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Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

RESEARCH ID S-2443-2016 (Miguel Gisbert Garzarán) ORCID 0000-0001-9815-0354 (Miguel Gisbert Garzarán) RESEARCHER ID M-3378-2014 (María Vallet Regí) ORCID 0000-0002-6104-4889 (María Vallet Regí), Mesoporous silica nanoparticles have been widely applied as carriers for cancer treatment. Among the different types of stimuli-responsive drug delivery systems, those sensitive to redox stimuli have attracted much attention. Their relevance arises from the high concentration of reduc-tive species that are found within the cells, compared to bloodstream, which leads to the drug re-lease taking place only inside cells. This review is intended to provide a comprehensive overview of the most recent trends in the design of redox-responsive mesoporous silica nanoparticles. First, a general description of the biological rationale of this stimulus is presented. Then, the different types of gatekeepers that are able to open the pore entrances only upon application of reductive conditions will be introduced. In this sense, we will distinguish among those targeted and those non-targeted toward cancer cells. Finally, a new family of bridged silica nanoparticles able to degrade their struc-ture upon application of this type of stimulus will be presented., Unión Europea. Horizonte 2020, Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, TRUE, pub

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitro cell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.

Drug targeting of tumor cells is one of the great challenges in cancer therapy; nanoparticles based on natural polymers represent valuable tools to achieve this aim. The ability to respond to environmental signals from the pathological site (e.g., altered redox potential), together with the specific interaction with membrane receptors overexpressed on cancer cells membrane (e.g., CD44 receptors), represent the main features of actively targeted nanoparticles. In this work, redox-responsive micelle-like nanoparticles were prepared by self-assembling of a hyaluronic acid–human serum albumin conjugate containing cystamine moieties acting as a functional spacer. The conjugation procedure consisted of a reductive amination step of hyaluronic acid followed by condensation with albumin. After self-assembling, nanoparticles with a mean size of 70 nm and able to be destabilized in reducing media were obtained. Doxorubicin-loaded nanoparticles modulated drug release rate in response to different redox conditions. Finally, the viability and uptake experiments on healthy (BALB-3T3) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a drug vector in cancer therapy

Biological redox molecules play essential regulatory roles in diverse cellular processes. In particular, abnormal levels of redox signaling molecules are related to the progression of several diseases. Therefore, redox-responsive polymeric nanomaterials appear as competent candidates for disease-targeting drug delivery systems. In the past decades, considerable works have been done to develop polymeric nanomaterials showing controlled release in response to reactive oxygen species, glutathione or both. To further advance this research field, two new redox-responsive polymeric nanomaterials are described in this dissertation. In chapter 1, hydrogen peroxide-responsive polycaprolactone nanoparticles are reported. By exploiting an intramolecular cyclization strategy, polycaprolactone that contains pendant arylboronic ester motifs shows fast hydrogen peroxide-induced degradation. Nanoparticles formulated from this polycaprolactone exhibit high sensitivity to disease relevant levels of hydrogen peroxide. In chapter 2, a hydrogen sulfide-responsive nanogel is introduced. Cholesteryl groups were conjugated on dextran via hydrogen sulfide-responsive linkers to yield amphiphilic polysaccharides that can self-assemble to form nanogels in aqueous solutions. This work presents the first hydrogen sulfide-responsive nanogel that shows hydrogen sulfide-induced swelling behavior and controlled payload release.

Biological redox molecules play essential regulatory roles in diverse cellular processes. In particular, abnormal levels of redox signaling molecules are related to the progression of several diseases. Therefore, redox-responsive polymeric nanomaterials appear as competent candidates for disease-targeting drug delivery systems. In the past decades, considerable works have been done to develop polymeric nanomaterials showing controlled release in response to reactive oxygen species, glutathione or both. To further advance this research field, two new redox-responsive polymeric nanomaterials are described in this dissertation. In chapter 1, hydrogen peroxide-responsive polycaprolactone nanoparticles are reported. By exploiting an intramolecular cyclization strategy, polycaprolactone that contains pendant arylboronic ester motifs shows fast hydrogen peroxide-induced degradation. Nanoparticles formulated from this polycaprolactone exhibit high sensitivity to disease relevant levels of hydrogen peroxide. In chapter 2, a hydrogen sulfide-responsive nanogel is introduced. Cholesteryl groups were conjugated on dextran via hydrogen sulfide-responsive linkers to yield amphiphilic polysaccharides that can self-assemble to form nanogels in aqueous solutions. This work presents the first hydrogen sulfide-responsive nanogel that shows hydrogen sulfide-induced swelling behavior and controlled payload release.

A novel diblock copolymer consisting of poly(vinylferrocene) (PVFc) and poly(N,N-diethylacrylamide) (PDEA) is synthesized via a combination of anionic and RAFT polymerization. The use of a novel route to hydroxyl-end-functionalized metallopolymers in anionic polymerization and subsequent esterification with a RAFT agent leads to a PVFc macro-CTA (M̄n = 3800 g mol -1; D = 1.17). RAFT polymerization with DEA affords block copolymers as evidenced by 1H NMR spectroscopy as well as size exclusion chromatography (6400 ≤ M̄n≤ 33700 g mol-1; 1.31 ≤D 1.28). Self-assembly of the amphiphilic block copolymers in aqueous solution leads to micelles as shown via TEM. Importantly, the distinct thermo-responsive and redox-responsive character of the blocks is probed via dynamic light scattering and found to be individually and repeatedly addressable. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Specific induction of cell death in tumors is considered one of the most desired and effective anticancer therapies. Effective strategies to activate the apoptotic pathway, or other death mechanisms, are currently being intensely pursued. A potent chemotherapy option is directly arming the cancer cells with executioner proteins or apoptotic-inducing proteins that are not targeted by anti-apoptotic maneuvers found in many tumors. During this period, we showed that the tumor suppressor, cellular guardian p53 can be recombinantly produced, encapsulated into polymeric nanocapsules, and be delivered to different cancer cell lines. The super p53, which contains the S121F mutation can selectively kill tumor cells. In addition, we also developed a new nanocapsule synthesis strategy that allowed facile modification of polymer surface with tumor targeting ligands using click chemistry. Using such modified nanocapsule, we demonstrate the p53 cargo is only internalized into cancer cells that overexpress the targeting receptor. Animal studies will be performed in the next period (no cost extension)., The original document contains color images.

Apoptin-containing nanocapsules have been shown to be efficiently internalized by mammalian cells and induce tumor-specific apoptosis in vitro and in vivo. Identification of targeting moieties can further improve the efficacy of these nanoparticles. Targeting nanoparticles by conjugating various specific ligands has shown potential therapeutic efficacy in nanomedicine. However, poor penetration of antitumor drugs into solid tumors remains a major obstacle. We demonstrated a targeting strategy by conjugating nanoparticles with a tumor-penetrating peptide, iRGD. The results showed that iRGD could facilate the binding and cellular uptake of nanoparticles. Colocalization data revealed that iRGD-conjugated nanoparticles entered cells via the clathrin-mediated pathway, followed by endosome-lysosome transport. In addition, we were able to demonstrate that the biofunctional chelator AmBaSar could be used in the 64Cu labeling of nanoparticles and the positron emission tomography-based images of particle distribution could be obtained at several time points after intravenous administration of nanoparticles. Our data support the further experiment to use iRGD for targeting nanocapsules and to use PET imaging for investigating bioditribution of nanocapsule in vivo., The original document contains color images.

[EN] A novel type of hybrid material based on a PLGA nanoparticle core and a redox-responsive amorphous organosilica shell have been successfully synthesized. The outer layer is obtained by self-assembly of silicate ions with a silsesquioxane containing a disulfide bridge. These organic linkers work as molecular gates that can be selectively cleaved by reducing agents. This system is particularly suitable for storage and release of hydrophobic molecules, as the treatment with dithiothreitol leaves open doors that allow for the discharge of encapsulated molecules in the organic matrix. Using pyrene as a probe molecule, it has been shown that after partial disruption of the organic−inorganic coating, the release mechanism from PLGA particles fits pretty well into Higuchi s model, corresponding to a diffusion-mediated process. These nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles, are reasonably stable in a physiological medium, and show great potential as stimuli-responsive vehicles for drug delivery.

