Nejvíce citovaný článek - PubMed ID 2946403
The clinical prospects of cancer nanomedicines depend on effective patient stratification. Here we report the identification of predictive biomarkers of the accumulation of nanomedicines in tumour tissue. By using supervised machine learning on data of the accumulation of nanomedicines in tumour models in mice, we identified the densities of blood vessels and of tumour-associated macrophages as key predictive features. On the basis of these two features, we derived a biomarker score correlating with the concentration of liposomal doxorubicin in tumours and validated it in three syngeneic tumour models in immunocompetent mice and in four cell-line-derived and six patient-derived tumour xenografts in mice. The score effectively discriminated tumours according to the accumulation of nanomedicines (high versus low), with an area under the receiver operating characteristic curve of 0.91. Histopathological assessment of 30 tumour specimens from patients and of 28 corresponding primary tumour biopsies confirmed the score's effectiveness in predicting the tumour accumulation of liposomal doxorubicin. Biomarkers of the tumour accumulation of nanomedicines may aid the stratification of patients in clinical trials of cancer nanomedicines.
- MeSH
- biologické markery metabolismus MeSH
- doxorubicin * terapeutické užití analogy a deriváty MeSH
- lidé MeSH
- makrofágy spojené s nádory metabolismus MeSH
- myši MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory * patologie metabolismus farmakoterapie MeSH
- nanomedicína * metody MeSH
- polyethylenglykoly MeSH
- strojové učení MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biologické markery MeSH
- doxorubicin * MeSH
- liposomal doxorubicin MeSH Prohlížeč
- nádorové biomarkery MeSH
- polyethylenglykoly MeSH
Background: Efficient theranostic strategies concurrently bring and use both the therapeutic and diagnostic features, serving as a cutting-edge tool to combat advanced cancers. Goals of the Investigation: Here, we develop stimuli-sensitive theranostics consisting of tailored copolymers forming micellar conjugates carrying pyropheophorbide-a (PyF) attached by pH-sensitive hydrazone bonds, thus enabling the tumor microenvironment-sensitive activation of the photodynamic therapy (PDT) effect, fluorescence or phosphorescence. Results: The nanomedicines show superior anti-tumor PDT efficacy and huge tumor-imaging potential, while reducing their accumulation, and potentially side effects, in the liver and spleen. The developed theranostics exhibit clear selective tumor accumulation at high levels in the mouse sarcoma S180 tumor model with almost no PyF found in the healthy tissues after 48 h. Once in the tumor, illumination at λexc = 420 nm reaches the therapeutic effect due to the 1O2 generation. Indeed, an almost complete inhibition of tumor growth is observed up to 18 days after the treatment. Conclusion: The clear benefit of the specific PyF release and activation in the acidic tumor environment for the targeted delivery and tissue distribution dynamics was proved. Conjugates carrying pyropheophorbide-a (PyF) attached by pH-sensitive hydrazone bonds showed their excellent antitumor PDT effect and its applicability as advanced theranostics at very low dose of PyF.
- Klíčová slova
- HPMA polymers, fluorescence imaging, pH-responsive theranostics, photodynamic therapy, tumor-targeted nanomedicines,
- MeSH
- fotochemoterapie * metody MeSH
- fotosenzibilizující látky terapeutické užití MeSH
- hydrazony terapeutické užití MeSH
- individualizovaná medicína MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí MeSH
- nádory * diagnostické zobrazování farmakoterapie patologie MeSH
- polymery chemie MeSH
- teranostická nanomedicína metody MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fotosenzibilizující látky MeSH
- hydrazony MeSH
- polymery MeSH
Nanomedicines, including polymer nanocarriers with controlled drug release, are considered next-generation therapeutics with advanced therapeutic properties and reduced side effects. To develop safe and efficient nanomedicines, it is crucial to precisely determine the drug release kinetics. Herein, we present application of analytical methods, i.e., surface plasmon resonance biosensor technology (SPR), capillary electrophoresis, and 1H diffusion-ordered nuclear magnetic resonance spectroscopy, which were innovatively applied for drug release determination. The methods were optimised to quantify the pH-triggered release of three structurally different drugs from a polymer carrier. The suitability of these methods for drug release characterisation was evaluated and compared using several parameters including applicability for diverse samples, the biological relevance of the experimental setup, method complexity, and the analysis outcome. The SPR method was the most universal method for the evaluation of diverse drug molecule release allowing continuous observation in the flow-through setting and requiring a small amount of sample.
- Publikační typ
- časopisecké články MeSH
Over the last decades, the global life expectancy of the population has increased, and so, consequently, has the risk of cancer development. Despite the improvement in cancer therapies (e.g., drug delivery systems (DDS) and theranostics), in many cases recurrence continues to be a challenging issue. In this matter, the development of nanotechnology has led to an array of possibilities for cancer treatment. One of the most promising therapies focuses on the assembly of hierarchical structures in the form of nanoclusters, as this approach involves preparing individual building blocks while avoiding handling toxic chemicals in the presence of biomolecules. This review aims at presenting an overview of the major advances made in developing nanoclusters based on polymeric nanoparticles (PNPs) and/or inorganic NPs. The preparation methods and the features of the NPs used in the construction of the nanoclusters were described. Afterwards, the design, fabrication and properties of the two main classes of nanoclusters, namely noble-metal nanoclusters and hybrid (i.e., hetero) nanoclusters and their mode of action in cancer therapy, were summarized.
- Klíčová slova
- cancer therapy, drug delivery, inorganic nanoparticles, nanoclusters, polymeric nanoparticles, theranostics,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.
- Klíčová slova
- antibody–drug conjugates, liposomes, lymphoma, magnetic resonance imaging, nanomedicine, nuclear imaging, targeted drug delivery, theranostics,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Recently, the antitumor potential of benzimidazole anthelmintics, such as mebendazole and its analogues, have been reported to have minimal side effects, in addition to their well-known anti-parasitic abilities. However, their administration is strongly limited owing to their extremely poor solubility, which highly depletes their overall bioavailability. This study describes the design, synthesis, and physico-chemical properties of polymer-mebendazole nanomedicines for drug repurposing in cancer therapy. The conjugation of mebendazole to water-soluble and biocompatible polymer carrier was carried out via biodegradable bond, relying on the hydrolytic action of lysosomal hydrolases for mebendazole release inside the tumor cells. Five low-molecular-weight mebendazole derivatives, differing in their inner structure, and two polymer conjugates differing in their linker structure, were synthesized. The overall synthetic strategy was designed to enable the modification and polymer conjugation of most benzimidazole-based anthelmintics, such as albendazole, fenbendazole or albendazole, besides the mebendazole. Furthermore, the described methodology may be suitable for conjugation of other biologically active compounds with a heterocyclic N-H group in their molecules.
- Klíčová slova
- HPMA, controlled release, drug delivery, drug repurposing, mebendazole, polymer,
- Publikační typ
- časopisecké články MeSH
The study describes the synthesis, physicochemical properties, and biological evaluation of polymer therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers intended for a tumor-targeted immuno-oncotherapy. Water-soluble linear and cholesterol-containing HPMA precursors were synthesized using controlled reversible addition-fragmentation chain transfer polymerization to reach molecular weight Mn about 2 × 104 g·mol-1 and low dispersity. These linear or self-assembled micellar conjugates, containing immunomodulatory agent cucurbitacin-D (CuD) or the anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond, showed a hydrodynamic size of 10-30 nm in aqueous solutions. The CuD-containing conjugates were stable in conditions mimicking blood. Importantly, a massive release of active CuD in buffer mimicking the acidic tumor environment was observed. In vitro, both the linear (LP-CuD) and the micellar (MP-CuD) conjugates carrying CuD showed cytostatic/cytotoxic activity against several cancer cell lines. In a murine metastatic and difficult-to-treat 4T1 mammary carcinoma, only LP-CuD showed an anticancer effect. Indeed, the co-treatment with Dox-containing micellar polymer conjugate and LP-CuD showed potentiation of the anticancer effect. The results indicate that the binding of CuD, characterized by prominent hydrophobic nature and low bioavailability, to the polymer carrier allows a safe and effective delivery. Therefore, the conjugate could serve as a potential component of immuno-oncotherapy schemes within the next preclinical evaluation.
