3D-printed aerogels as theranostic implants monitored by fluorescence bioimaging.

Aerogel scaffolds are nanostructured materials with beneficial properties for tissue engineering applications. The tracing of the state of the aerogels after their implantation is challenging due to their variable biodegradation rate and the lack of suitable strategies capable of in vivo monitoring the scaffolds. Upconversion nanoparticles (UCNPs) have emerged as advanced tools for in vitro bioimaging because of their fluorescence properties. In this work, highly fluorescent UCNPs were loaded into aerogels to obtain theranostic implants for tissue engineering and bioimaging applications. 3D-printed alginate-hydroxyapatite aerogels labeled with UCNPs were manufactured by 3D-printing and supercritical CO2 drying to generate personalize-to-patient aerogels. The physicochemical performance of the resulting structures was evaluated by printing fidelity measurements, nitrogen adsorption-desorption analysis, and different microscopies (confocal, transmission and scanning electron microscopies). Stability of the aerogels in terms of physicochemical properties was also tested after 3 years of storage. Biocompatibility was evaluated in vitro by different cell and hemocompatibility assays, in ovo and in vivo by safety and bioimaging studies using different murine models. Cytokines profile, tissue index and histological evaluations of the main organs unveiled an in vivo downregulation of the inflammation after implantation of the scaffolds. UCNPs-decorated aerogels were first-time manufactured and long-term traceable by fluorescence-based bioimaging until 3 weeks post-implantation, thereby endorsing their suitability as tissue engineering and theranostic nanodevices (i.e. bifunctional implants).

Enhanced Cytotoxicity against a Pancreatic Cancer Cell Line Combining Radiation and Gold Nanoparticles.

The present work consisted of an exploratory study aiming to evaluate in vitro the potential of AuNPs during Radiation Therapy (RT) in human pancreatic adenocarcinoma cells. AuNPs coated with hyaluronic and oleic acids (HAOA-AuNPs) or with bombesin peptides (BBN-AuNPs) were used. AuNPs were characterized by Atomic Force Microscopy (AFM) and Dynamic Light Scattering. BxPC-3 tumor cells were irradiated with a 6 MV X-rays beam, in the absence or presence of AuNPs. AFM showed that HAOA-AuNPs and BBN-AuNPs are spherical with a mean size of 83 ± 20 nm and 49 ± 12 nm, respectively. For RT alone, a reduction in cell viability of up to 33 ± 12% was obtained compared to the control (p ≤ 0.0001). HAOA-AuNPs alone at 200 and 400 µM showed a reduction in cell viability of 20 ± 4% and 35 ± 4%, respectively, while for BBN-AuNPs, at 50 and 200 µM, a reduction in cell viability of 25 ± 3% and 37 ± 3% was obtained, respectively, compared to the control (p < 0.0001). At 72 h post-irradiation, a decrease in cell viability of 26 ± 3% and 22 ± 2% between RT + HAOA-AuNPs at 400 µM and RT + BBN-AuNPs at 50 µM, compared to RT alone, was obtained (p < 0.004). The combination of RT with AuNPs led to a significant decrease in cell viability compared to the control, or RT alone, thus representing an improved effect.

A Step Forward for the Treatment of Localized Prostate Cancer Using Gold Nanoparticles Combined with Laser Irradiation.

Prostate cancer (PCA) is the second most common cancer diagnosis in men and the fifth leading cause of death worldwide. The conventional treatments available are beneficial to only a few patients and, in those, some present adverse side effects that eventually affect the quality of life of most patients. Thus, there is an urgent need for effective, less invasive and targeted specific treatments for PCA. Photothermal therapy (PTT) is a minimally invasive therapy that provides a localized effect for tumour cell ablation by activating photothermal agents (PTA) that mediate the conversion of the light beam's energy into heat at the site. As tumours are unable to easily dissipate heat, they become more susceptible to temperature increases. In the PTT field, gold nanoparticles (AuNPs) have been attracting interest as PTA. The aim of this study was to formulate AuNPs capable of remaining retained in the tumour and subsequently generating heat at the tumour site. AuNPs were synthesized and characterized in terms of size, polydispersity index (PdI), zeta potential (ZP), morphology and the surface plasmon resonance (SPR). The safety of AuNPs and their efficacy were assessed using in vitro models. A preliminary in vivo safety assessment of AuNPs with a mean size lower than 200 nm was confirmed. The morphology was spherical-like and the SPR band showed good absorbance at the laser wavelength. Without laser, AuNPs proved to be safe both in vitro (>70% viability) and in vivo. In addition, with laser irradiation, they proved to be relatively effective in PCA cells. Overall, the formulation appears to be promising for use in PTT.

