Thermoresponsive dicarboxy hyaluronan/phenanthriplatin nanogels with very high carrier capacity and improved anticancer efficacy

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F70883521%3A28610%2F23%3A63574298" target="_blank" >RIV/70883521:28610/23:63574298 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Thermoresponsive dicarboxy hyaluronan/phenanthriplatin nanogels with very high carrier capacity and improved anticancer efficacy

Popis výsledku v původním jazyce

One of the major drawbacks of hyaluronan {HA) is the low density of -COOH groups, which are the most convenient target for both drug attachment and other advanced modifications. Functional modifications of HA thus often have to be performed at expense of drug carrier capacity and vice versa.Here, a novel approach how to circumvent this issue is presented and the synthesis of thermoresponsive nanogels with very high carrier capacity for phenanthriplatin (Ph Pt), a next-generation platinum anticancer drug, is performed. lnitially, poly(N-isopropyl acrylamide), a thermoresponsive polymer undergoing a sol/gel transition change around 32°C, is grafted to HA carboxylic group using DMTMM. Next, regioselective sequential periodate/chlorite oxidation, only recently described by us for unmodified HA,111 is performed. Selectivity of the oxidation towards vicinal diol ensures that it runs only at C2 and C3 of the glucuronate unit of HA and grafted pNIPAM is not impacted. The resulting pNIPAM-grafted 2,3-carboxy hyaluronan {DCH-P) features pair of carboxy groups in perfect distance and orientation for the chelation of platinum anticancer complexes. DCH-P is soluble at laboratory temperature, but, when loaded with PhPt and heated to 37°C, it self-assembles into nanogels containing up to 60 wt.% of PhPt, nearly twice the maximum capacity of unmodified HA. pNIPAM sol/gel transition also slows the PhPt release rates compared to the unmodified carrier and protects carried drug.The in vitro testing revealed greatly improved anticancer efficacy of PhPt-loaded DCH-P nanogels compared to a free drug (more than l0x lower ICso for the A2780 ovarian cancer cell line; 4x lower against the MiaPaCa-2 pancreatic cancer cell line) and showed a moderate migrastatic potential.To summarize, sequential regioselective oxidation, which essentially triples the amount of carboxylic group in HA, can be used in tandem with other selective modifications to prepare various functional derivatives of HA. The DCH-P nanogel prepared by this method combines both thermoresponsivity and high drug carrier capacity into a highly promising drug delivery system, thus demonstrating the potential of this method.

Název v anglickém jazyce

Thermoresponsive dicarboxy hyaluronan/phenanthriplatin nanogels with very high carrier capacity and improved anticancer efficacy

Popis výsledku anglicky

One of the major drawbacks of hyaluronan {HA) is the low density of -COOH groups, which are the most convenient target for both drug attachment and other advanced modifications. Functional modifications of HA thus often have to be performed at expense of drug carrier capacity and vice versa.Here, a novel approach how to circumvent this issue is presented and the synthesis of thermoresponsive nanogels with very high carrier capacity for phenanthriplatin (Ph Pt), a next-generation platinum anticancer drug, is performed. lnitially, poly(N-isopropyl acrylamide), a thermoresponsive polymer undergoing a sol/gel transition change around 32°C, is grafted to HA carboxylic group using DMTMM. Next, regioselective sequential periodate/chlorite oxidation, only recently described by us for unmodified HA,111 is performed. Selectivity of the oxidation towards vicinal diol ensures that it runs only at C2 and C3 of the glucuronate unit of HA and grafted pNIPAM is not impacted. The resulting pNIPAM-grafted 2,3-carboxy hyaluronan {DCH-P) features pair of carboxy groups in perfect distance and orientation for the chelation of platinum anticancer complexes. DCH-P is soluble at laboratory temperature, but, when loaded with PhPt and heated to 37°C, it self-assembles into nanogels containing up to 60 wt.% of PhPt, nearly twice the maximum capacity of unmodified HA. pNIPAM sol/gel transition also slows the PhPt release rates compared to the unmodified carrier and protects carried drug.The in vitro testing revealed greatly improved anticancer efficacy of PhPt-loaded DCH-P nanogels compared to a free drug (more than l0x lower ICso for the A2780 ovarian cancer cell line; 4x lower against the MiaPaCa-2 pancreatic cancer cell line) and showed a moderate migrastatic potential.To summarize, sequential regioselective oxidation, which essentially triples the amount of carboxylic group in HA, can be used in tandem with other selective modifications to prepare various functional derivatives of HA. The DCH-P nanogel prepared by this method combines both thermoresponsivity and high drug carrier capacity into a highly promising drug delivery system, thus demonstrating the potential of this method.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

20903 - Bioproducts (products that are manufactured using biological material as feedstock) biomaterials, bioplastics, biofuels, bioderived bulk and fine chemicals, bio-derived novel materials

Projekt

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Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů