Dual-responsive chondroitin sulfate self-assembling nanoparticles for combination therapy in metastatic cancer cells.

In this study, we developed self-assembling nanoparticles (LCPs) able to trigger the release of Chlorambucil (Chl) and Doxorubicin (DOX) to MDA-MB-231 cells by exploiting the enzyme and redox signals. The DOX loaded LCPs was prepared by the self-assembly of two chondroitin sulphate (CS) derivatives, obtained by the covalent conjugation of Lipoic Acid (LA) and Chlorambucil (Chl) to the CS backbone. After the physic-chemical characterization of the conjugates by FT-IR, 1H NMR, and determination of the critical aggregation concentration, spherical nanoparticles with mean hydrodynamic diameter of 45 nm (P.D.I. 0.24) and Z-potential of - 44 mV were obtained by water addition/solvent evaporation method. In vitro experiments for the release of Chl and DOX were performed in healthy and cancer cells, using a cell culture media to maintain the physiological intracellular conditions (pH 7.4) (and concentration of esterase and GSH. The results allowed the selective release of the payloads to be detected: Chl release of 0 and 41% were obtained after 2 h incubation in normal and in cancer cells respectively, while values of 35 (in healthy cells) and 60% (in cancer cells) were recorded for DOX release after 96 h. Finally, viability studies proved the ability of the newly proposed nanosystem to enhance the cytotoxic activity of the two drugs against cancer cells.

Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation.

The key properties and high versatility of metal nanoparticles have shed new perspectives on cancer therapy, with copper nanoparticles gaining great interest because of the ability to couple the intrinsic properties of metal nanoparticles with the biological activities of copper ions in cancer cells. Copper, indeed, is a cofactor involved in different metabolic pathways of many physiological and pathological processes. Literature data report on the use of copper in preclinical protocols for cancer treatment based on chemo-, photothermal-, or copper chelating-therapies. Copper nanoparticles exhibit anticancer activity via multiple routes, mainly involving the targeting of mitochondria, the modulation of oxidative stress, the induction of apoptosis and autophagy, and the modulation of immune response. Moreover, compared to other metal nanoparticles (e.g. gold, silver, palladium, and platinum), copper nanoparticles are rapidly cleared from organs with low systemic toxicity and benefit from the copper's low cost and wide availability. Within this review, we aim to explore the impact of copper in cancer research, focusing on glioma, the most common primary brain tumour. Glioma accounts for about 80% of all malignant brain tumours and shows a poor prognosis with the five-year survival rate being less than 5%. After introducing the glioma pathogenesis and the limitation of current therapeutic strategies, we will discuss the potential impact of copper therapy and present the key results of the most relevant literature to establish a reliable foundation for future development of copper-based approaches.

Curcumin-Sodium Alginate and Curcumin-Chitosan Conjugates as Drug Delivery Systems: An Interesting Rheological Behaviour.

The conjugation of polyphenols is a valuable strategy with which to confer tailored properties to polymeric materials of biomedical interest. Within this investigation, we aim to explore the possibility to use this synthetic approach to increase the viscosity of conjugates, thus allowing the release of a loaded therapeutic to be better controlled over time than in neat polyphenols. Curcumin (CUR) was conjugated to sodium alginate (CA) and chitosan (CS) with functionalisation degrees of 9.2 (SA-CUR) and 15.4 (CS-CUR) mg g-1. Calorimetric analyses showed higher degrees of chain rigidity upon conjugation, with a shift of the degradation peaks to higher temperatures (from 239 to 245 °C and from 296 to 303 °C for SA-CUR and CS-CUR, respectively). Rheological analyses were used to prove the enhanced interconnection between the polymer chains in the conjugates, confirmed by the weak gel parameters, A and z. Moreover, the typical non-Newtonian behaviour of the high-molecular-weight polysaccharides was recorded, together with an enhancement of the activation energy, Ea, in CS-CUR vs. CS (opposite behaviour recorded for SA-CUR vs. SA). The evaluation of the delivery performance (of Doxorubicin as a model drug) showed sustained release profiles, opening opportunities for the development of controlled delivery systems.

Nanomaterials for Drug Delivery and Cancer Therapy.

In recent decades, the interest in nanomaterials has grown rapidly for their applications in many research fields, including drug delivery and cancer therapy [...].

CD44-targeted nanoparticles with GSH-responsive activity as powerful therapeutic agents against breast cancer.

