RESUMO
As an emerging research direction, nanomedicine has been increasingly utilized to treat inflammatory diseases. In this head-to-head comparison study, four established nanomedicine formulations of dexamethasone, including liposomes (L-Dex), core-cross-linked micelles (M-Dex), slow releasing polymeric prodrugs (P-Dex-slow), and fast releasing polymeric prodrugs (P-Dex-fast), were evaluated in an adjuvant-induced arthritis rat model with an equivalent dose treatment design. It was found that after a single i.v. injection, the formulations with the slower drug release kinetics (i.e., M-Dex and P-Dex-slow) maintained longer duration of therapeutic activity than those with relatively faster drug release kinetics, resulting in better joint protection. This finding will be instructional in the future development and optimization of nanomedicines for the clinical management of rheumatoid arthritis. The outcome of this study also illustrates the value of such head-to-head comparison studies in translational nanomedicine research.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite/tratamento farmacológico , Dexametasona/uso terapêutico , Lipossomos , Micelas , Nanomedicina , Polímeros , Absorciometria de Fóton , Animais , Densidade Óssea , Ratos , Microtomografia por Raio-XRESUMO
Synthesis, physicochemical and biological properties and preliminary anticancer activity of new star-shaped polymer-doxorubicin (DOX) conjugates targeted with anti-CD20 monoclonal antibody were investigated. Mild reduction of antibody (Ab) with dithiothreitol (DTT) resulted in introduction of thiol groups into Ab. Polymer precursors used for the synthesis of the conjugates were based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with a functional group at the polymer chain end. The copolymers were linked to the thiol groups of the reduced Ab via one-point attachment forming a star-shaped structure with central antibody surrounded by hydrophilic polymer chains. Neither reduction nor polymer modification of Ab influenced binding activity of the Ab to its specific cancer cell membrane antigen as it was confirmed in vitro by standard flow cytometry. The anticancer drug DOX was attached to the HPMA copolymer chain in an Ab-polymer system via a pH-labile hydrazone linkage or via an oligopeptide sequence degradable by lysosomal enzymes. Such Ab-polymer-DOX conjugates were fairly stable in aqueous solution at pH 7.4 and the drug was readily released in mildly acid environment at pH 5-5.5 by hydrolysis of hydrazone bond or more slowly by enzymolysis with lysosomal enzymes. The cytostatic activity of the anti-CD20 monoclonal Ab-targeted conjugates tested on several CD20-positive or negative human and mouse cancer cell lines confirmed considerable targeting capacity of the monoclonal Ab after its binding to the polymer carrier. New method of synthesis of star antibody-targeted polymer-drug conjugates with pH-controlled drug release described in this paper opens new perspectives for development of new therapeutics intended for cancer therapy.
Assuntos
Citostáticos/metabolismo , Portadores de Fármacos/síntese química , Sistemas de Liberação de Medicamentos , Metacrilatos/química , Polímeros/química , Acrilamidas/química , Animais , Antibióticos Antineoplásicos/química , Anticorpos Monoclonais/imunologia , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/química , Portadores de Fármacos/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/metabolismo , Masculino , Camundongos , Modelos Químicos , Peso Molecular , Solubilidade , Água/químicaRESUMO
Copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) are prototypic and well-characterized polymeric drug carriers that have been broadly implemented in the delivery of anticancer therapeutics. In an attempt to improve the tumor accumulation of HPMA copolymer-based drug delivery systems, their in vivo application was combined with radiotherapy and hyperthermia. As the effects of radiotherapy and hyperthermia were considered to depend significantly on the tumor model used, we first analyzed the accumulation of two differently sized HPMA copolymers in three different types of tumors, based on the syngeneic Dunning rat prostate carcinoma model. Subsequently, in these three models, the effects of different doses of radiotherapy and hyperthermia on the tumor accumulation of 31 kDa poly(HPMA), 65 kDa poly(HPMA) and 28 kDa poly(HPMA)-GFLG-doxorubicin were evaluated. It was found that the polymeric drug delivery systems accumulated effectively in all three tumor models. In addition, as opposed to hyperthermia, radiotherapy was found to improve the concentrations of the copolymers independent of the tumor model used. Based on these findings, we conclude that radiotherapy is an effective means for increasing the tumor accumulation of (polymeric) drug delivery systems, and we propose that the combination of carrier-based chemotherapy with radiotherapy holds significant potential for improving the treatment of advanced solid malignancies.