Pickering emulsions (including nanoparticles degradation) took less than 24 h. Finally, neither accumulation of nanoparticles nor harmful component release happened during the process, making this stimuli-responsive vector safe and environmentally friendly.

Effect of Starvation in Reversing Cancer Chemoresistance Based on Drug-Resistance Detection by Dextran Nanoparticles.

IntroductionChemoresistance leads to chemotherapy failure in patients with cancer. Multidrug resistance (MDR) in cancer is mainly caused by the high expression of P-glycoprotein encoded by the MDR1 gene, which is an ATP-dependent protease. Keeping the stronger invasion and migration abilities of chemoresistant cells in cancer also requires more ATP consumption. Herein, we aimed to reverse resistance by reducing the glucose supply in the cellular environment.MethodsA starvation approach in reversing chemoresistance was applied, which was implemented through preparing fluorescent dextran-based nanoparticles to detect the proportion of chemoresistant cells in the chemoresistant/chemosensitive cell mixture after cells cultured in a low-glucose condition.ResultsChemoresistant cells had higher glucose consumption with higher ATPase expression and stronger glucose dependence compared to chemosensitive cells. Moreover, cancer cells cultured in a low-glucose condition reduced the proportion of chemoresistant cells.ConclusionStarvation therapy can be used as a new method to reverse drug resistance in cancer.

Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation

Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus “synchronizing” the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy.

Dual-peptide functionalized acetalated dextran-based nanoparticles for sequential targeting of macrophages during myocardial infarction.

The advent of nanomedicine has recently started to innovate the treatment of cardiovascular diseases, in particular myocardial infarction. Although current approaches are very promising, there is still an urgent need for advanced targeting strategies. In this work, the exploitation of macrophage recruitment is proposed as a novel and synergistic approach to improve the addressability of the infarcted myocardium achieved by current peptide-based heart targeting strategies. For this purpose, an acetalated dextran-based nanosystem is designed and successfully functionalized with two different peptides, atrial natriuretic peptide (ANP) and linTT1, which target, respectively, cardiac cells and macrophages associated with atherosclerotic plaques. The biocompatibility of the nanocarrier is screened on both macrophage cell lines and primary macrophages, showing high safety, in particular after functionalization of the nanoparticles' surface. Furthermore, the system shows higher association versus uptake ratio towards M2-like macrophages (approximately 2-fold and 6-fold increase in murine and human primary M2-like macrophages, respectively, compared to M1-like). Overall, the results demonstrate that the nanosystem has potential to exploit the "hitchhike" effect on M2-like macrophages and potentially improve, in a dual targeting strategy, the ability of the ANP peptide to target infarcted heart.

Nanoparticles for the multivalent presentation of a TnThr mimetic and as tool for solid state NMR coating investigation

Abstract The fully characterization of tumor associated antigens (TAAs) and of tumor associated carbohydrate antigens (TACAs) have opened the avenue of cancer immunotherapy. The intrinsic poor immunogenicity of TACAs, however, spotlighted the importance of multivalent presentation of the antigen(s) to trigger an immune response. Nanoparticles are excellent scaffolds for this purpose. Here we reported on the easy glycosylation of iron-based and biocompatible dextran-based nanoparticles with 1, a mimetic of the TnThr antigen. The multivalent presentation of 1 induced the induction of TNF-α and IL-6/IL10, respectively. The multivalent glycosylation of silica nanoparticles (GSiNPs) was also performed and saccharide loading qualitative assessed by solid state NMR. Our results offer the proof of concept that biomolecules coating can also be investigated on solid system by NMR.

Dextran-based therapeutic nanoparticles for hepatic drug delivery.

Evaluation of dextran-based nanoparticles (DNP) as a drug delivery system to target myeloid cells of the liver. DNP were synthesized and optionally PEGylated. Their toxicity and cellular uptake were studied in vitro. Empty and siRNA-carrying DNP were tested in vivo with regard to biodistribution and cellular uptake. In vitro, DNP were taken up by cells of the myeloid lineage without compromising their viability. In vivo, empty and siRNA-carrying DNP distributed to the liver where a single treatment addressed approximately 70% of macrophages and dendritic cells. Serum parameters indicated no in vivo toxicity. DNP are multifunctional liver-specific drug carriers which lack toxic side effects and may be utilized in clinical applications targeting liver macrophages.

P0312 : Preclinical evaluation of dextran-based therapeutic nanoparticles for hepatic drug delivery

P0312 : Preclinical evaluation of dextran-based therapeutic nanoparticles for hepatic drug delivery

Characterizing the interactions of organic nanoparticles with renal epithelial cells in vivo.