DOX-loaded nanoparticles able to actively target CD44-receptors and respond to redox stimuli were proposed as non-conventional chemotherapeutic strategy in breast cancer. A covalent conjugate of human serum albumin and hyaluronic acid was prepared and assembled by a GSH-mediated desolvation in disulfide-crosslinked solid nanoparticles with mean diameter of 120 nm ± 3.4. The effective internalization of nanoparticles in cancer cells via CD44-receptors, together with the more efficient intracellular release, resulted in a significant increase of drug efficacy, with IC50 reduced from 0.9959 and 2.516 µg mL-1 to 0.4014 and 0.3094 µg mL-1 for MCF-7 and MDA-MB-231, respectively. Conversely, no enhancement in drug toxicity was recorded in healthy MCF-10A cells. The efficacy of the proposed formulation was further investigated in the different biological steps involved in metastasis process, paving the way for further in vivo experiments.

Hyaluronic Acid within Self-Assembling Nanoparticles: Endless Possibilities for Targeted Cancer Therapy.

Self-assembling nanoparticles (SANPs) based on hyaluronic acid (HA) represent unique tools in cancer therapy because they combine the HA targeting activity towards cancer cells with the advantageous features of the self-assembling nanosystems, i.e., chemical versatility and ease of preparation and scalability. This review describes the key outcomes arising from the combination of HA and SANPs, focusing on nanomaterials where HA and/or HA-derivatives are inserted within the self-assembling nanostructure. We elucidate the different HA derivatization strategies proposed for this scope, as well as the preparation methods used for the fabrication of the delivery device. After showing the biological results in the employed in vivo and in vitro models, we discussed the pros and cons of each nanosystem, opening a discussion on which approach represents the most promising strategy for further investigation and effective therapeutic protocol development.

Encapsulation of Alpha-Lipoic Acid in Functional Hybrid Liposomes: Promising Tool for the Reduction of Cisplatin-Induced Ototoxicity.

In this study, in order to address the drawback of cisplatin (CDDP)-induced ototoxicity, we propose a straightforward strategy based on the delivery of a sulfur-based antioxidant, such as lipoic acid (LA), to HEI-OC1 cells. To this aim, hybrid liposomes (LA@PCGC) with a spherical shape and a mean diameter of 25 nm were obtained by direct sonication of LA, phosphatidylcholine and a gelatin-curcumin conjugate in a physiological buffer. LA@PCGC were found to be stable over time, were quickly (i.e., by 1 h) taken up by HEI-OC1 cells, and guaranteed strong retention of the bioactive molecule, since LA release was less than 20%, even after 100 h. Cell viability studies showed the efficiency of LA@PCGC for stabilizing the protective activity of LA. Curcumin residues within the functional liposomes were indeed able to maintain the biological activity of LA, significantly improving (up to 2.19-fold) the viability of HEI-OC1 cells treated with 5 µM CDDP. Finally, LA@PCGC was incorporated within an alginate-based injectable hydrogel carrier to create a formulation with physical chemical features suitable for potential ear applications.

Smart Lipid-Polysaccharide Nanoparticles for Targeted Delivery of Doxorubicin to Breast Cancer Cells.

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid-polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC50 values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin.

Carbon Nanotubes Hybrid Hydrogels for Environmental Remediation: Evaluation of Adsorption Efficiency under Electric Field.

The performance of Carbon Nanotubes hybrid hydrogels for environmental remediation was investigated using Methylene Blue (MB), Rhodamine B (RD), and Bengal Rose (BR) as model contaminating dyes. An acrylate hydrogel network with incorporated CNT was synthesized by photo-polymerization without any preliminary derivatization of CNT surface. Thermodynamics, isothermal and kinetic studies showed favorable sorption processes with the application of an external 12 V electric field found to be able to influence the amount of adsorbed dyes: stronger interactions with cationic MB molecules (qexp and qexp12 of 19.72 and 33.45 mg g-1, respectively) and reduced affinity for anionic RD (qexp and qexp12 of 28.93 and 13.06 mg g-1, respectively) and neutral BR (qexp and qexp12 of 36.75 and 15.85 mg g-1, respectively) molecules were recorded. The influence of pH variation on dyes adsorption was finally highlighted by reusability studies, with the negligible variation of adsorption capacity after five repeated sorption cycles claiming for the suitability of the proposed systems as effective sorbent for wastewater treatment.

Polymeric Biomaterials for the Treatment of Cardiac Post-Infarction Injuries.