[EN] A novel type of hybrid material based on a PLGA nanoparticle core and a redox-responsive amorphous organosilica shell have been successfully synthesized. The outer layer is obtained by self-assembly of silicate ions with a silsesquioxane containing a disulfide bridge. These organic linkers work as molecular gates that can be selectively cleaved by reducing agents. This system is particularly suitable for storage and release of hydrophobic molecules, as the treatment with dithiothreitol leaves open doors that allow for the discharge of encapsulated molecules in the organic matrix. Using pyrene as a probe molecule, it has been shown that after partial disruption of the organic−inorganic coating, the release mechanism from PLGA particles fits pretty well into Higuchi s model, corresponding to a diffusion-mediated process. These nanohybrids impose a better control and slower release of encapsulated molecules than bare PLGA nanoparticles, are reasonably stable in a physiological medium, and show great potential as stimuli-responsive vehicles for drug delivery.

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The development of stimuli-responsive, nano-scale therapeutics that can selectively target tumors is a major research focus in cancer nanotechnology. A potent therapeutic option is directly arming the cancer cells with apoptotic-inducing proteins that are not targeted by anti-apoptotic maneuvers found in tumors. The avian virus derived apoptin forms a high molecular weight protein complex that selectively accumulates in the nuclei of cancer cells to induce apoptotic cell death. To enable the efficient delivery of this tumor-selective complex in functional form, we synthesized degradable, sub-100 nm, core-shell protein nanocapsules containing the 2.4 MDa apoptin complexes. Recombinant apoptin is reversibly encapsulated in a positively charged, water soluble polymeric shell and is released in native forms in response to reducing conditions such as the cytoplasm. The nanocapsules are efficiently internalized by mammalian cells lines as characterized by confocal microscopy, and rhodamine-labeled apoptin can be observed in the nuclei of cancer cells only. Released apoptin induced tumor-specific apoptosis in several cell lines and inhibited tumor growth in vivo, demonstrating the potential of this polymer-protein combination as a cancer therapeutic., The original document contains color images.

The development of stimuli-responsive, nano-scale therapeutics that can selectively target tumors is a major research focus in cancer nanotechnology. A potent therapeutic option is directly arming the cancer cells with apoptotic-inducing proteins that are not targeted by anti-apoptotic maneuvers found in tumors. The avian virus derived apoptin forms a high molecular weight protein complex that selectively accumulates in the nuclei of cancer cells to induce apoptotic cell death. To enable the efficient delivery of this tumor-selective complex in functional form, we synthesized degradable, sub-100 nm, core-shell protein nanocapsules containing the 2.4 MDa apoptin complexes. Recombinant apoptin is reversibly encapsulated in a positively charged, water soluble polymeric shell and is released in native forms in response to reducing conditions such as the cytoplasm. The nanocapsules are efficiently internalized by mammalian cells lines as characterized by confocal microscopy, and rhodamine-labeled apoptin can be observed in the nuclei of cancer cells only. Released apoptin induced tumor-specific apoptosis in several cell lines and inhibited tumor growth in vivo, demonstrating the potential of this polymer-protein combination as a cancer therapeutic., The original document contains color images.

Drug delivery systems in the size range of ~ 10-250 nm are enabling tools for site-specific targeting and controlled release applications. To take advantage of these capabilities, various nanocarriers e.g., micelles, dendrimers, liposomes, nanoparticles, nanocapsules, nanotubes, and nanogels, have been designed for drug delivery. Specifically, micelle-based drug carrier systems have emerged as promising tools for site-specific delivery and controlled release applications. Despite several advantages over conventional drugs, some limitations of micelle-based drug delivery have also been reported. These drawbacks include low stability in vivo, poor penetration, modest accumulation in tumour tissues, and inadequate control over drug release. To overcome these limitations, stimuli-responsive or smart polymeric nanocarriers have been developed for drug delivery and tumour therapy, previously. The most well-known internal stimuli in cancerous regions include higher acidity associated with dysregulated metabolism in tumour tissues, elevated levels of glutathione in the cytosol and nucleus of cancer cells, and altered degradative enzymes in the lysosomes, and reactive oxygen species in the mitochondria. These intrinsic microenvironments can be exploited as internal stimuli to attain active drug release in the tumour tissues or cancer cells. In particular, the reducing potential inside the cancer cells is considerably higher than found in the extracellular environment and bloodstream. Such varying redox potential can be exploited for tumour-specific drug delivery and controlled release applications. Various types of redox-responsive micelles have been developed, previously. Generally, redox-responsive micelles have disulfide linkages that undergo rapid cleavage in the presence of reducing agents in the intracellular components, however, are stable at oxidising extracellular environment. The redox-responsive disulfide bridges can be incorporated into nanocarriers by placing mu