Nanotechnology approaches are actively being pursued for drug delivery, novel diagnostics, implantable devices, and consumer products. While considerable research has been performed on the effects of these materials on targeted tumor or phagocytic cells, relatively little is known about their effects on renal cells. This becomes critical for supersmall nanoparticles (<10 nm), designed to be renally excreted. The active endocytic machinery of kidney proximal tubules avidly internalizes filtered proteins, which may also be the case for filtered nanoparticles. To test whether such interactions affect kidney function, we injected mice with either 5 nm dextran-based nanoparticles (DNP) that are similar in composition to FDA-approved materials or poly(amido amine) dendrimer nanoparticles (PNP) of comparable size. These fluorescently tagged nanoparticles were both filtered and internalized by renal tubular epithelial cells in a dose- and time-dependent fashion. The biological effects were quantitated by immunocytochemistry, measuring kidney injury markers and performing functional tests. DNP administration resulted in a dose-dependent increase in urinary output, while cellular albumin endocytosis was increased. The expression of megalin, a receptor involved in albumin uptake, was also increased, but AQP1 expression was unaffected. The effects after PNP administration were similar but additionally resulted in increased clathrin expression and increased endocytosis of dextran. We conclude that there are no major detrimental renal effects of DNP on overall kidney function, but changes in endocytosis-mediating protein expression do occur. These studies provide a framework for the testing of additional nanoparticle preparations as they become available.

Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study

The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches. We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR. To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS(R2) and SKOV-3(TR) in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells. Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS(R2). Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs. Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.

PH-Sensitive Nanoparticles of Derivated Dextran Grafted with 1-(3-Aminopropyl) Imidazole

Dextran catches increasing attentions as a drug carrier because of its biocompatibility, biodegradability and ease of modification. In this study, we synthesized the derivated dextran by grafting with 1-(3-aminopropyl) imidazole. The dextran-based nanoparticles with sizes of 1H NMR, SEM, AFM and Zetasizer.

Rapid identification of Mycobacterium tuberculosis complex by a novel hybridization signal amplification method based on self-assembly of DNA-streptavidin nanoparticles

Rapid detection of Mycobacterium tuberculosis complex (MTBC) is a critical step in controlling tuberculosis (TB). In this study, we used IS6110 as the specific identification target to develop a novel hybridization signal amplification method (HSAM) for the rapid and direct detection of MTBC from clinical sputum specimens. This system consists of magnetic bead-linked capture probes for target isolation, dextran-based nanoparticles for amplifying the reporter molecule (biotinylated-FITC), and detection probes (2B-DNA) for binding the nanoparticles. Both the capture and detection probes were specific to the IS6110 target sequence. Our results determined that as few as 10 copies of the IS6110 sequence or 10 M. tuberculosis bacteria could be detected, indicating that the HSAM assay is as sensitive as conventional PCR, and the assay was specific enough to distinguish MTBC from nontuberculosis mycobacteria (NTM). A total of 176 clinical sputum specimens were collected for HSAM evaluation, and the results were compared to those from traditional culture and biochemical identification techniques. This assay had a sensitivity of 88.3%, a specificity of 91.8%, a positive predictive value of 93.8% and a negative predictive value of 84.8% for the detection of MTBC. This technique is highly sensitive and specific, is easy to perform, and does not require any sophisticated detection equipment; thus, this approach has great potential in clinical TB detection and diagnostic applications.

Rapid identification of Mycobacterium tuberculosis complex by a novel hybridization signal amplification method based on self-assembly of DNA-streptavidin nanoparticles

Rapid detection of Mycobacterium tuberculosis complex (MTBC) is a critical step in controlling tuberculosis (TB). In this study, we used IS6110 as the specific identification target to develop a novel hybridization signal amplification method (HSAM) for the rapid and direct detection of MTBC from clinical sputum specimens. This system consists of magnetic bead-linked capture probes for target isolation, dextran-based nanoparticles for amplifying the reporter molecule (biotinylated-FITC), and detection probes (2B-DNA) for binding the nanoparticles. Both the capture and detection probes were specific to the IS6110 target sequence. Our results determined that as few as 10 copies of the IS6110 sequence or 10 M. tuberculosis bacteria could be detected, indicating that the HSAM assay is as sensitive as conventional PCR, and the assay was specific enough to distinguish MTBC from nontuberculosis mycobacteria (NTM). A total of 176 clinical sputum specimens were collected for HSAM evaluation, and the results were compared to those from traditional culture and biochemical identification techniques. This assay had a sensitivity of 88.3%, a specificity of 91.8%, a positive predictive value of 93.8% and a negative predictive value of 84.8% for the detection of MTBC. This technique is highly sensitive and specific, is easy to perform, and does not require any sophisticated detection equipment; thus, this approach has great potential in clinical TB detection and diagnostic applications.