Improving Cellular Uptake and Cytotoxicity of Chitosan-Coated Poly(Lactic-
            <i>Co</i>
            -Glycolic Acid) Nanoparticles in Macrophages

Hees, Sofie Van; Elbrink, Kimberley; Schryver, Marjorie De; Delputte, Peter; Kiekens, Filip

doi:10.2217/nnm-2020-0317

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…At later timepoints, these particles continued to be internalized and accumulation was observed in these cells' cytoplasm. These results are in agreement with other studies of professional phagocytes, including RAW 264 and J774 macrophage cell-lines and primary resident and inflammatory macrophages, which have been shown to internalize NPs at early timepoints, such as at 30 min of incubation (Cohen-Sela et al, 2009;Nicolete et al, 2011;Petersen et al, 2018;Couto et al, 2020;Van Hees et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor

et al. 2021

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Leishmaniasis is a spectrum of neglected tropical diseases and its cutaneous form (CL) is characterized by papillary or ulcerated skin lesions that negatively impact patients' quality of life. Current CL treatments suffer limitations, such as severe side effects and high cost, making the search for new therapeutic alternatives an imperative. In this context, heat shock protein 90 (Hsp90) could present a novel therapeutic target, as evidence suggests that Hsp90 inhibitors, such as 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG), may represent promising chemotherapeutic agents against CL. As innovative input for formulation development of 17-DMAG, nano-based drug delivery systems could provide controlled release, targeting properties, and reduced drug toxicity. In this work, a double emulsion method was used to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles containing 17-DMAG. The nanoparticle was developed using two distinct protocols: Protocol 1 (P1) and Protocol 2 (P2), which differed concerning the organic solvent (acetone or dichloromethane, respectively) and procedure used to form double-emulsions (Ultra-Turrax® homogenization or sonication, respectively). The nanoparticles produced by P2 were comparatively smaller (305.5 vs. 489.0 nm) and more homogeneous polydispersion index (PdI) (0.129 vs. 0.33) than the ones made by P1. Afterward, the P2 was optimized and the best composition consisted of 2 mg of 17-DMAG, 100 mg of PLGA, 5% of polyethylene glycol (PEG 8000), 1.5 mL of the internal aqueous phase, 1% of polyvinyl alcohol (PVA), and 4 mL of the organic phase. Optimized P2 nanoparticles had a particle size of 297.2 nm (288.6–304.1) and encapsulation efficacy of 19.35% (15.42–42.18) by the supernatant method and 31.60% (19.9–48.79) by the filter/column method. Release kinetics performed at 37°C indicated that ~16% of the encapsulated 17-DMAG was released about to 72 h. In a separate set of experiments, a cell uptake assay employing confocal fluorescence microscopy revealed the internalization by macrophages of P2-optimized rhodamine B labeled nanoparticles at 30 min, 1, 2, 4, 6, 24, 48, and 72 h. Collectively, our results indicate the superior performance of P2 concerning the parameters used to assess nanoparticle development. Therefore, these findings warrant further research to evaluate optimized 17-DMAG-loaded nanoparticles (NP2-17-DMAG) for toxicity and antileishmanial effects in vitro and in vivo.

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Section: Discussionsupporting

confidence: 92%

Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor

et al. 2021

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“…Therefore, functionalization of these small-sized 2% PLGA NPs might have attributed to increased uptake rates for these formulations. In contrast, the larger 0.2% PLGA NPs, of which augmented uptake rates during the first hours were formerly observed (Van Hees et al 2020 ), did not show any differences in MFI between the groups after 1 and 4 h and were therefore discontinued from further experiments. Noticeably, the large isotype control antibody-conjugated PLGA NPs seemed to establish the highest uptake after 4 h, although no significant difference was present due to an outlier causing a large standard deviation.…”

Section: Discussionmentioning

confidence: 80%

“…In previous research, an increase in total NP uptake in macrophages when coating PLGA NPs with chitosan derivatives was demonstrated (Van Hees et al 2020 ). Therefore, it was unexpected that the functionalization of the PLGA NPs with specific antibodies against Sn did not lead to differences in total NP uptake for 2% FITC-loaded PLGA NPs after 24 h. As chitosan is presumably facilitating endocytosis through uptake via the mannose receptor (Vu-Quang et al 2016 ; Durán et al 2019 ), supposedly, the engulfment through the Sn receptor might be less efficient (Klaas and Crocker 2012 ).…”

