Exploiting cyanine dye J-aggregates/monomer equilibrium in hydrophobic protein pockets for efficient multi-step phototherapy: An innovative concept for smart nanotheranostics

After several decades of development in the field of near-infrared (NIR) dyes for photothermal therapy (PTT), indocyanine green (ICG) still remains the only FDA-approved NIR contrast agent. However, upon NIR light irradiation ICG can react with molecular oxygen to form reactive oxygen species and degrade the ICG core, losing the convenient dye properties. In this work, we introduce a new approach for expanding the application of ICG in nanotheranostics, which relies on the confinement of self-organized J-type aggregates in hydrophobic protein domains acting as monomer depots. Upon the fast photobleaching, while the dye is irradiated, this strategy permits the equilibrium-driven monomer replacement after each irradiation cycle that radically increases the systems' effectivity and applicability. Gadolinium-doped casein micelles were designed to prove this novel concept at the same time as endowing the nanosystems with further magnetic resonance imaging (MRI) ability for dual-modal imaging-guided PTT. By teaching a new trick to a very old dog, the clinical prospect of ICG will undoubtedly be boosted laying the foundation for novel therapeutics. It is anticipated that future research could be expanded to other relevant J-aggregates-forming cyanine dyes or nanocrystal formulations of poorly water-soluble photosensitizers.Fil: Picchio, Matías Luis. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Bergueiro, Julian. Freie Universität Berlin; AlemaniaFil: Wedepohl, Stefanie. Freie Universität Berlin; AlemaniaFil: Minari, Roque Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Calderón, Marcelo. Polymat; Españ

Crosslinked casein-based micelles as a dually responsive drug delivery system

New types of biodegradable nanocarriers for drug delivery were prepared using casein (CAS) micelles as particle templates and glyceraldehyde (GAL) as a crosslinking agent. We found that highly crosslinked casein micelles (CCM) maintained their structural integrity at pH 7.4 (plasma conditions) but were easily degraded in the presence of proteases at pH 5 (lysosomal conditions). Nile red (NR) was chosen as a hydrophobic model drug inspired by the natural role of casein as lipophilic nutrient nanotransporter. The cumulative release of the NR-loaded micelles showed marginal dye leakage at pH 7.4 but was significantly accelerated by protease and pH-mediated degradation of the nanocarriers in a dual-responsive fashion. The prepared nanocarriers possess many favorable features for drug delivery: excellent biocompatibility and biodegradability, high stability in physiological conditions, remarkable capacity for the encapsulation of hydrophobic drugs, minimal drug leakage under extracellular conditions, and rapid drug release in response to the endo-lysosomal levels of pH and proteases. In this regard, the prepared CCM represent a promising candidate for the delivery and triggered release of anti-cancer drugs in lysosomal environments.Fil: Picchio, Matías Luis. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Nagel, Gregor. Freie Universitat Berlin; AlemaniaFil: Wedepohl, Stefanie. Freie Universitat Berlin; AlemaniaFil: Minari, Roque Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; Argentina. Freie Universitat Berlin; AlemaniaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Calderon, Marcelo. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; Argentina. Freie Universitat Berlin; Alemani

Crosslinked casein micelles bound paclitaxel as enzyme activated intracellular drug delivery systems for cancer therapy

Nanomedicine for cancer therapy is a successful tool to diminish the side effect of chemotherapeutics such as paclitaxel (PTX). In this regard, Abraxane®, a human serum albumin (HSA)-based nanomedicine system has shown lesser side effects than Taxol®. However, the large-scale production of HSA protein is limited and expensive, which is traduced in a high cost of the treatments in clinical applications. Thus, the use of easily-available alternative nanocarriers could increment the accessibility of patients to nanomedicine for cancer treatments. Casein is a low-cost protein able to self-assemble into micelles which could efficiently encapsulate PTX into their structure. In this work, the synthesis of chemically crosslinked casein micelles (CCM), used to prepare PTX-based nanoformulations, is presented. CCM@PTX nanoformulations showed promising results in vitro to be applied as nanomedicine for cancer therapy. Thus, the obtained nanoformulations are great candidates to be parenterally administered, accumulate in tumor by passive targeting without leakage of PTX in plasma, and release the drug within the tumor microenvironment, in response to overexpressed proteases such as trypsin.Fil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Picchio, Matías Luis. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Gugliotta, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bürgi Fissolo, María de Los Milagros. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ronco, Ludmila Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Calderón, Marcelo. Polymat; EspañaFil: Etcheverrigaray, Marina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Minari, Roque Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentin

Stimulus responsive nanogels for drug delivery

Nanogels have attracted growing interest in the last five decades owing to their potential for biomedical applications, including drug delivery systems and bioimaging. They are able to encapsulate highly amounts of biologically active agents such as drugs, proteins, and genetic material inside the polymer networks and release them in a controlled manner. Internal and external microenvironmental such as pH, ionic force, magnetic field, temperature, enzyme, glucose, redox potential, light, or a combination of them, can stimuli the response of nanogels and are useful for the controlled release of bioactive compounds. This chapter aims to cover the main features regarding the most outstanding contributions in the area of drug delivery from stimulus responsive nanogels. The recent advances in their main biomedical applications and physicochemical attributes for potential application of nanogels in cancer treatment will be highlighted.Fil: García, Mónica Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentin

Synthesis, characterization and slow drug delivery of hydrogels based in N-acryloyl-tris-(hydroxymethyl) aminomethane and N-isopropyl acrylamide

In this study, new hydrogels in rod shape were prepared from N-isopropyl acrylamide (NIPA), N-acryloyl-tris-(hydroxymethyl) aminomethane (NAT) and N,N´-methylenebisacrylamide (BIS). The effect of the incorporation of NAT into poly(N-isopropyl acrylamide) (PNIPA) structures for which the monomer composition was varied from NIPA 100% to NAT 100% was explored. The rheological studies were used to test their viscoelastic properties. Swelling experiments were used to test the capacity of water absorption, the modification of the network parameters, the swelling kinetics, the temperature and pH swelling response and n (number that determines the type of diffusion of water). NAT-containing hydrogels showed values of n between 0.5 and 1, therefore the diffusion of water into the hydrogels was found to have a non-Fickian character. The elastic moduli and the equilibrium water content (EWC) measurements suggest that these materials may have a potential application as biomaterials. The structure of shrunken NIPA 100 at high temperature that maintains the drug and hinders the release was controlled by the introduction of NAT into the network, to allow a slow drug release of ibuprofen at 37 ºC and pH 7.4.Fil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); ArgentinaFil: Strumia, Miriam Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentin

Functional Nanogels in Biomedical Applications

This review addresses current and future perspectives of nanogel technology for nanomedicine. The synthetic methodologies and material properties of nanogels prepared by chemical meanings are discussed in detail, and examples that illustrate the different methodologies are presented. Applications in the fields of drug and gene delivery, smart imaging modalities, responsive materials, and multivalency as a therapeutic approach highlight the enormous potential of the functional nanogels as novel polymeric platforms for biomedicine.Fil: Asadian Birjand, Mazdak. Freie Universität Berlin; AlemaniaFil: Sousa Herves, Ana. Freie Universität Berlin; AlemaniaFil: Steinhilber, Dirk. Freie Universität Berlin; AlemaniaFil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Calderon, Marcelo. Freie Universität Berlin; Alemani

Mucoadhesive and responsive nanogels as carriers for sustainable delivery of timolol for glaucoma therapy

Topical administration to the eye for the treatment of glaucoma is a convenient route because it increases the patient comfort. Timolol can efficiently diminish the intraocular pressure (IOP) of the eye; however the topical application as a solution of timolol maleate (TM) has poor therapeutic index and presents severe side effects. The encapsulation of timolol in nanomaterials has appeared as a technology to increase its residence time in the eye thus achieving a sustained release and consequently diminishing the doses of this drug and their number. The preparation of nanogels (NGs) based on N-isopropylacrylamide (NIPA) and acrylic acid (AAc), easily synthesized by precipitation/dispersion free radical polymerization, is reported in this paper. Such NGs presented excellent dispersability in eye simulated fluid and ideal size for topical application. NGs can load efficiently timolol through ionic interaction, and the in vitro release showed that NGs deliver timolol in a sustained manner. In vivo sustained efficacy of the NGs-timolol nanoformulations was demonstrated in rabbit´s glaucoma model, in which the IOP could be diminished and maintained constant for 48 h with only one application. Overall, the synthesized NGs in combination with timolol have potential as drug delivery system for glaucoma therapy.Fil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Tartara, Luis Ignacio. Universidad Nacional de Córdoba; ArgentinaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Palma, Santiago Daniel. Universidad Nacional de Córdoba; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba; Argentin

Responsive nanogels for application as smart carriers in endocytic pH-triggered drug delivery systems

Various specially designed poly(N-isopropylacrylamide-co-acrylic acid) (NIPA-co-AAc) nanogels (NGs) with different NIPA/AAc molar composition were synthesized by precipitation/dispersion polymerization and evaluated as carriers for drug delivery systems (DDSs) of doxorubicin hydrochloride (DOXO·HCl) for cancer therapies. The NGs presented excellent dispersability in physiological environments (pH 7.4 and 5 at 37 °C), as shown by dynamic light scattering (DLS). Moreover, the NGs exhibited high drug loading capacity and efficiency due to the ionic interaction of the cationic drug with the anionic NGs. NG-DOXO·HCl formulation presented excellent dispersability in water and minimal leakage of the cargo at plasma simulated medium (pH 7.4 and 0.14 M NaCl) at 37 °C and a triggered release at lysosomal simulated medium (pH 5 and 0.14 M NaCl). This release behavior together with their size and the low cytotoxicity determined by the MTT assay converts these NGs in great candidates for their application as carriers in cancer therapies based on the enhanced permeability and retention effect (EPR) with drug pH-triggered release after endocytosis in tumor cells.Fil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Molina, Maria. Freie Universität Berlin. Institut für Chemie und Biochemie; AlemaniaFil: Wedepohl, Stefanie. Freie Universität Berlin. Institut für Chemie und Biochemie; AlemaniaFil: Alvarez Igarzabal, Cecilia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Calderon, Marcelo. Freie Universität Berlin. Institut für Chemie und Biochemie; AlemaniaFil: Gugliotta, Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentin

Crossing biological barriers with nanogels to improve drug delivery performance

The current limitations in the use of nanocarriers to treat constantly evolving diseases call for the design of novel and smarter drug delivery systems (DDS). Nanogels (NGs) are three-dimensional crosslinked polymers with dimensions on the nanoscale and with a great potential for use in the biomedical field. Particular interest focuses on their application as DDS to minimize severe toxic effects and increase the therapeutic index of drugs. They have recently gained attention, since they can include responsive modalities within their structure, which enable them to excerpt a therapeutic function on demand. Their bigger sizes and controlled architecture and functionality, when compared to non-crosslinked polymers, make them particularly interesting to explore novel modalities to cross biological barriers. The present review summarizes the most significant developments of NGs as smart carriers, with focus on smart modalities to cross biological barriers such as cellular membrane, tumor stroma, mucose, skin, and blood brain barrier. We discuss the properties of each barrier and highlight the importance that the NG design has on their capability to overcome them and deliver the cargo at the site of action.Fil: Cuggino, Julio César. Universidad Tecnológica Nacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Blanco, Ernesto Rafael Osorio. Freie Universität Berlin; Alemania. Universidad del Pais Vasco. Polymat.; EspañaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Calderon, Marcelo. Universidad del Pais Vasco. Polymat.; España. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Orgánica; Argentin

Dually responsive nanogels as smart carriers for improving the therapeutic index of doxorubicin for breast cancer

Nanocarriers can significantly improve the therapeutic index of drug in cancer therapy. At present, parenteral administration of free doxorubicin (Dox) to treat breast tumor produces severe side effects including cardiotoxicity. This work reports the preparation of N-isopropyacrylamide/acrylic acid nanogels (NGs), NIPA/AAc NGs, crosslinked by a disulfide-bearing monomer, which can be used as smart carriers of Dox for cancer therapy. The NGs prepared showed high load percentage of Dox through ionic interaction. The size of the NGs in simulated physiological medium was ideal to be applied as a carrier in cancer therapy. In vitro release studies demonstrated that the designed drug delivery system (DDS) can active the release of a large amount of drug in simulated intracellular medium in response to redox potential and pH, but with minimal release in simulated plasma conditions. Cellular uptake studies showed that NGs loaded with Dox can be internalized in human breast cancer cell line MDA-MB-231. Cell toxicity studies demonstrate that unloaded NGs are nontoxic for human breast cancer cell line MDA-MB-231 and mouse breast cancer cell line 4T1. In addition, it was shown that Dox-loaded NGs are more toxic for the cell than free Dox for both cell lines. In vivo studies in mice showed that Dox-loaded NGs improve the drug therapeutic index with a notable decrease in tumor size, as compared with a similar dose of free Dox. Finally, the development of this nanoformulation could improve the results and patient compliance in chemotherapy treatments of breast cancer.Fil: Cuggino, Julio César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Gatti, Gerardo Alberto. Fundación Para El Progreso de la Medicina; ArgentinaFil: Picchio, Matías Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Maccioni, Mariana. Universidad Nacional de Córdoba; ArgentinaFil: Gugliotta, Luis Marcelino. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Alvarez Igarzabal, Cecilia Ines. Universidad Nacional de Córdoba; Argentin