Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon.

• Klíčová slova
• Acid-cleavable linkage, Chemical carcinogenesis, Controlled drug release, Dendrimer-derived polymer conjugate, EPR effect, HPMA polymer conjugate, Pirarubicin (THP),
• MeSH
• berberinové alkaloidy chemie   farmakokinetika   MeSH
• dendrimery chemie   farmakokinetika   MeSH
• doxorubicin analogy a deriváty   chemie   farmakokinetika   farmakologie   MeSH
• HeLa buňky MeSH
• lidé MeSH
• melanom experimentální MeSH
• methakryláty chemie   farmakokinetika   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• nosiče léků chemie   farmakokinetika   MeSH
• polymery chemie   farmakokinetika   MeSH
• protinádorové látky chemie   farmakokinetika   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2,3,10,11-tetrahydroxytetrahydroprotoberberine MeSH Prohlížeč
• berberinové alkaloidy MeSH
• dendrimery MeSH
• doxorubicin MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• nosiče léků MeSH
• PAMAM Starburst MeSH Prohlížeč
• pirarubicin MeSH Prohlížeč
• polymery MeSH
• protinádorové látky MeSH

A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer via a benzylthiourea linkage. The Gd(III) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3+via three nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere. The monomer Gd(III) chelates bearing nitrobenzyl and aminobenzyl groups ([Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-) as well as the dendrimeric Gd(III) complex G5-(Gd(DTTAP))63) were studied by multiple-field, variable temperature 17O and 1H NMR. The rate of water exchange is faster than that of [Gd(DTPA)(H2O)]2- and very similar on the two monomeric complexes (8.9 and 8.3 x 10(6) s-1 for [Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-, respectively), while it is decreased on the dendrimeric conjugate (5.0 x 10(6) s-1). The Gd(III) complex of the dendrimer conjugate has a relaxivity of 26.8 mM-1 s-1 at 37 degrees C and 0.47 T (corresponding to 1H Larmor frequency of 20 MHz). Given the contribution of the second sphere water molecules to the overall relaxivity, this value is slightly higher than those reported for similar size dendrimers. The experimental 17O and 1H NMR data were fitted to the Solomon-Bloembergen-Morgan equations extended with a contribution from second coordination sphere water molecules. The rotational dynamics of the dendrimeric conjugate was described in terms of global and local motions with the Lipari-Szabo approach.

• MeSH
• chelátory chemická syntéza   MeSH
• dendrimery MeSH
• fosfiny chemie   MeSH
• gadolinium chemie   MeSH
• indikátory a reagencie MeSH
• izotopy kyslíku chemie   MeSH
• kyselina pentetová analogy a deriváty   chemická syntéza   MeSH
• luminiscence MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární konformace MeSH
• polyaminy chemie   MeSH
• rozpouštědla MeSH
• vodík chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• dendrimery MeSH
• fosfiny MeSH
• gadolinium MeSH
• indikátory a reagencie MeSH
• izotopy kyslíku MeSH
• kyselina pentetová MeSH
• PAMAM Starburst MeSH Prohlížeč
• polyaminy MeSH
• rozpouštědla MeSH
• vodík MeSH

The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.

• MeSH
• chemorezistence MeSH
• cytostatické látky * MeSH
• doxorubicin farmakologie   MeSH
• inhibitory proteas farmakologie   MeSH
• myši MeSH
• nádory * MeSH
• nanomedicína MeSH
• polymery MeSH
• ritonavir MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytostatické látky * MeSH
• doxorubicin MeSH
• inhibitory proteas MeSH
• polymery MeSH
• ritonavir MeSH

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.

• Klíčová slova
• Doxorubicin, Drug delivery systems, Drug targeting, HPMA copolymers, Malignant lymphoma, Theranostics,
• MeSH
• akrylamidy chemie   MeSH
• dendrimery chemie   MeSH
• doxorubicin chemie   terapeutické užití   MeSH
• fluorescenční barviva chemie   MeSH
• heterografty MeSH
• hydrazony chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lymfom diagnostické zobrazování   farmakoterapie   patologie   MeSH
• methakryláty chemie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanokapsle chemie   MeSH
• polymerizace MeSH
• polymery chemie   MeSH
• protinádorové látky chemie   terapeutické užití   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• dendrimery MeSH
• doxorubicin MeSH
• fluorescenční barviva MeSH
• hydrazony MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
• nanokapsle MeSH
• polymery MeSH
• protinádorové látky MeSH

Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120-CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers' mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection.

• Klíčová slova
• HIV, carbosilane dendrimer, mechanism, microbicide, nanotechnology,
• MeSH
• antivirové látky chemie   farmakologie   MeSH
• dendrimery chemie   MeSH
• fúze membrán účinky léků   MeSH
• HIV infekce prevence a kontrola   virologie   MeSH
• HIV obalový protein gp120 antagonisté a inhibitory   chemie   metabolismus   MeSH
• HIV-1 účinky léků   MeSH
• lidé MeSH
• molekulární modely MeSH
• polyelektrolyty MeSH
• polymery chemie   MeSH
• replikace viru účinky léků   MeSH
• silany chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• carbosilane MeSH Prohlížeč
• dendrimery MeSH
• HIV obalový protein gp120 MeSH
• polyanions MeSH Prohlížeč
• polyelektrolyty MeSH
• polymery MeSH
• silany MeSH