Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389013%3A_____%2F18%3A00493938" target="_blank" >RIV/61389013:_____/18:00493938 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/18:10382062 RIV/00064165:_____/18:10382062

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.jconrel.2018.09.018" target="_blank" >http://dx.doi.org/10.1016/j.jconrel.2018.09.018</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jconrel.2018.09.018" target="_blank" >10.1016/j.jconrel.2018.09.018</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging

Popis výsledku v původním jazyce

In this study, we report the in vivo anti-lymphoma efficacy and diagnostic potential of newly designed near-infrared fluorescent dye containing polymer-doxorubicin conjugates using murine models of malignant lymphomas including one cell line-derived xenograft (RAJI) and two patient-derived lymphoma xenografts (VFN-D1 and VFN-M2). Two types of passively targeted conjugates differing in architecture of the polymer backbone were synthesized. One of the conjugates was designed using a single linear polymer chain, and the second was more sophisticated with a star-shaped high-molecular-weight (HMW) polymer employing a dendrimer core. The linear HPMA copolymers were linked to the dendrimer core via a one-point attachment, thus forming a hydrophilic polymer shell. Both polymer-doxorubicin conjugates were long-circulating with reduced side effects. Both polymer prodrugs were designed as stimuli-sensitive systems in which the anti-cancer drug doxorubicin was attached to the hydrophilic copolymers via a pH-labile hydrazone linkage. Such polymer prodrugs were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acid environments at pH 5–6.5 by hydrolysis of the hydrazone bonds. In addition, polymers were labelled with near-infrared fluorescent dye enabling long term in vivo visualization. Malignant lymphomas represent the most common type of haematological malignancies. Therapy for the majority of malignant lymphomas consists of multi-agent chemotherapy based on an anthracycline doxorubicin, the most prominent side effect of which is cardiotoxicity. We have demonstrated significant anti-lymphoma efficacy of the polymer-doxorubicin conjugates when compared to equally toxic doses of conventional (unbound) doxorubicin in all tested models. Favourable pharmacokinetics for carried drug and labelled polymer carrier was observed, showing predominant uptake of the drug and polymer itself in the tumour mass. In addition, we have observed a promising diagnostic potential of fluorescently labelled polymer prodrugs. Dynamically analyzed fluorescence intensity over subcutaneously xenografted lymphomas closely corresponded to changes in the lymphoma tumour volumes, thereby enabling a non-invasive assessment of treatment efficacy

Název v anglickém jazyce

Effective doxorubicin-based nano-therapeutics for simultaneous malignant lymphoma treatment and lymphoma growth imaging

Popis výsledku anglicky

In this study, we report the in vivo anti-lymphoma efficacy and diagnostic potential of newly designed near-infrared fluorescent dye containing polymer-doxorubicin conjugates using murine models of malignant lymphomas including one cell line-derived xenograft (RAJI) and two patient-derived lymphoma xenografts (VFN-D1 and VFN-M2). Two types of passively targeted conjugates differing in architecture of the polymer backbone were synthesized. One of the conjugates was designed using a single linear polymer chain, and the second was more sophisticated with a star-shaped high-molecular-weight (HMW) polymer employing a dendrimer core. The linear HPMA copolymers were linked to the dendrimer core via a one-point attachment, thus forming a hydrophilic polymer shell. Both polymer-doxorubicin conjugates were long-circulating with reduced side effects. Both polymer prodrugs were designed as stimuli-sensitive systems in which the anti-cancer drug doxorubicin was attached to the hydrophilic copolymers via a pH-labile hydrazone linkage. Such polymer prodrugs were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acid environments at pH 5–6.5 by hydrolysis of the hydrazone bonds. In addition, polymers were labelled with near-infrared fluorescent dye enabling long term in vivo visualization. Malignant lymphomas represent the most common type of haematological malignancies. Therapy for the majority of malignant lymphomas consists of multi-agent chemotherapy based on an anthracycline doxorubicin, the most prominent side effect of which is cardiotoxicity. We have demonstrated significant anti-lymphoma efficacy of the polymer-doxorubicin conjugates when compared to equally toxic doses of conventional (unbound) doxorubicin in all tested models. Favourable pharmacokinetics for carried drug and labelled polymer carrier was observed, showing predominant uptake of the drug and polymer itself in the tumour mass. In addition, we have observed a promising diagnostic potential of fluorescently labelled polymer prodrugs. Dynamically analyzed fluorescence intensity over subcutaneously xenografted lymphomas closely corresponded to changes in the lymphoma tumour volumes, thereby enabling a non-invasive assessment of treatment efficacy

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10404 - Polymer science

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Journal of Controlled Release

ISSN

0168-3659

e-ISSN

—

Svazek periodika

289

Číslo periodika v rámci svazku

10 November

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

44-55

Kód UT WoS článku

000448396000006

EID výsledku v databázi Scopus

2-s2.0-85054018077