Hyaluronic acid/polyethylene glycol nanoparticles for controlled delivery of mitoxantrone

Abstract

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.

CD44 as a tumor biomarker and therapeutic target

“…For instance, HA-coated cationic liposomes containing cabazitaxel (a tumor cell inhibitor) and silibinin (a CSC inhibitor), displayed enhanced cytotoxicity with low IC50, hampered cell migration, and triggered apoptosis among human prostate tumor cells with CD44 expression [147]. HA-coated nanoparticles containing anti-tumor drugs could also target CD44-positive cancer cells with high specialization and efficient drug delivery, refining the current anticancer management [148][149][150][151][152][153]. It has been observed that a rationally designed nanosystem containing gold nanostar/siRNA of heat shock protein 72/HA is endowed with the property of selectively sensitizing CD44-positive TNBC cells to hyperthermia, and improves the therapeutic accuracy and efficacy to TNBC with decreased unpleasant side effects both in vitro and in vivo [153].…”

Hierarchical Drug Release Designed Au @PDA-PEG-MTX NPs for Targeted Delivery to Breast Cancer with Combined Photothermal-chemotherapy

“…In vitro MTX release pattern from Au @PDA-PEG-MTX NPs Au @ The PDA-PEG-MTX NPs bioconjugate was dissolved in 10 mL phosphate buffer solution (20 mM) with pH 5.4 and 7.4, and the solution system was placed in a ready-to-use dialysis bag with a molecular weight cut-off of 1 kda. At the same time, add protease (1 mg/ml) to the phosphate buffer to cleave the amide bond between MTX and PEG [35]. At the speci ed time point, 500μl of the dialyzed solution was collected to obtain the released MTX, and the absorbance was measured at 305 nm by ultraviolet-visible spectroscopy (UV-vis, PerkinElmer, Singapore) [36].…”

Utilização de antibióticos quimioterápicos na oncológica de pequenos animais: Revisão

“…A MIT é uma antraciclina sintética com mecanismo de ação similar à DOX, pela da quebra na fita dupla de DNA, formando um complexo entre o DNA e a enzima topoisomerase II, inibindo assim a replicação de DNA e transcrição de RNA (Rossato et al, 2013;Sargazi et al, 2018). Os efeitos citotóxicos da MIT em células saudáveis como mielossupressão, cardiotoxicidade e alteração em membranas mucosas são mais brandos se comparados àqueles observados na utilização de DOX (Liu et al, 2016;Liu et al, 2018;Wang et al, 2016).…”

“…A aplicação de DOX conjugada a nanopartículas de ouro demonstra potencial para administração intratumoral como alternativa a aplicação intravenosa clássica, reduzindo assim os riscos sistêmicos de toxicidade e permitindo uma maior concentração da droga no local definido (Zabielska-Koczywąs & Lechowski, 2017). Sargazi et al (2018) sugerem que a administração de MIT associada à nanopartículas poliméricas como o polietilenoglicol e ácido hialurônico demonstram maior estabilidade, biocompatibilidade, podendo permanecer no interior de células neoplásicas devido ao efeito de permeabilidade e retenção, e menor toxicidade se comparado aos efeitos da MIT em sua forma convencional. Além disso, sua utilização demonstra maior eficácia antineoplásica e capacidade de ativação através de direcionamento das partículas diretamente às células neoplásicas (Sargazi et al, 2018).…”