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1.
Molecules ; 20(11): 19849-64, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26556320

RESUMO

Here we describe the synthesis and biological properties of two types of star-shaped polymer-doxorubicin conjugates: non-targeted conjugate prepared as long-circulating high-molecular-weight (HMW) polymer prodrugs with a dendrimer core and a targeted conjugate with the anti-CD20 monoclonal antibody (mAb) rituximab (RTX). The copolymers were linked to the dendrimer core or to the reduced mAb via one-point attachment forming a star-shaped structure with a central antibody or dendrimer surrounded by hydrophilic polymer chains. The anticancer drug doxorubicin (DOX) was attached to the N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer chain in star polymer systems via a pH-labile hydrazone linkage. Such polymer-DOX conjugates were fairly stable in aqueous solutions at pH 7.4, and the drug was readily released in mildly acidic environments at pH 5-5.5 by hydrolysis of the hydrazone bonds. The cytotoxicity of the polymer conjugates was tested on several CD20-positive or negative human cell lines. Similar levels of in vitro cytotoxicity were observed for all tested polymer conjugates regardless of type or structure. In vivo experiments using primary cell-based murine xenograft models of human diffuse large B-cell lymphoma confirmed the superior anti-lymphoma efficacy of the polymer-bound DOX conjugate when compared with the original drug. Targeting with RTX did not further enhance the anti-lymphoma efficacy relative to the non-targeted star polymer conjugate. Two mechanisms could play roles in these findings: changes in the binding ability to the CD-20 receptor and a significant loss of the immunological properties of RTX in the polymer conjugates.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Polímeros , Pró-Fármacos , Rituximab/química , Rituximab/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Linfoma/tratamento farmacológico , Linfoma/mortalidade , Linfoma/patologia , Camundongos , Polímeros/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
ACS Omega ; 8(43): 40508-40516, 2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37929096

RESUMO

Protein conjugates have found applications in a wide variety of fields, ranging from therapeutics to imaging and detection. However, robust control over the parameters of the conjugation process (such as sites and degree of conjugation) remains challenging. Previously, our group introduced Equimolar NAtive Chemical Tagging (ENACT), a method which allows for the monofunctionalization of proteins by combining an iterative low-conversion bioconjugation, an automated process, and a bioorthogonal trans-tagging reaction. However, while the automated ENACT was dimensioned to achieve monoconjugation at the mg scale, in early stage research, because of the rarity and cost of the starting materials, it is often necessary to prepare conjugates at the lower, µg, scale. Here, we introduce modified ENACT protocols, as well as a new ENACT conjugation reagent, which allow for the monofunctionalization of proteins on the micrograms scale, using minimal quantities of payload.

3.
J Control Release ; 337: 546-556, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34375687

RESUMO

Obstructed blood flow and erratic blood supply in the tumor region attenuate the distribution and accumulation of nanomedicines in the tumor. Therefore, improvement of these conditions is crucial for efficient drug delivery. In this study, we designed and synthesized a novel N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymer conjugate of BK, which possessed adequate systemic stability and tumor-selective action required to improve the accumulation of nanomedicines in the tumor. Levulinoyl-BK (Lev-BK) was conjugated to an HPMA-based polymer via an acid-cleavable hydrazone bond (P-BK). An acid-responsive release of Lev-BK from P-BK was observed, and P-BK alone after intradermal application showed below 10% of the BK activity, thus proving a reduction in the vascular permeability activity of BK when attached to the polymer carrier. P-BK pre-treatment improved blood flow in the tumor tissue by 1.4-1.7-fold, which was maintained for more than 4 h. In addition, P-BK pre-treatment increased the tumor accumulation of pegylated liposomal doxorubicin (PLD) by approximately 3-fold. Furthermore, P-BK pre-treatment led to superior antitumor activity of PLD and significantly improved the survival of tumor-bearing mice. The release of BK from P-BK in the acidic milieu of the tumor was a prerequisite for P-BK to exert its effect, as the vascular permeability enhancing activity of P-BK was negligible. Collectively, P-BK pre-treatment improved intratumoral blood flow and augmented tumor accumulation of nanomedicine, thereby resulting in a significant suppression of tumor growth. Therefore, these findings demonstrate that P-BK is a potential concomitant drug for improving the tumor delivery of nanomedicines.


Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/uso terapêutico , Bradicinina/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Portadores de Fármacos/uso terapêutico , Metacrilatos , Camundongos , Nanomedicina , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico
4.
J Control Release ; 328: 160-170, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-32860930

RESUMO

B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.


Assuntos
Antineoplásicos , Linfoma não Hodgkin , Preparações Farmacêuticas , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Polímeros/uso terapêutico , Rituximab
5.
J Control Release ; 289: 44-55, 2018 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-30248447

RESUMO

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.


Assuntos
Antineoplásicos/química , Doxorrubicina/química , Corantes Fluorescentes/química , Linfoma/diagnóstico por imagem , Linfoma/tratamento farmacológico , Nanocápsulas/química , Acrilamidas/química , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros/química , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Xenoenxertos , Humanos , Hidrazonas/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Linfoma/patologia , Metacrilatos/química , Camundongos , Polimerização , Polímeros/química
6.
J Control Release ; 246: 1-11, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-27940304

RESUMO

The tumor-specific targeting of cancerostatics using polymer drug carriers represents a potential strategy to achieve an effective treatment with reduced side toxicity. Synthetic water-soluble copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) are carriers with tunable architecture and drug loading, tumor-specific accumulation of the drug, and its controlled release. We describe a combination treatment of murine EL4 T cell lymphoma with HPMA-based star conjugates (Mw 250,000gmol-1) of doxorubicin (Dox) or docetaxel (Dtx) designed for enhanced tumor accumulation and combination therapy. Although the combination of linear conjugates (Mw=28,000gmol-1) containing Dox or Dtx resulted in an additive effect in the treatment of the lymphoma, the opposite was observed in the combination of two star conjugates with Dox or Dtx, as the star Dtx conjugate decreased the treatment efficacy of the star Dox conjugate. The Dtx conjugate alone was virtually ineffective in the reduction of tumor growth or survival time extension; thus, a curative effect could be solely attributed to the Dox-containing conjugate. When Dtx was delivered to the tumor on the same polymer carrier as Dox, the efficacy of the Dox-induced treatment was reduced to a lesser extent. No reduction was found when Dtx was delivered by a linear polymer or applied as a free drug. The phenomenon was strictly related to the enhanced permeability and retention (EPR) effect, as it was not observed in BCL1 leukemia, a model without EPR. The diminished treatment outcome in the combination therapy with the two star conjugates was underlined by the significantly decreased accumulation of Dox in the tumor. The use of the drug-free polymer carrier instead of the Dtx-containing star conjugate did not reduce the treatment efficacy of the Dox conjugate. Thus, the physicochemical characteristics of the polymer carrier designed for tumor-specific drug delivery systems control the activity of the respective drug, leading to changes within the tumor microenvironment that can determine ultimate efficacy of the combination therapy.


Assuntos
Acrilamidas/química , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Taxoides/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Docetaxel , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Taxoides/química , Taxoides/farmacocinética , Taxoides/uso terapêutico
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