There are huge demands on multifunctional nanocarriers to be used in nanomedicine. Herein, we present a simple and efficient method for the preparation of multifunctional magnetically responsive polymeric-based nanocarriers optimized for biomedical applications. The hybrid delivery system is composed of drug-loaded polymer nanoparticles (poly(caprolactone), PCL) coated with a multilayer shell of polyglutamic acid (PGA) and superparamagnetic iron oxide nanoparticles (SPIONs), which are known as bio-acceptable components. The PCL nanocarriers with a model anticancer drug (Paclitaxel, PTX) were formed by the spontaneous emulsification solvent evaporation (SESE) method, while the magnetically responsive multilayer shell was formed via the layer-by-layer (LbL) method. As a result, we obtained magnetically responsive polycaprolactone nanocarriers (MN-PCL NCs) with an average size of about 120 nm. Using the 9.4 T preclinical magnetic resonance imaging (MRI) scanner we confirmed, that obtained MN-PCL NCs can be successfully used as a MRI-detectable drug delivery system. The magnetic hyperthermia effect of the MN-PCL NCs was demonstrated by applying a 25 mT radio-frequency (f = 429 kHz) alternating magnetic field. We found a Specific Absorption Rate (SAR) of 55 W g-1. The conducted research fulfills the first step of investigation for biomedical application, which is mandatory for the planning of any in vitro and in vivo studies.
- Publikační typ
- časopisecké články MeSH
Cancer treatment has been greatly improved by the combined use of targeted therapies and novel biotechnological methods. Regarding the former, pegylated liposomal doxorubicin (PLD) has a preferential accumulation within cancer tumors, thus having lower toxicity on healthy cells. PLD has been implemented in the targeted treatment of sarcoma, ovarian, breast, and lung cancer. In comparison with conventional doxorubicin, PLD has lower cardiotoxicity and hematotoxicity; however, PLD can induce mucositis and palmo-plantar erythrodysesthesia (PPE, hand-foot syndrome), which limits its use. Therapeutical apheresis is a clinically proven solution against early PLD toxicity without hindering the efficacy of the treatment. The present review summarizes the pharmacokinetics and pharmacodynamics of PLD and the beneficial effects of extracorporeal apheresis on the incidence of PPE during chemoradiotherapy in cancer patients.
- Klíčová slova
- chemotherapy, chemotoxicity, palmar-plantar erythrodysesthesia, pegylated liposomal doxorubicin, therapeutic apheresis,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Design, controlled synthesis, physico-chemical and biological characteristics of novel well-defined biodegradable star-shaped copolymers intended for advanced drug delivery is described. These new biocompatible star copolymers were synthesised by grafting monodispersed semitelechelic linear (sL) N-(2-hydroxypropyl)methacrylamide copolymers onto a 2,2-bis(hydroxymethyl)propionic acid (bisMPA)-based polyester dendritic core of various structures. The hydrodynamic diameter of the star copolymer biomaterials can be tuned from 13 to 31 nm and could be adjusted to a given purpose by proper selection of the bisMPA dendritic core type and generation and by considering the sL copolymer molecular weight and polymer-to-core molar ratio. The hydrolytic degradation was proved for both the star copolymers containing either dendron or dendrimer core, showing the spontaneous hydrolysis in duration of few weeks. Finally, it was shown that the therapy with the biodegradable star conjugate with attached doxorubicin strongly suppresses the tumour growth in mice and is fully curative in most of the treated animals at dose corresponding approximately to one fourth of maximum tolerated dose (MTD) value. Both new biodegradable systems show superior efficacy and tumour accumulation over the first generation of star copolymers containing non-degradable PAMAM core.
- Klíčová slova
- Cancer, Doxorubicin, Drug delivery, HPMA, Star-like polymers, bisMPA,
- MeSH
- akrylamidy MeSH
- biokompatibilní materiály * MeSH
- doxorubicin MeSH
- léčivé přípravky * MeSH
- lékové transportní systémy MeSH
- methakryláty MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků MeSH
- polymery MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- akrylamidy MeSH
- biokompatibilní materiály * MeSH
- doxorubicin MeSH
- hydroxypropyl methacrylate MeSH Prohlížeč
- léčivé přípravky * MeSH
- methakryláty MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Prohlížeč
- nosiče léků MeSH
- polymery MeSH