Rational approach to design gold nanoparticles for photothermal therapy: the effect of gold salt on physicochemical, optical and biological properties.

Among the unique characteristics associated to gold nanoparticles (AuNPs) in biomedicine, their ability to convert light energy into heat opens ventures for improved cancer therapeutic options, such as photothermal therapy (PTT). PTT relies on the local hyperthermia of tumor cells upon irradiation with light beams, and the association of AuNPs with radiation within the near infrared (NIR) range constitutes an advantageous strategy to potentially improve PTT efficacy. Herein, it was explored the effect of the gold salt on the AuNPs' physicochemical and optical properties. Mostly spherical-like negatively charged AuNPs with variable sizes and absorbance spectra were obtained. In addition, photothermal features were assessed using in vitro phantom models. The best formulation showed the ability to increase their temperature in aqueous solution up to 19 °C when irradiated with a NIR laser for 20 min. Moreover, scanning transmission electron microscopy confirmed the rearrangement of the gold atoms in a face-centered cubic structure, which further allowed to calculate the photothermal conversion efficiency upon combination of theoretical and experimental data. AuNPs also showed local retention after being locally administered in in vivo models. These last results obtained by computerized tomography allow to consider these AuNPs as promising elements for a PTT system. Moreover, AuNPs showed high potential for PTT by resulting in in vitro cancer cells' viability reductions superior to 70 % once combine with 5 min of NIR irradiation.

Exploring the Potential of Using Marine-Derived Ingredients: From the Extraction to Cutting-Edge Cosmetics.

The growing understanding and knowledge of the potential of marine species, as well as the application of "blue biotechnology" have been motivating new innovative solutions in cosmetics. It is widely noted that that marine species are important sources of compounds with several biological activities that are yet to be discovered. This review explores various biological properties of marine-derived molecules and briefly outlines the main extraction methods. Alongside these, it is well known the legislative and normative framework of cosmetics is increasingly being developed. In this research segment, there is a growing concern with sustainability. In this sense, "blue biotechnology", together with the use of invasive species or marine waste products to obtain new active ingredients, haven been emerging as innovative and sustainable solutions for the future's cosmetics industry. This review also examines the regulatory framework and focus on the recent advancements in "blue biotechnology" and its relevance to the sustainable development of innovative cosmetics.

Nanoparticle-Based Treatment in Glioblastoma.

Glioblastoma (GB) is a malignant glioma associated with a mean overall survival of 12 to 18 months, even with optimal treatment, due to its high relapse rate and treatment resistance. The standardized first-line treatment consists of surgery, which allows for diagnosis and cytoreduction, followed by stereotactic fractionated radiotherapy and chemotherapy. Treatment failure can result from the poor passage of drugs through the blood-brain barrier (BBB). The development of novel and more effective therapeutic approaches is paramount to increasing the life expectancy of GB patients. Nanoparticle-based treatments include epitopes that are designed to interact with specialized transport systems, ultimately allowing the crossing of the BBB, increasing therapeutic efficacy, and reducing systemic toxicity and drug degradation. Polymeric nanoparticles have shown promising results in terms of precisely directing drugs to the brain with minimal systemic side effects. Various methods of drug delivery that pass through the BBB, such as the stereotactic injection of nanoparticles, are being actively tested in vitro and in vivo in animal models. A significant variety of pre-clinical studies with polymeric nanoparticles for the treatment of GB are being conducted, with only a few nanoparticle-based drug delivery systems to date having entered clinical trials. Pre-clinical studies are key to testing the safety and efficacy of these novel anticancer therapies and will hopefully facilitate the testing of the clinical validity of this promising treatment method. Here we review the recent literature concerning the most frequently reported types of nanoparticles for the treatment of GB.