Section: Discussionmentioning

confidence: 88%

“…An increase in the uptake of cAb-conjugated PLGA NPs was also noticed after 4 h, hence to a lesser extent. It was previously observed that uptake rates of small PLGA NPs were low, but the total NP uptake after 24 h was high (Van Hees et al 2020 ). Therefore, functionalization of these small-sized 2% PLGA NPs might have attributed to increased uptake rates for these formulations.…”

Section: Discussionmentioning

confidence: 94%

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Targeting of sialoadhesin-expressing macrophages through antibody-conjugated (polyethylene glycol) poly(lactic-co-glycolic acid) nanoparticles

et al. 2022

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This research aims to evaluate different-sized nanoparticles consisting of (polyethylene glycol) (PEG) poly(lactic-co-glycolic acid) (PLGA), loaded with fluorescein isothiocyanate for nanoparticle uptake and intracellular fate in sialoadhesin-expressing macrophages, while being functionalized with anti-sialoadhesin antibody. Sialoadhesin is a macrophage-restricted receptor, expressed on certain populations of resident tissue macrophages, yet is also upregulated in some inflammatory conditions. The nanocarriers were characterized for nanoparticle size (84–319 nm), zeta potential, encapsulation efficiency, and in vitro dye release. Small (86 nm) antibody-functionalized PEG PLGA nanoparticles showed persisting benefit from sialoadhesin-targeting after 24 h compared to the control groups. For small (105 nm) PLGA nanoparticles, uptake rate was higher for antibody-conjugated nanoparticles, though the total amount of uptake was not enhanced after 24 h. For both plain and functionalized small-sized (PEG) PLGA nanoparticles, no co-localization between nanoparticles and (early/late) endosomes nor lysosomes could be observed after 1-, 4-, or 24-h incubation time. In conclusion, decorating (PEG) PLGA nanocarriers with anti-sialoadhesin antibodies positively impacts macrophage targeting, though it was found to be formulation-specific.

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“…To investigate the anticancer activity of a BRD4 protein degrader (ARV), different nanoformulations were explored for parental delivery. PLGA-PEG NPs were produced to encapsulate lipophilic ARV for passive targeting and improving its cytotoxic effect (Van Hees et al, 2020). These NPs (ARV-NPs) were prepared by nanoprecipitation method by using a biodegradable PLGA-PEG polymer.…”

Section: Guided and Smart Nps For The Controlled Release Of Protacsmentioning

confidence: 99%

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Juan¹,

Noblejas-López

Arenas-Moreira³

et al. 2022

Front. Cell Dev. Biol.

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Classical targeting in cancer focuses on the development of chemical structures able to bind to protein pockets with enzymatic activity. Some of these molecules are designed to bind the ATP side of the kinase domain avoiding protein activation and the subsequent oncogenic activity. A further improvement of these agents relies on the generation of non-allosteric inhibitors that once bound are able to limit the kinase function by producing a conformational change at the protein and, therefore, augmenting the antitumoural potency. Unfortunately, not all oncogenic proteins have enzymatic activity and cannot be chemically targeted with these types of molecular entities. Very recently, exploiting the protein degradation pathway through the ubiquitination and subsequent proteasomal degradation of key target proteins has gained momentum. With this approach, non-enzymatic proteins such as Transcription Factors can be degraded. In this regard, we provide an overview of current applications of the PROteolysis TArgeting Chimeras (PROTACs) compounds for the treatment of solid tumours and ways to overcome their limitations for clinical development. Among the different constraints for their development, improvements in bioavailability and safety, due to an optimized delivery, seem to be relevant. In this context, it is anticipated that those targeting pan-essential genes will have a narrow therapeutic index. In this article, we review the advantages and disadvantages of the potential use of drug delivery systems to improve the activity and safety of PROTACs.

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Improving Cellular Uptake and Cytotoxicity of Chitosan-Coated Poly(Lactic- Co -Glycolic Acid) Nanoparticles in Macrophages

Cited by 13 publications

References 38 publications

Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor

Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor

Targeting of sialoadhesin-expressing macrophages through antibody-conjugated (polyethylene glycol) poly(lactic-co-glycolic acid) nanoparticles

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

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