CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity.

Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.

Tailored-Made Polydopamine Nanoparticles to Induce Ferroptosis in Breast Cancer Cells in Combination with Chemotherapy.

Ferroptosis is gaining followers as mechanism of selective killing cancer cells in a non-apoptotic manner, and novel nanosystems capable of inducing this iron-dependent death are being increasingly developed. Among them, polydopamine nanoparticles (PDA NPs) are arousing interest, since they have great capability of chelating iron. In this work, PDA NPs were loaded with Fe3+ at different pH values to assess the importance that the pH may have in determining their therapeutic activity and selectivity. In addition, doxorubicin was also loaded to the nanoparticles to achieve a synergist effect. The in vitro assays that were performed with the BT474 and HS5 cell lines showed that, when Fe3+ was adsorbed in PDA NPs at pH values close to which Fe(OH)3 begins to be formed, these nanoparticles had greater antitumor activity and selectivity despite having chelated a smaller amount of Fe3+. Otherwise, it was demonstrated that Fe3+ could be released in the late endo/lysosomes thanks to their acidic pH and their Ca2+ content, and that when Fe3+ was co-transported with doxorubicin, the therapeutic activity of PDA NPs was enhanced. Thus, reported PDA NPs loaded with both Fe3+ and doxorubicin may constitute a good approach to target breast tumors.

Antibody-Loaded Nanoplatforms for Colorectal Cancer Diagnosis and Treatment: An Update.

At present, colorectal cancer (CRC) is the second deadliest type of cancer, partly because a high percentage of cases are diagnosed at advanced stages when tumors have already metastasized. Thus, there is an urgent need to develop novel diagnostic systems that allow early detection as well as new therapeutic systems that are more specific than those currently available. In this context, nanotechnology plays a very important role in the development of targeted platforms. In recent decades, many types of nanomaterials with advantageous properties have been used for nano-oncology applications and have been loaded with different types of targeted agents, capable of recognizing tumor cells or biomarkers. Indeed, among the different types of targeted agents, the most widely used are monoclonal antibodies, as the administration of many of them is already approved by the main drug regulatory agencies for the treatment of several types of cancer, including CRC. In this way, this review comprehensively discusses the main drawbacks of the conventional screening technologies and treatment for CRC, and it presents recent advances in the application of antibody-loaded nanoplatforms for CRC detection, therapy or theranostics applications.

Survival Impact of an On-Site Medicalization Program in the Control of COVID-19 Outbreaks in 11 Nursing Homes.

BACKGROUND: The elderly admitted to nursing homes have especially suffered the havoc of the COVID-19 pandemic since most of them are not prepared to face such health problems. METHODS: An innovative coordinated on-site medicalization program (MP) in response to a sizeable COVID-19 outbreak in three consecutive waves was deployed, sharing coordination and resources among primary care, the referral hospital, and the eleven residences. The objectives were providing the best possible medical care to residents in their environment, avoiding dehumanization and loneliness of hospital admission, and reducing the saturation of hospitals and the risk of spreading the infection. The main outcomes were a composite endpoint of survival or optimal palliative care (SOPC), survival, and referral to the hospital. RESULTS: 587 of 1199 (49%) residents were infected, of whom 123 (21%) died. Patients diagnosed before the start of the MP presented SOPC, survival, and referrals to the hospital of 83%, 74%, and 22.4%, opposite to 96%, 84%, and 10.6% of patients diagnosed while the MP was set up. The SOPC was independently associated with an MP (OR 3.4 [1.6-7.2]). CONCLUSION: During the COVID-19 outbreak, a coordinated MP successfully obtained a better rate of SOPC while simultaneously reducing the need for hospital admissions, combining optimal medical management with a more compassionate and humanistic approach in older people.

Biodegradable gellan gum hydrogels loaded with paclitaxel for HER2+ breast cancer local therapy.

Hydrogels loaded with chemotherapeutics are promising tools for local tumor treatment. In this work, redox-responsive implantable hydrogels based on gellan gum were prepared as paclitaxel carriers for HER2-positive breast cancer therapy. To achieve different degrees of chemical crosslinking, hydrogels were synthesized in both acetate buffer and phosphate buffer and crosslinked with different concentrations of l-cysteine. It was shown that both, the type of buffer and the l-cysteine concentration used, conditioned the dynamic modulus, equilibrium swelling rate, porosity, and thermal stability of the hydrogels. Then, the biocompatibility of the hydrogels with the most suitable porosity for drug delivery applications was assessed. Once confirmed, these hydrogels were loaded with paclitaxel:ß-cyclodextrin inclusion complexes, and they showed a glutathione-responsive controlled release of the taxane. Moreover, when tested in vitro, paclitaxel-loaded hydrogels exhibited great antitumor activity. Thus, they could act as excellent local tailored carriers of paclitaxel for future, post-surgical treatment of HER2-overexpressing breast tumors.

