Cell-penetrating compounds are substances that enhance the cellular uptake of various molecular cargoes that do not easily cross the cellular membrane. The majority of cell-penetrating compounds described in the literature are cell-penetrating peptides (CPPs). This review summarizes the various structural types of cell-penetrating compounds, with the main focus on CPPs. The authors present a brief overview of the history of CPPs, discuss the various types of conjugation of CPPs to biologically active cargoes intended for cell internalization, examine the cell-entry mechanisms of CPPs, and report on the applications of CPPs in research and in preclinical and clinical studies., E. Böhmová, D. Machová, M. Pechar, R. Pola, K. Venclíková, O. Janoušková, T. Etrych., and Obsahuje bibliografii
In this review we summarize several synthetic approaches to the advanced synthesis of star-like polymer-based drug carriers. Moreover, their application as nanomedicines for therapy or the diagnosis of neoplastic diseases and their biodistribution are reviewed in detail. From a broad spectrum of star-like systems, we focus only on fully water-soluble systems, mainly based on poly(ethylene glycol) or N-(2-hydroxypropyl)methacrylamide polymer and copolymer arms and polyamidoamine dendrimers serving as the core of the star-like systems., L. Kotrchová, L. Kostka, T. Etrych., and Obsahuje bibliografii
In this work, design and synthesis of high-molecular-weight N-(2- hydroxypropyl)methacrylamide-based polymer drug delivery systems tailored for cancer therapy is summarized. Moreover, the influence of their architecture on tumor accumulation and in vivo anti-cancer efficacy is discussed. Mainly, the high-molecularweight delivery systems, such as branched, grafted, multi-block, star-like or micellar systems, with molecular weights greater than the renal threshold are discussed and reviewed in detail., L. Kostka, T. Etrych., and Obsahuje bibliografii
In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0-6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl groupterminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity., O. Lidický, M. Šírová, T. Etrych., and Obsahuje bibliografii
Nanocarriers bearing anticancer drugs are promising candidates to improve the efficacy of cancer therapy and minimize side effects. The most potent cytostatics used in the treatment of various cancers are anthracyclines, e.g. doxorubicin or pirarubicin. Recently, polymer therapeutics carrying anthracyclines have been intensively studied. The precise characterization of in vitro nanocarrier biological behavior brings a better understanding of the nanocarrier characteristics and enables prediction of the behavior of the nanocarrier during in vivo application. Advanced fluorescence detection methods, e.g. fluorescence lifetime imaging microscopy (FLIM), were successfully exploited to describe the properties of various polymeric nano-systems and contributed to a complex view of anthracyclines’ intracellular transport and DNA intercalation. Here, we report the application of a specific technique for processing FLIM images, called fluorescence pattern decomposition, to evaluate early events after doxorubicin or pirarubicin treatment of cells. Moreover, we characterized changes in the intracellular localization and release of the anthracyclines during the incubation of cells with polymer nanotherapeutics based on poly[N-(2-hydroxypropyl)- methacrylamide] (pHPMA)., J. Panek, E. Koziolova, P. Stepanek, T. Etrych, O. Janouskova., and Obsahuje bibliografii
Inflammation is a vital defense mechanism of living organisms. However, persistent and chronic inflammation may lead to severe pathological processes and evolve into various chronic inflammatory diseases (CID), e.g. rheumatoid arthritis, multiple sclerosis, multiple sclerosis, systemic lupus erythematosus or inflammatory bowel diseases, or certain types of cancer. Their current treatment usually does not lead to complete remission. The application of nanotherapeutics may significantly improve CID treatment, since their accumulation in inflamed tissues has been described and is referred to as extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS). Among nanotherapeutics, water-soluble polymer-drug conjugates may be highly advantageous in CID treatment due to the possibility of their passive and active targeting to the inflammation site and controlled release of active agents once there. The polymer-drug conjugate consists of a hydrophilic biocompatible polymer backbone along which the drug molecules are covalently attached via a biodegradable linker that enables controlled drug release. Their active targeting or bio-imaging can be achieved by introducing the cell-specific targeting moiety or imaging agents into the polymer conjugate. Here, we review the relationship between polymer conjugates and inflammation, including the benefits of the application of polymer conjugates in inflammation treatment, the anti-inflammatory activity of polymer drug conjugates and potential polymer-promoted inflammation and immunogenicity., E. Koziolová, K. Venclíková, T. Etrych., and Obsahuje bibliografii
The present review focuses on the description of the design, synthesis and physico-chemical and biological evaluation of polymer nanogels. Nanogels are robust swollen cross-linked polymer nanoparticles that can be used as highly efficient and biodegradable carriers for the transport of drugs in controlled drug delivery. In this article, various types of nanogels are described and methods for their preparation discussed. The possibility of using synthesized nanosystems for targeting are reviewed to show the potential of tailored structures to reach either solid tumor tissue or direct tumor cells. Finally, the methods for encapsulation or attachment of biologically active molecules, e.g. drugs, proteins, are described and compared., J. Kousalová, T. Etrych., and Obsahuje bibliografii
Novel star polymers based on the water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer and cyclodextrin were synthesized and the physico-chemical behavior of these precursors was studied. Semitelechelic HPMA copolymers were grafted onto the cyclodextrin core, thus forming star-like structure. Both prepared systems were designed as possible polymer carriers for the controlled release of cytostatic drugs, which after the drug release and degradation will be eliminated from the organism. Two synthesis approaches were used to obtain similar polymer carriers with different degradation rates. All the polymers were prepared by reversible additionfragmentation chain-transfer polymerization, which guarantees low dispersity of the prepared systems., L. Kotrchová, T. Etrych., and Obsahuje bibliografii
Cytarabine is one of the most efficient drugs in the treatment of hematological malignancies. In this work, we describe the synthesis and characterization of two different polymer conjugates of cytarabine that were designed for the controlled release of cytarabine within the leukemia cells. Reactive copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA) and 3-(3-methacrylamidopropanoyl)thiazolidine-2-thione) or 3-(Nmethacryloylglycyl- phenylalanylleucylglycyl)thiazolidine-2-thione were used in the study as reactive polymer precursors for reaction with cytarabine. The enzymatic release of cytarabine from the conjugate containing a GFLG spacer utilizing cathepsin B was verified. In addition to enzymolysis, the pH-dependent hydrolysis of cytarabine from both copolymers was also confirmed. Approximately 40 % and 20 % of the drug was released by spontaneous hydrolysis at pH 7.4 within 72 h from the polymer conjugates with the GFLG and β-Ala spacers, respectively. At pH 6.0, the spontaneous hydrolysis slowed down, and less than 10 % of the drug was liberated within 72 h. The results of the cytotoxicity evaluation of the polymer conjugates in vitro against various cell lines showed that the cytotoxicity of the polymer conjugates is approximately three times lower in comparison to free cytarabine., R. Pola, O. Janoušková, T. Etrych., and Obsahuje bibliografii