Enhancement of temozolomide stability by loading in chitosan-carboxylated polylactide-based nanoparticles

Martino, Antonio Di; Kucharczyk, Pavel; Capáková, Zdenka; Humpolíček, Petr; Sedlařík, Vladimír

doi:10.1007/s11051-017-3756-3

Cited by 33 publications

(17 citation statements)

References 60 publications

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“…Stabilization of TMZ's core to achieve a longer plasma half-life could enable a dosing regimen with the same treatment benefits, but without negatively impacting the patient's quality of life. TMZ has previously been stabilized by loading it onto functionalized nanoparticles, nanoliposomes, or nanotubes, resulting in a more effective chemotherapeutic in various tested models (12)(13)(14)(15)(16)(17)(18)(19)(20). However, nanoparticles have numerous drawbacks that reduce their clinical potential, such as generally low drug-loading efficiencies, undefined toxicity profiles, and a high production cost (21).…”

Section: Introductionmentioning

confidence: 99%

Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma

Renziehausen

Tsiailanis

Perryman

et al. 2019

Molecular Cancer Therapeutics

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The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumor in adults. However, its poor stability and unfavorable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and used 1 H-NMR, LC-MS, and UV-Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and European Medicines Agency guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix in vivo. The therapeutic efficacy of TMZ@Calix was compared with that of unbound TMZ in GBM cell lines and patient-derived primary cells with known O6-methylguanine-DNA methyltransferase (MGMT) expression status and in vivo in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient-derived primary lines expressing MGMT and highly resistant to TMZ. In vivo, native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced threefold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance, serving as an inexpensive and highly efficient treatment that could be made readily available to patients with GBM and warrants further preclinical and clinical evaluation.

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Section: Introductionmentioning

confidence: 99%

Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma

Renziehausen

Tsiailanis

Perryman

et al. 2019

Molecular Cancer Therapeutics

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“…This result supports the previous suggestion of TMZ interacting with Trp-214 in domain II of HSA. The complexation of TMZ to other macromolecules and nanoparticles has also been reported to enhance drug stability, with decomposition kinetics slower than that of free TMZ [1,77,78]. This result could explain the different decomposition half-lives reported in the literature, for TMZ at 37 • C in buffer (1 h) and blood plasma (1.8 h) [3,6].…”

Section: Stability Of Tmz-hsa Complexmentioning

confidence: 99%

The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug

et al. 2020

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The interaction of temozolomide (TMZ) (the main chemotherapeutic agent for brain tumors) with blood components has not been studied at the molecular level to date, even though such information is essential in the design of dosage forms for optimal therapy. This work explores the binding of TMZ to human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), as well as to blood cell-mimicking membrane systems. Absorption and fluorescence experiments with model membranes indicate that TMZ does not penetrate into the lipid bilayer, but binds to the membrane surface with very low affinity. Fluorescence experiments performed with the plasma proteins suggest that in human plasma, most of the bound TMZ is attached to HSA rather than to AGP. This interaction is moderate and likely mediated by hydrogen-bonding and hydrophobic forces, which increase the hydrolytic stability of the drug. These experiments are supported by docking and molecular dynamics simulations, which reveal that TMZ is mainly inserted in the subdomain IIA of HSA, establishing π-stacking interactions with the tryptophan residue. Considering the overexpression of albumin receptors in tumor cells, our results propose that part of the administered TMZ may reach its target bound to plasma albumin and suggest that HSA-based nanocarriers are suitable candidates for designing biomimetic delivery systems that selectively transport TMZ to tumor cells.

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“…For these reasons, previous works have already demonstrated the possibility of stabilizing TMZ through its encapsulation in both nanoparticles and nanoliposomes [ 76 , 77 ]. Among the many possibilities, the encapsulation of TMZ in amphiphilic nanoparticles demonstrates greater stability compared to the free drug, based on chitosan and polylactic enriched with carboxy acids [ 78 ].…”

Section: Application Of Calixarene On Cancer Therapymentioning

confidence: 99%

Role of Calixarene in Chemotherapy Delivery Strategies

et al. 2021

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Since cancer is a multifactorial disease with a high mortality rate, the study of new therapeutic strategies is one of the main objectives in modern research. Numerous chemotherapeutic agents, although widely used, have the disadvantage of being not very soluble in water or selective towards cancerous cells, with consequent side effects. Therefore, in recent years, a greater interest has emerged in innovative drug delivery systems (DDSs) such as calixarene, a third-generation supramolecular compound. Calixarene and its water-soluble derivatives show good biocompatibility and have low cytotoxicity. Thanks to their chemical–physical characteristics, calixarenes can be easily functionalized, and by itself can encapsulate host molecules forming nanostructures capable of releasing drugs in a controlled way. The encapsulation of anticancer drugs in a calixarene derivate improves their bioavailability and efficacy. Thus, the use of calixarenes as carriers of anticancer drugs could reduce their side effects and increase their affinity towards the target. This review summarizes the numerous research advances regarding the development of calixarene nanoparticles capable of encapsulating various anticancer drugs.

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Enhancement of temozolomide stability by loading in chitosan-carboxylated polylactide-based nanoparticles

Cited by 33 publications

References 60 publications

Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma

Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma

The Interaction of Temozolomide with Blood Components Suggests the Potential Use of Human Serum Albumin as a Biomimetic Carrier for the Drug

Role of Calixarene in Chemotherapy Delivery Strategies

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