Cardiac regeneration aims to reconstruct the heart contractile mass, preventing the organ from a progressive functional deterioration, by delivering pro-regenerative cells, drugs, or growth factors to the site of injury. In recent years, scientific research focused the attention on tissue engineering for the regeneration of cardiac infarct tissue, and biomaterials able to anatomically and physiologically adapt to the heart muscle have been proposed as valuable tools for this purpose, providing the cells with the stimuli necessary to initiate a complete regenerative process. An ideal biomaterial for cardiac tissue regeneration should have a positive influence on the biomechanical, biochemical, and biological properties of tissues and cells; perfectly reflect the morphology and functionality of the native myocardium; and be mechanically stable, with a suitable thickness. Among others, engineered hydrogels, three-dimensional polymeric systems made from synthetic and natural biomaterials, have attracted much interest for cardiac post-infarction therapy. In addition, biocompatible nanosystems, and polymeric nanoparticles in particular, have been explored in preclinical studies as drug delivery and tissue engineering platforms for the treatment of cardiovascular diseases. This review focused on the most employed natural and synthetic biomaterials in cardiac regeneration, paying particular attention to the contribution of Italian research groups in this field, the fabrication techniques, and the current status of the clinical trials.

Alginate Bioconjugate and Graphene Oxide in Multifunctional Hydrogels for Versatile Biomedical Applications.

In this work, we combined electrically-conductive graphene oxide and a sodium alginate-caffeic acid conjugate, acting as a functional element, in an acrylate hydrogel network to obtain multifunctional materials designed to perform multiple tasks in biomedical research. The hybrid material was found to be well tolerated by human fibroblast lung cells (MRC-5) (viability higher than 94%) and able to modify its swelling properties upon application of an external electric field. Release experiments performed using lysozyme as the model drug, showed a pH and electro-responsive behavior, with higher release amounts and rated in physiological vs. acidic pH. Finally, the retainment of the antioxidant properties of caffeic acid upon conjugation and polymerization processes (Trolox equivalent antioxidant capacity values of 1.77 and 1.48, respectively) was used to quench the effect of hydrogen peroxide in a hydrogel-assisted lysozyme crystallization procedure.

Combining Dextran Conjugates with Stimuli-Responsive and Folate-Targeting Activity: A New Class of Multifunctional Nanoparticles for Cancer Therapy.

Nanoparticles with active-targeting and stimuli-responsive behavior are a promising class of engineered materials able to recognize the site of cancer disease, targeting the drug release and limiting side effects in the healthy organs. In this work, new dual pH/redox-responsive nanoparticles with affinity for folate receptors were prepared by the combination of two amphiphilic dextran (DEX) derivatives. DEXFA conjugate was obtained by covalent coupling of the polysaccharide with folic acid (FA), whereas DEXssPEGCOOH derived from a reductive amination step of DEX was followed by condensation with polyethylene glycol 600. After self-assembling, nanoparticles with a mean size of 50 nm, able to be destabilized in acidic pH and reducing media, were obtained. Doxorubicin was loaded during the self-assembling process, and the release experiments showed the ability of the proposed system to modulate the drug release in response to different pH and redox conditions. Finally, the viability and uptake experiments on healthy (MCF-10A) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a new drug vector in cancer therapy.

Dual-Targeted Hyaluronic Acid/Albumin Micelle-Like Nanoparticles for the Vectorization of Doxorubicin.

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.

Natural Polysaccharide Carriers in Brain Delivery: Challenge and Perspective.

Targeted drug delivery systems represent valuable tools to enhance the accumulation of therapeutics in the brain. Here, the presence of the blood brain barrier strongly hinders the passage of foreign substances, often limiting the effectiveness of pharmacological therapies. Among the plethora of materials used for the development of these systems, natural polysaccharides are attracting growing interest because of their biocompatibility, muco-adhesion, and chemical versatility which allow a wide range of carriers with tailored physico-chemical features to be synthetized. This review describes the state of the art in the field of targeted carriers based on natural polysaccharides over the last five years, focusing on the main targeting strategies, namely passive and active transport, stimuli-responsive materials and the administration route. In addition, in the last section, the efficacy of the reviewed carriers in each specific brain diseases is summarized and commented on in terms of enhancement of either blood brain barrier (BBB) permeation ability or drug bioavailability in the brain.

Functionalized Carbon Nanostructures Versus Drug Resistance: Promising Scenarios in Cancer Treatment.