The current role of cannabis and cannabinoids in health: A comprehensive review of their therapeutic potential.

There has been an increased interest of the scientific community in cannabis and its constituents for therapeutic purposes. Although it is believed that cannabinoids can be effective for a few different conditions and syndromes, there are little objective data that clearly support the use of cannabis, cannabis extracts or even cannabidiol (CBD) oil. This review aims to explore the therapeutic potential of phytocannabinoids and synthetic cannabinoids for the treatment of several diseases. A broad search covering the past five years, was performed in PubMed and ClinicalTrial.gov databases, to identify papers focusing on the use of medical phytocannabinoids in terms of tolerability, efficacy and safety. Accordingly, there are preclinical data supporting the use of phytocannabinoids and synthetic cannabinoids for the management of neurological pathologies, acute and chronical pain, cancer, psychiatric disorders and chemotherapy-induced emetic symptoms. However, regarding the clinical trials, most of the collected data do not fully support the use of cannabinoids in the treatment of such conditions. Consequently, more studies are still needed to clarify ascertain if the use of these compounds is useful in the management of different pathologies.

Safety of Gold Nanoparticles: From In Vitro to In Vivo Testing Array Checklist.

In recent years, gold nanoparticles (AuNPs) have aroused the interest of many researchers due to their unique physicochemical and optical properties. AuNPs are being explored in a variety of biomedical fields, either in diagnostics or therapy, particularly for localized thermal ablation of cancer cells after light irradiation. Besides the promising therapeutic potential of AuNPs, their safety constitutes a highly important issue for any medicine or medical device. For this reason, in the present work, the production and characterization of physicochemical properties and morphology of AuNPs coated with two different materials (hyaluronic and oleic acids (HAOA) and bovine serum albumin (BSA)) were firstly performed. Based on the above importantly referred issue, the in vitro safety of developed AuNPs was evaluated in healthy keratinocytes, human melanoma, breast, pancreatic and glioblastoma cancer cells, as well as in a three-dimensional human skin model. Ex vivo and in vivo biosafety assays using, respectively, human red blood cells and Artemia salina were also carried out. HAOA-AuNPs were selected for in vivo acute toxicity and biodistribution studies in healthy Balb/c mice. Histopathological analysis showed no significant signs of toxicity for the tested formulations. Overall, several techniques were developed in order to characterize the AuNPs and evaluate their safety. All these results support their use for biomedical applications.

Edible Seaweeds Extracts: Characterization and Functional Properties for Health Conditions.

Seaweeds are popular foods due to claimed beneficial health effects, but for many there is a lack of scientific evidence. In this study, extracts of the edible seaweeds Aramé, Nori, and Fucus are compared. Our approach intends to clarify similarities and differences in the health properties of these seaweeds, thus contributing to target potential applications for each. Additionally, although Aramé and Fucus seaweeds are highly explored, information on Nori composition and bioactivities is scarce. The aqueous extracts of the seaweeds were obtained by decoction, then fractionated and characterized according to their composition and biological activity. It was recognized that fractioning the extracts led to bioactivity reduction, suggesting a loss of bioactive compounds synergies. The Aramé extract showed the highest antioxidant activity and Nori exhibited the highest potential for acetylcholinesterase inhibition. The identification of the bioactive compounds in the extracts allowed to see that these contained a mixture of phloroglucinol polymers, and it was suggested that Nori's effect on acetylcholinesterase inhibition may be associated with a smaller sized phlorotannins capable of entering the enzyme active site. Overall, these results suggest a promising potential for the use of these seaweed extracts, mainly Aramé and Nori, in health improvement and management of diseases, namely those associated to oxidative stress and neurodegeneration.

Highlighted Advances in Therapies for Difficult-To-Treat Brain Tumours Such as Glioblastoma.

