Abstract:Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood–brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-… Show more
“…3 C, * p < 0.05, ** p < 0.01 and **** p < 0.0001). This observation confirms the pH-sensitivity of the prodrug micelles ( Chu et al, 2022 ; Malfanti et al, 2022 ). Fig.…”
Section: Resultssupporting
confidence: 84%
“…Previous results highlighted how C12 chain can enhance the cytotoxicity of drugs in the context of GBM treatment ( Bastiancich et al, 2019 ). The hydrazone-based linking chemistry used to prepare DOXC 12 has been selected due to its easy preparation method, pH sensitivity allowing DOX release without forming a new chemical entity ( Malfanti et al, 2022 ; Zheng et al, 2019 ). Moreover, even though Hao et al developed TPGS 2000 micelles loaded with DOX base, DOXC 12 not only provides higher affinity to the lipophilic core of micelles but also enables DOX release by the breakage of hydrazone bond in acidic pH ( Hao et al, 2015 ).…”
Section: Resultsmentioning
confidence: 99%
“…The synthesis of DOXC 12 was carried out according to a modified procedure reported in the literature ( Malfanti et al, 2022 ). Briefly, doxorubicin hydrochloride (Chemieliva, China) (100 mg, 0.17 mmol, 1.0 eq) and dodecanoic hydrazide (ChemCruz, Netherlands) (53.5 mg, 0.25 mmol, 1.5 eq) were dissolved in methanol in a round-bottomed flask.…”
“…3 C, * p < 0.05, ** p < 0.01 and **** p < 0.0001). This observation confirms the pH-sensitivity of the prodrug micelles ( Chu et al, 2022 ; Malfanti et al, 2022 ). Fig.…”
Section: Resultssupporting
confidence: 84%
“…Previous results highlighted how C12 chain can enhance the cytotoxicity of drugs in the context of GBM treatment ( Bastiancich et al, 2019 ). The hydrazone-based linking chemistry used to prepare DOXC 12 has been selected due to its easy preparation method, pH sensitivity allowing DOX release without forming a new chemical entity ( Malfanti et al, 2022 ; Zheng et al, 2019 ). Moreover, even though Hao et al developed TPGS 2000 micelles loaded with DOX base, DOXC 12 not only provides higher affinity to the lipophilic core of micelles but also enables DOX release by the breakage of hydrazone bond in acidic pH ( Hao et al, 2015 ).…”
Section: Resultsmentioning
confidence: 99%
“…The synthesis of DOXC 12 was carried out according to a modified procedure reported in the literature ( Malfanti et al, 2022 ). Briefly, doxorubicin hydrochloride (Chemieliva, China) (100 mg, 0.17 mmol, 1.0 eq) and dodecanoic hydrazide (ChemCruz, Netherlands) (53.5 mg, 0.25 mmol, 1.5 eq) were dissolved in methanol in a round-bottomed flask.…”
“…GBM represents a high unmet need with a limited number of therapeutic agents available for treatment, therefore, it is imperative to look at potential drugs, which can be used in combination. Interestingly, doxorubicin-based nanoparticles have been reported as a novel approach to treating multidrug resistance (MDR) glioma cells [38][39][40] and improving survival in intracranial glioma orthotopic models [41]. Taken together, we considered the use of doxorubicin in combination with PYR as the best strategy to treat GBM cells in in vitro studies.…”
Glioblastoma (GBM) is an aggressive form of brain tumor with a median survival of approximately 12 months. With no new drugs in the last few decades and limited success in clinics for known therapies, drug repurposing is an attractive choice for its treatment. Here, we examined the efficacy of pyronaridine (PYR), an anti-malarial drug in GBM cells. PYR induced anti-proliferative activity in GBM cells with IC50 ranging from 1.16 to 6.82 µM. Synergistic activity was observed when PYR was combined with Doxorubicin and Ritonavir. Mechanistically, PYR triggered mitochondrial membrane depolarization and enhanced the ROS levels causing caspase-3 mediated apoptosis. PYR significantly decreased markers associated with proliferation, EMT, hypoxia, and stemness and upregulated the expression of E-cadherin. Interestingly, PYR induced the expression of intracellular as well as secretory Par-4, a tumor suppressor in GBM cells, which was confirmed using siRNA. Notably, Par-4 levels in plasma samples of GBM patients were significantly lower than normal healthy volunteers. Thus, our study demonstrates for the first time that PYR can be repurposed against GBM with a novel mechanism of action involving Par-4. Herewith, we discuss the role of upregulated Par-4 in a highly interconnected signaling network thereby advocating its importance as a therapeutic target.
“…Additionally, HA-CF/CB hydrogel has the potential to be a strong candidate for drug delivery vehicles, especially for the treatment of GB. Injections of DOX -loaded HA-CF/CB hydrogel into GB ex vivo human tissue samples showed an efficient attachment of the gel within diffusion and the release of the compound into the surrounding tissue [ 165 ]. Another system for GB treatment consisted of a polymer-drug conjugate releasing DOX which has shown a decrease in cell viability and the inhibition of the tumor growth [ 166 ].…”
Section: Ha-based Specific Device For Various Applicationsmentioning
Hyaluronic acid (HA) is a Glycosaminoglycan made of disaccharide units containing N-acetyl-D-glucosamine and glucuronic acid. Its molecular mass can reach 10 MDa and its physiological properties depend on its polymeric property, polyelectrolyte feature and viscous nature. HA is a ubiquitous compound found in almost all biological tissues and fluids. So far, HA grades are produced by biotechnology processes, while in the human organism it is a major component of the extracellular matrix (ECM) in brain tissue, synovial fluid, vitreous humor, cartilage and skin. Indeed, HA is capable of forming hydrogels, polymer crosslinked networks that are very hygroscopic. Based on these considerations, we propose an overview of HA-based scaffolds developed for brain cancer treatment, central and peripheral nervous systems, discuss their relevance and identify the most successful developed systems.
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