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Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

ABSTRACT: Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment not only has elevated ROS levels but also has a lower pH than healthy tissues, making pH and ROS highly suitable triggers to target inflammatory diseases. The anti-inflammatory cyclooxygenase inhibitor naproxen was modified with an ROS-responsive phenylboronic acid (PBA) and conjugated onto dextran. The dextran units were functionalized with up to 87% modified naproxen. This resulted in a complete drug release from the polymer within 20 min at 10 mM H2O2. The dual-responsive NPs reduced the levels of the proinflammatory cytokine IL-6 120 times more efficiently and TNF? 6 times more efficiently than free naproxen from lipopolysaccharide (LPS)-activated macrophages. These additional anti-inflammatory effects were found to be mainly attributed to ROS-scavenging effects. In addition, the model cargo fluorescein diacetate was released in an LPS-induced inflammatory response in vitro. We believe that drug conjugation using PBA can be applied to various drugs and dextran-based materials for enhanced drug efficacy, where this work demonstrates the significance of functionalized carbohydrates polymer-drug conjugates.

SUBMITTER: Lee S

PROVIDER: S-EPMC7170936 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

Lee Sangeun S Stubelius Alexandra A Hamelmann Naomi N Tran Vincent V Almutairi Adah A

ACS applied materials & interfaces 20181113 47

Stimuli-responsive nanoparticles (NPs) are especially interesting to enhance the drug delivery specificity for biomedical applications. With the aim to achieve a highly stable and inflammation-specific drug release, we designed a reactive oxygen species (ROS)-responsive dextran-drug conjugate (Nap-Dex). By blending Nap-Dex with the acid-sensitive acetalated dextran polymer, we achieved a dual-responsive NP with high specificity toward the inflammatory environment. The inflammatory environment no ...[more]

PMID: 30067018

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Project description:PurposeHeavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy for various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentage of injected dose (%ID/g) that localizes to tumors and which shorten the window for effective radiation enhancement due to rapid tumor washout.Methods and materialsTo address these challenges, we sought to conjugate gadolinium-based ultrasmall (<5 nm) NPs to an antibody directed against the oncogenic MUC1-C subunit that is overexpressed on the surface of many different human cancer types. The binding of the anti-MUC1-C antibody 3D1 to MUC1-C on the surface of a cancer cell is associated with its internalization and, thereby, to effective intracellular delivery of the antibody-associated payload, promoting its effective tumor retention. As such, we examined whether systemically administered anti-MUC1-C antibody-conjugated, gadolinium-based NPs (anti-MUC1-C/NPs) could accumulate within cell-line xenograft models of MUC1-C-expressing (H460) lung and (E0771) breast cancers to improve the efficacy of radiation therapy (XRT).ResultsThe %ID/g of anti-MUC1-C/NPs that accumulated within tumors was found to be similar to that of their unconjugated counterparts (6.6 ± 1.4 vs 5.9 ± 1.7 %ID/g, respectively). Importantly, the anti-MUC1-C/NPs demonstrated prolonged retention in in vivo tumor microenvironments; as a result, the radiation boost was maintained during the course of fractionated therapy (3 × 5.2 Gy). We found that by administering anti-MUC1-C/NPs with XRT, it was possible to significantly augment tumor growth inhibition and to prolong the animals' overall survival (46.2 ± 3.1 days) compared with the administration of control NPs with XRT (31.1 ± 2.4 days) or with XRT alone (27.3 ± 1.6 days; P < .01, log-rank).ConclusionsThese findings suggest that anti-MUC1-C/NPs could be used to enhance the effectiveness of radiation therapy and potentially to improve clinical outcomes.

Project description:ObjectiveTitanium dioxide nanoparticles (TiO2) nanoparticles have been widely explored in the prevention of cancer risk. Due to the difficult solubility of TiO2 nanoparticles, it is essential to synthesize new surfactants to increase its bioavailability and anti-tumor activity and reduce its cytotoxicity. Furthermore, oxidative and inflammation are closely associated with the osteosarcoma risk. Chitosan has biocompatibility, antioxidant and anti-inflammatory properties. The effects of chitosan-coated TiO2-embedded paclitaxel nanoparticles on an osteosarcoma model were explored.MethodsAn osteosarcoma model was established and chitosan-coated TiO2-embedded paclitaxel nanoparticles were prepared using a freeze-drying strategy. The morphological characteristics of nanoparticles were observed using scanning electron microscopy (SEM). The physicochemical properties of nanoparticle were evaluated by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The cytotoxicity was tested by using human osteoblast cells hFob1.19 and osteosarcoma cells 143B. Osteosarcoma mice were treated with PBS buffer, paclitaxel, TiO2-embedded paclitaxel and chitosan-coated TiO2-embedded paclitaxel nanoparticles. The biomarkers of oxidative-inflammatory status, anti-tumor activities and survival rates of the model were measured.ResultsXRD analysis showed that the peaks of chitosan/TiO2 (anatase) were consistent with those of crystalline TiO2 and broad phase of chitosan. The FTIR spectrum indicated the relevant functional groups in TiO2. Chitosan-coated TiO2-embedded paclitaxel nanoparticles had good biocompatibility and improve antioxidant and anti-inflammatory properties in the osteosarcoma model. Chitosan-coated TiO2-embedded paclitaxel nanoparticles was less toxic to the cells hFob1.19 and more toxic to the cells 143B than TiO2-embedded paclitaxel nanoparticles. Chitosan-coated TiO2-embedded paclitaxel nanoparticles showed significant antitumor activity and increased the survival rate of the osteosarcoma model (P < 0.05).ConclusionsChitosan improved anti-tumor potential of TiO2-embedded paclitaxel nanoparticles in the prevention of osteosarcoma.

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Dataset Information

Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

Publications

Inflammation-Responsive Drug-Conjugated Dextran Nanoparticles Enhance Anti-Inflammatory Drug Efficacy.

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