The development of stimuli-responsive drug delivery systems enables targeted delivery and environment-controlled drug release, thereby minimizing off-target effects and systemic toxicity. We prepared and studied tailor-made dual-responsive systems (thermo- and pH-) based on synthetic diblock copolymers consisting of a fully hydrophilic block of poly[N-(1,3-dihydroxypropyl)methacrylamide] (poly(DHPMA)) and a thermoresponsive block of poly[N-(2,2-dimethyl-1,3-dioxan-5-yl)methacrylamide] (poly(DHPMA-acetal)) as drug delivery and smart stimuli-responsive materials. The copolymers were designed for eventual medical application to be fully soluble in aqueous solutions at 25 °C. However, they form well-defined nanoparticles with hydrodynamic diameters of 50-800 nm when heated above the transition temperature of 27-31 °C. This temperature range is carefully tailored to align with the human body's physiological conditions. The formation of the nanoparticles and their subsequent decomposition was studied using dynamic light scattering (DLS), transmission electron microscopy (TEM), isothermal titration calorimetry (ITC), and nuclear magnetic resonance (NMR). 1H NMR studies confirmed that after approximately 20 h of incubation at pH 5, which closely mimics tumor microenvironment, approximately 40% of the acetal groups were hydrolyzed, and the thermoresponsive behavior of the copolymers was lost. This smart polymer response led to disintegration of the supramolecular structures, possibly releasing the therapeutic cargo. By tuning the transition temperature to the values relevant for medical applications, we ensure precise and effective drug release. In addition, our systems did not exhibit any cytotoxicity against any of the three cell lines. Our findings underscore the immense potential of these nanoparticles as eventual advanced drug delivery systems, especially for cancer therapy.

• Klíčová slova
• RAFT polymerization, drug delivery systems, pH-sensitive polymers, self-assembling block copolymers, thermoresponsive polymers,
• MeSH
• antitumorózní látky chemie   farmakologie   chemická syntéza   aplikace a dávkování   MeSH
• biokompatibilní materiály chemie   farmakologie   chemická syntéza   MeSH
• doxorubicin chemie   farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• molekulární struktura MeSH
• nanočástice * chemie   MeSH
• nosiče léků chemie   MeSH
• polymery * chemie   chemická syntéza   farmakologie   MeSH
• systémy cílené aplikace léků MeSH
• teplota * MeSH
• testování materiálů * MeSH
• uvolňování léčiv MeSH
• velikost částic * MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• biokompatibilní materiály MeSH
• doxorubicin MeSH
• nosiče léků MeSH
• polymery * MeSH

Recently, numerous polymer materials have been employed as drug carrier systems in medicinal research, and their detailed properties have been thoroughly evaluated. Water-soluble polymer carriers play a significant role between these studied polymer systems as they are advantageously applied as carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, antimicrobial molecules, or multidrug resistance inhibitors. Covalent attachment of carried molecules using a biodegradable spacer is strongly preferred, as such design ensures the controlled release of the drug in the place of a desired pharmacological effect in a reasonable time-dependent manner. Importantly, the synthetic polymer biomaterials based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers are recognized drug carriers with unique properties that nominate them among the most serious nanomedicines candidates for human clinical trials. This review focuses on advances in the development of HPMA copolymer-based nanomedicines within the passive and active targeting into the place of desired pharmacological effect, tumors, inflammation or bacterial infection sites. Specifically, this review highlights the safety issues of HPMA polymer-based drug carriers concerning the structure of nanomedicines. The main impact consists of the improvement of targeting ability, especially concerning the enhanced and permeability retention (EPR) effect.

• Klíčová slova
• EPR effect, HPMA copolymers, controlled release, drug delivery, nanomedicines,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Targeted drug delivery using nano-sized carrier systems with targeting functions to malignant and inflammatory tissue and tailored controlled drug release inside targeted tissues or cells has been and is still intensively studied. A detailed understanding of the correlation between the pharmacokinetic properties and structure of the nano-sized carrier is crucial for the successful transition of targeted drug delivery nanomedicines into clinical practice. In preclinical research in particular, fluorescence imaging has become one of the most commonly used powerful imaging tools. Increasing numbers of suitable fluorescent dyes that are excitable in the visible to near-infrared (NIR) wavelengths of the spectrum and the non-invasive nature of the method have significantly expanded the applicability of fluorescence imaging. This chapter summarizes non-invasive fluorescence-based imaging methods and discusses their potential advantages and limitations in the field of drug delivery, especially in anticancer therapy. This chapter focuses on fluorescent imaging from the cellular level up to the highly sophisticated three-dimensional imaging modality at a systemic level. Moreover, we describe the possibility for simultaneous treatment and imaging using fluorescence theranostics and the combination of different imaging techniques, e.g., fluorescence imaging with computed tomography.

• Klíčová slova
• drug delivery, fluorescence imaging, noninvasive imaging, polymers, theranostics,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

• Klíčová slova
• Chemotherapeutic and immunostimulant, Immunogenic cell death, Nanomedicine and biomaterials, Nanoparticle and microparticle, Pattern recognition receptor,
• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• nádory farmakoterapie   imunologie   terapie   MeSH
• nanomedicína metody   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• protinádorové vakcíny MeSH

Peptide immunogens provide an approach to focus antibody responses to specific neutralizing sites on the HIV envelope protein (Env) trimer or on other pathogens. However, the physical characteristics of peptide immunogens can limit their pharmacokinetic and immunological properties. Here, we have designed synthetic "star" nanoparticles based on biocompatible N-[(2-hydroxypropyl)methacrylamide] (HPMA)-based polymer arms extending from a poly(amidoamine) (PAMAM) dendrimer core. In mice, these star nanoparticles trafficked to lymph nodes (LNs) by 4 hours following vaccination, where they were taken up by subcapsular macrophages and then resident dendritic cells (DCs). Immunogenicity optimization studies revealed a correlation of immunogen density with antibody titers. Furthermore, the co-delivery of Env variable loop 3 (V3) and T-helper peptides induced titers that were 2 logs higher than if the peptides were given in separate nanoparticles. Finally, we performed a nonhuman primate (NHP) study using a V3 glycopeptide minimal immunogen that was structurally optimized to be recognized by Env V3/glycan broadly neutralizing antibodies (bnAbs). When administered with a potent Toll-like receptor (TLR) 7/8 agonist adjuvant, these nanoparticles elicited high antibody binding titers to the V3 site. Similar to human V3/glycan bnAbs, certain monoclonal antibodies (mAbs) elicited by this vaccine were glycan dependent or targeted the GDIR peptide motif. To improve affinity to native Env trimer affinity, nonhuman primates (NHPs) were boosted with various SOSIP Env proteins; however, significant neutralization was not observed. Taken together, this study provides a new vaccine platform for administration of glycopeptide immunogens for focusing immune responses to specific bnAb epitopes.

• MeSH
• epitopy imunologie   MeSH
• HIV infekce imunologie   MeSH
• HIV obalový protein gp120 chemie   MeSH
• HIV séropozitivita imunologie   MeSH
• HIV-1 imunologie   MeSH
• Macaca mulatta MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nanočástice chemie   terapeutické užití   MeSH
• neutralizující protilátky imunologie   MeSH
• peptidy MeSH
• primáti MeSH
• tvorba protilátek imunologie   MeSH
• vakcíny proti AIDS imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• epitopy MeSH
• HIV obalový protein gp120 MeSH
• neutralizující protilátky MeSH
• peptidy MeSH
• vakcíny proti AIDS MeSH