Hyaluronic acid/polyethylene glycol nanoparticles for controlled delivery of mitoxantrone.

Hyaluronic acid (HA) has inherent ability to target the CD44 receptors and internalize into tumour cells via receptor-mediated endocytosis. Therefore, conjugation of this natural linear polysaccharide to polymeric NPs or micelles, as one of the most promising approaches, could be useful for future clinical applications such as drug delivery. Accordingly, we report on the synthesis of mitoxantrone (MTX)-conjugated polymeric nanoparticles (NPs) composed of polyethylene glycol-HA (PEG-HA) for MTX delivery toward special tumour cells. To determine the size of the polymeric NPs, field emission scanning electron microscopy (FESEM) and particle size analyzer system Zetasizer_nanoZS were employed. The in vitro cytotoxicity analysis of MTX-loaded HA-PEG NPs and free MTX against two cell lines with different levels of CD44 expression (MDA-MB-231 (very high) and MCF-7 (low) was conducted by MTT assay. Also, computational molecular docking was employed to study in detail the active site residues and the critical interactions between HA-EDA-PEG-EDA-MTX NPs and CD44 receptor. The particle size analysis and electron microscopy showed the average size of polymeric NPs less than 350 nm. FT-IR spectrophotometry analysis and also NMR confirmed the conjugation of HA and MTX onto the PEG. Cytotoxicity assay revealed that the engineered polymeric NPs were able to specifically bind to and significantly inhibit the CD44 receptor-positive MDA-MB-231 cells, but not the CD44-negative MCF-7 cells. Furthermore, analysis of the binding modes revealed that for the best-docked pose nearly 10 conventional hydrogen bond can occur between the MTX-EDA-PEG-EDA-HA NPs and amino acids of CD44 receptor. Based on these findings, we suggest the HA-PEG-MTX NPs as an effective functional-targeted nanomedicine toward therapy of CD44-positive cancers.

Hyaluronan magnetic nanoparticle for mitoxantrone delivery toward CD44-positive cancer cells.

Hyaluronic acid (HA) is increasingly investigated for biomedical applications such as regenerative medicine, aesthetic medicine, and drug delivery. Accordingly, conjugation of HA to PEGylated MNPs could increase the active targeting ability of nano-drug carriers toward CD44 receptors and be useful in a clinical setting such as drug delivery. So, we chemically conjugated mitoxantrone (MTX) to HA-PEGylated MNPs to use concurrent advantages such as prolong the circulation time, decrease the side effects and delivery toward special tumor cells. Size of the Fe3O4-DPA-PEG-HA-MTX NPs was determined ∼200 nm utilizing FESEM and DLS. Stability analysis confirmed that prepared MNPs were stable in physiological conditions even after 8 days and only 47.3% of MTX was liberated from nanocarriers, in the event that, acidic condition and also presence of protease enzyme accelerated the amount of MTX release to 100% after 8 days of incubation. The in vitro cytotoxicity analysis by MTT assay revealed that viable cell numbers were reduced by 32% when MTX-HA-MNPs were applied against MDA-MB-231 cell lines, while they showed significant decreased cellular cytotoxic effects on cell viability in the MCF-7 cell lines which express lower levels of CD44 receptor at the cell surface. Also, results of flow cytometry analysis following 24 h exposure confirmed that MTX-HA-MNPs have significant induction of apoptosis in MDA-MB-231 cell lines (70.3%) which contains high levels of CD44 expression, whereas there was little effect on the induction of apoptosis in MCF-7 cell lines (5%). The obtained binding models through molecular docking simulation related to each single moieties of prepared MNPs clearly confirmed that MTX-HA-MNPs can easily be bonded to the CD44 receptor with more affinity value in comparison to HA ligand, and so conjugation of HA to MNPs can be a good way for MTX delivery toward special tumor cells or tissues.

Evaluation of host-guest system to enhance the tamoxifen efficiency.

Hydrophobic drugs can absorb as guest molecules inside the cavity of cyclodextrins as host sites. So, forming the drug-cyclodextrin complex can exert a profound effect on the physicochemical and biological properties of the drugs. According to these advantages, in this study, we synthesized the tamoxifen (TMX) loaded cyclodextrin (CD)-conjugated MNPs to evaluate simultaneously the cytotoxicity and sustained release as well as hepatoprotective effect of this nanomedicine. The average size of Fe3O4-DPA-PEG-CD-TMX NPs was approximately 31 nm. By energy-dispersive X-ray spectroscopy (EDS), it was revealed that Fe3O4 constitutes 14.34% of the composition of modified MNPs. In the other words, nearly 85% of Fe3O4-DPA-PEG-CD NPs are made of dopamine (DPA), polyethylene glycol (PEG) and ß-cyclodextrin (ß-CD). The TMX loaded MNPs (with entrapment efficiency of 33 mg TMX per unit CD (mg) and loading efficiency of 87.5%) showed sustained liberation of TMX molecules (with 91% release in 120 h). Cytotoxicity assay and apoptosis assay by TUNEL analysis revealed that the engineered Fe3O4-DPA-PEG-CD-TMX NPs were able to significantly inhibit the MCF-7 breast cancer cells. According to effect of CD on TMX sustained release, it was found that CD can decrease the hepatotoxicity induced by TMX nearly 30%. Based upon these findings, we suggest the Fe3O4-DPA-PEG-CD-TMX NPs as an effective multifunctional nanomedicine with simultaneous therapeutic and hepatoprotective effects.