Carbon nanostructures (CN) are emerging valuable materials for the assembly of highly engineered multifunctional nanovehicles for cancer therapy, in particular for counteracting the insurgence of multi-drug resistance (MDR). In this regard, carbon nanotubes (CNT), graphene oxide (GO), and fullerenes (F) have been proposed as promising materials due to their superior physical, chemical, and biological features. The possibility to easily modify their surface, conferring tailored properties, allows different CN derivatives to be synthesized. Although many studies have explored this topic, a comprehensive review evaluating the beneficial use of functionalized CNT vs G or F is still missing. Within this paper, the most relevant examples of CN-based nanosystems proposed for MDR reversal are reviewed, taking into consideration the functionalization routes, as well as the biological mechanisms involved and the possible toxicity concerns. The main aim is to understand which functional CN represents the most promising strategy to be further investigated for overcoming MDR in cancer.

Functional Albumin Nanoformulations to Fight Adrenocortical Carcinoma: a Redox-Responsive Approach.

PURPOSE: Solid tumors exhibit an altered redox state in comparison with normal tissues due to tumor hypoxia, lower pH, and elevated levels of the tripeptide glutathione. This study describes the preparation of functional redox-responsive nanoparticles proposed as delivery vehicle of Doxorubicin in adrenocortical cancer in vitro. METHODS: Curcumin and Lipoic acid were conjugated to Human Serum Albumin and nanoparticle systems were prepared via a modified desolvation method. Scanning electron microscopy, Fourier transmission IR, dynamic light scattering and differential scanning calorimetry analyses were used to characterize the nanoparticles. Balb3T3 and H295R were used as in vitro models of health and cancer cells, respectively. RESULTS: Nanoparticles with a spherical shape and a mean diameter of 70 nm were observed, increasing up to ten-folds upon exposure to glutathione 10 mM. Redox responsive Doxorubicin release was recorded, with loaded nanoparticles significantly enhancing the drug cytotoxicity against H295R adrenocortical tumor cells. Cell uptake experiments revealed a rapid and efficient internalization of the nanoparticles. CONCLUSIONS: A valuable tools to actively improve the in vitro anticancer activity of Doxorubicin against adrenocortical cancer was proposed. The effectiveness of the delivery vehicle is related to the presence of both Lipoic acid and Curcumin moieties, enhancing the glutathione responsivity, and the drug cytotoxicity, respectively.

Self-assembling Dextran prodrug for redox- and pH-responsive co-delivery of therapeutics in cancer cells.

Self-assembling prodrug containing pH- and redox-responsive functional groups was prepared by covalent conjugation of Doxorubicin (Dox) and lipoic acid (LA) to a polyaldehyde Dextran (PAD). The resultant amphiphilic DoxPADLA forms, in a single step, hemocompatible vesicular systems able to respond to intracellular signals without using external crosslinking agents. Camptothecin (CPT) was encapsulated exploiting the hydrophobic interactions with the vesicle membrane, and release experiments, carried out in media mimicking the physiological and endolysosomial compartments, in the absence or presence of Glutathione, proved the ability of the system to modulate drug release in relation to the variation of pH and redox potential. Cytotoxicity assays and confocal experiments demonstrated the efficacy of the vesicle formulation in enhancing the synergistic anticancer effect of the delivered Dox and CPT and a rapid and significant internalization of the carrier in cancer cells.

Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy.

With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.

Injectable Hydrogels for Cancer Therapy over the Last Decade.

The interest in injectable hydrogels for cancer treatment has been significantly growing over the last decade, due to the availability of a wide range of starting polymer structures with tailored features and high chemical versatility. Many research groups are working on the development of highly engineered injectable delivery vehicle systems suitable for combined chemo-and radio-therapy, as well as thermal and photo-thermal ablation, with the aim of finding out effective solutions to overcome the current obstacles of conventional therapeutic protocols. Within this work, we have reviewed and discussed the most recent injectable hydrogel systems, focusing on the structure and properties of the starting polymers, which are mainly classified into natural or synthetic sources. Moreover, mapping the research landscape of the fabrication strategies, the main outcome of each system is discussed in light of possible clinical applications.

When polymers meet carbon nanostructures: expanding horizons in cancer therapy.

The development of hybrid materials, which combine inorganic with organic materials, is receiving increasing attention by researchers. As a consequence of carbon nanostructures high chemical versatility, they exhibit enormous potential for new highly engineered multifunctional nanotherapeutic agents for cancer therapy. Whereas many groups are working on drug delivery systems for chemotherapy, the use of carbon nanohybrids for radiotherapy is rarely applied. Thus, nanotechnology offers a wide range of solutions to overcome the current obstacles of conventional chemo- and/or radiotherapies. Within this review, the structure and properties of carbon nanostructures (carbon nanotubes, nanographene oxide) functionalized preferentially with different types of polymers (synthetic, natural) are discussed. In short, synthesis approaches, toxicity investigations and anticancer efficacy of different carbon nanohybrids are described.