Nature-Inspired Nanoparticles as Paclitaxel Targeted Carrier for the Treatment of HER2-Positive Breast Cancer.

Despite the advances made in the fight against HER2-positive breast cancer, the need for less toxic therapies and strategies that avoid the apparition of resistances is indisputable. For this reason, a targeted nanovehicle for paclitaxel and trastuzumab, used in the first-line treatment of this subtype of breast cancer, had already been developed in a previous study. It yielded good results in vitro but, with the aim of further reducing paclitaxel effective dose and its side effects, a novel drug delivery system was prepared in this work. Thus, polydopamine nanoparticles, which are gaining popularity in cancer nanomedicine, were novelty loaded with paclitaxel and trastuzumab. The effectiveness and selectivity of the nanoparticles obtained were validated in vitro with different HER2-overexpressing tumor and stromal cell lines. These nanoparticles showed more remarkable antitumor activity than the nanosystem previously designed and, in addition, to affect stromal cell viability rate less than the parent drug. Moreover, loaded polydopamine nanoparticles, which notably increased the number of apoptotic HER2-positive breast cancer cells after treatment, also maintained an efficient antineoplastic effect when validated in tumor spheroids. Thereby, these bioinspired nanoparticles charged with both trastuzumab and paclitaxel may represent an excellent approach to improve current HER2-positive breast cancer therapies.

Antineoplastic behavior of polydopamine nanoparticles prepared in different water/alcohol media.

Polydopamine nanoparticles (PD NPs) have been synthesized in the present work through the oxidative polymerization of dopamine in aqueous media containing five different types of alcohol in a constant solvent volume ratio. We have shown that the type of alcohol, along with the ammonium hydroxide concentration used in the synthesis process, conditions particle size. Additionally, it has been found that the type of alcohol employed influences the well-known capacity of polydopamine nanoparticles to adsorb iron. As a consequence, since a ferroptosis-like mechanism may account for the cytotoxicity of these nanoparticles, the type of alcohol could also have a determining role in their antineoplastic activity. Here, the existence of a correlation between the ability of polydopamine nanoparticles to load Fe3+ and their toxic effect on breast cancer cells has been proven. For instance, nanoparticles synthesized using 2-propanol adsorbed more Fe3+ and had the greatest capacity to reduce breast tumor cell viability. Moreover, none of the nanoparticle synthesized with the different alcohols significantly decreased normal cell survival. Cancer cells present greater iron-dependence than healthy cells and this fact may explain why polydopamine nanoparticles toxicity, in which Fenton chemistry could be implicated, seems tumor-specific.

Trastuzumab: More than a Guide in HER2-Positive Cancer Nanomedicine.

HER2 overexpression, which occurs in a fifth of diagnosed breast cancers as well as in other types of solid tumors, has been traditionally linked to greater aggressiveness. Nevertheless, the clinical introduction of trastuzumab has helped to improve HER2-positive patients' outcomes. As a consequence, nanotechnology has taken advantage of the beneficial effects of the administration of this antibody and has employed it to develop HER2-targeting nanomedicines with promising therapeutic activity and limited toxicity. In this review, the molecular pathways that could be responsible for trastuzumab antitumor activity will be briefly summarized. In addition, since the conjugation strategies that are followed to develop targeting nanomedicines are essential to maintaining their efficacy and tolerability, the ones most employed to decorate drug-loaded nanoparticles and liposomes with trastuzumab will be discussed here. Thus, the advantages and disadvantages of performing this trastuzumab conjugation through adsorption or covalent bindings (through carbodiimide, maleimide, and click-chemistry) will be described, and several examples of targeting nanovehicles developed following these strategies will be commented on. Moreover, conjugation methods employed to synthesized trastuzumab-based antibody drug conjugates (ADCs), among which T-DM1 is well known, will be also examined. Finally, although trastuzumab-decorated nanoparticles and liposomes and trastuzumab-based ADCs have proven to have better selectivity and efficacy than loaded drugs, trastuzumab administration is sometimes related to side toxicities and the apparition of resistances. For this reason also, this review focuses at last on the important role that newer antibodies and peptides are acquiring these days in the development of HER2-targeting nanomedicines.

Size Matters in the Cytotoxicity of Polydopamine Nanoparticles in Different Types of Tumors.

Polydopamine has acquired great relevance in the field of nanomedicine due to its physicochemical properties. Previously, it has been reported that nanoparticles synthetized from this polymer are able to decrease the viability of breast and colon tumor cells. In addition, it is well known that the size of therapeutic particles plays an essential role in their effect. As a consequence, the influence of this parameter on the cytotoxicity of polydopamine nanoparticles was studied in this work. For this purpose, polydopamine nanoparticles with three different diameters (115, 200 and 420 nm) were synthetized and characterized. Their effect on the viability of distinct sorts of human carcinomas (breast, colon, liver and lung) and stromal cells was investigated, as well as the possible mechanisms that could be responsible for such cytotoxicity. Moreover, polydopamine nanoparticles were also loaded with doxorubicin and the therapeutic action of the resulting nanosystem was analyzed. As a result, it was demonstrated that a smaller nanoparticle size is related to a more enhanced antiproliferative activity, which may be a consequence of polydopamine's affinity for iron ions. Smaller nanoparticles would be able to adsorb more lysosomal Fe3+ and, when they are loaded with doxorubicin, a synergistic effect can be achieved.

Paclitaxel-Trastuzumab Mixed Nanovehicle to Target HER2-Overexpressing Tumors.

Paclitaxel is one of the most widely used chemotherapeutic agents thanks to its effectiveness and broad spectrum of antitumor activity. However, it has a very poor aqueous solubility and a limited specificity. To solve these handicaps, a novel paclitaxel-trastuzumab targeted transport nanosystem has been developed and characterized in this work to specifically treat cancer cells that overexpress the human epidermal growth factor receptor-2 (HER2). METHODS: Alginate and piperazine nanoparticles were synthetized and conjugated with paclitaxel:ß-cyclodextrins complexes and trastuzumab. Conjugated nanoparticles (300 nm) were characterized and their internalization in HER2-overexpressing tumor cells was analyzed by immunofluorescence. Its specific antitumor activity was studied in vitro using human cell lines with different levels of HER2-expression. RESULTS: In comparison with free paclitaxel:ß-cyclodextrins complexes, the developed conjugated nanovehicle presented specificity for the treatment of HER2-overpressing cells, in which it was internalized by endocytosis. CONCLUSIONS: It seems that potentially avoiding the conventional adverse effects of paclitaxel treatment could be possible with the use of the proposed mixed nanovehicle, which improves its bioavailability and targets HER2-positive cancer cells.

Polydopamine nanoparticles kill cancer cells.

Polydopamine (PD) is a synthetic melanin analogue of growing importance in the field of biomedicine, especially with respect to cancer research, due, in part, to its biocompatibility. But little is known about the cytotoxic effects of PD on cancer cell lines. PD is a UV-vis absorbing material whose absorbance overlaps with that of formazan salts, which are used to assess cell viability in MTT assays. In this study, a protocol has been established to eliminate the contributing absorbance of PD at 550 nm, and has been applied to characterize the cytotoxicity of PD nanoparticles in both healthy and breast cancer cell lines. Once the protocol is applied, it was found that PD is per se an antineoplastic system, meaning it selectively kills cancer cells, especially those of breast cancer, but it has no toxic effect on healthy cells. The mechanism of action could be related to the production of ROS and the alteration of iron homeostasis in lysosomes. To the best of our knowledge there are only a few examples of nanoparticle systems devoid of drugs that selectively kill cancer cells.

Cytotoxicity of paramagnetic cations-Loaded polydopamine nanoparticles.

Polydopamine (PD) is a synthetic melanin pigment of great importance in biomedicine, where its affinity for metallic cations, especially paramagnetic ions, has sparked interest in its use in the development of magnetic resonance imaging (MRI) contrast agents. In this work, we report the cytotoxicity of metal-enriched PD nanoparticles on NIH3T3, a healthy cell line and BT474, a breast cancer cell line. Remarkably, it was found that the metal- enriched PD particles (Mn+ = Fe3+, Fe2+ and Cu2+) were highly cytotoxic to the breast cancer cells, even after 24 h of treatment. Although, this effect was not selective systems, since an acute cytotoxic effect was also observed on the healthy cell line, this system can be considered as starting point for designing advanced antineoplastic agents.