Glioblastoma multiforme (GBM) remains a challenging disease, as it is the most common and deadly brain tumour in adults and has no curative solution and an overall short survival time. This incurability and short survival time means that, despite its rarity (average incidence of 3.2 per 100,000 persons), there has been an increased effort to try to treat this disease. Standard of care in newly diagnosed glioblastoma is maximal tumour resection followed by initial concomitant radiotherapy and temozolomide (TMZ) and then further chemotherapy with TMZ. Imaging techniques are key not only to diagnose the extent of the affected tissue but also for surgery planning and even for intraoperative use. Eligible patients may combine TMZ with tumour treating fields (TTF) therapy, which delivers low-intensity and intermediate-frequency electric fields to arrest tumour growth. Nonetheless, the blood-brain barrier (BBB) and systemic side effects are obstacles to successful chemotherapy in GBM; thus, more targeted, custom therapies such as immunotherapy and nanotechnological drug delivery systems have been undergoing research with varying degrees of success. This review proposes an overview of the pathophysiology, possible treatments, and the most (not all) representative examples of the latest advancements.

Pluronic® F127 Hydrogel Containing Silver Nanoparticles in Skin Burn Regeneration: An Experimental Approach from Fundamental to Translational Research.

Presently, skin burns are considered one of the main public health problems and lack therapeutic options. In recent years, silver nanoparticles (AgNPs) have been widely studied, playing an increasingly important role in wound healing due to their antibacterial activity. This work is focused on the production and characterization of AgNPs loaded in a Pluronic® F127 hydrogel, as well as assessing its antimicrobial and wound-healing potential. Pluronic® F127 has been extensively explored for therapeutic applications mainly due to its appealing properties. The developed AgNPs had an average size of 48.04 ± 14.87 nm (when prepared by method C) and a negative surface charge. Macroscopically, the AgNPs solution presented a translucent yellow coloration with a characteristic absorption peak at 407 nm. Microscopically, the AgNPs presented a multiform morphology with small sizes (~50 nm). Skin permeation studies revealed that no AgNPs permeated the skin after 24 h. AgNPs further demonstrated antimicrobial activity against different bacterial species predominant in burns. A chemical burn model was developed to perform preliminary in vivo assays and the results showed that the performance of the developed AgNPs loaded in hydrogel, with smaller silver dose, was comparable with a commercial silver cream using higher doses. In conclusion, hydrogel-loaded AgNPs is potentially an important resource in the treatment of skin burns due to their proven efficacy by topical administration.

Marine Natural Products as Innovative Cosmetic Ingredients.

Over the course of the last 20 years, numerous studies have identified the benefits of an array of marine natural ingredients for cosmetic purposes, as they present unique characteristics not found in terrestrial organisms. Consequently, several marine-based ingredients and bioactive compounds are under development, used or considered for skin care and cosmetics. Despite the multitude of cosmetics based on marine sources, only a small proportion of their full potential has been exploited. Many cosmetic industries have turned their attention to the sea to obtain innovative marine-derived compounds for cosmetics, but further research is needed to determine and elucidate the benefits. This review gathers information on the main biological targets for cosmetic ingredients, different classes of marine natural products of interest for cosmetic applications, and the organisms from which such products can be sourced. Although organisms from different phyla present different and varied bioactivities, the algae phylum seems to be the most promising for cosmetic applications, presenting compounds of many classes. In fact, some of these compounds present higher bioactivities than their commercialized counterparts, demonstrating the potential presented by marine-derived compounds for cosmetic applications (i.e., Mycosporine-like amino acids and terpenoids' antioxidant activity). This review also summarizes the major challenges and opportunities faced by marine-derived cosmetic ingredients to successfully reach the market. As a future perspective, we consider that fruitful cooperation among academics and cosmetic industries could lead to a more sustainable market through responsible sourcing of ingredients, implementing ecological manufacturing processes, and experimenting with inventive recycling and reuse programs.

Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole.

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand's coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 µM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.

Current Insights and Progress in the Clinical Management of Head and Neck Cancer.

Head and neck cancer (HNC), also known as the cancer that can affect the structures between the dura mater and the pleura, is the 6th most common type of cancer. This heterogeneous group of malignancies is usually treated with a combination of surgery and radio- and chemotherapy, depending on if the disease is localized or at an advanced stage. However, most HNC patients are diagnosed at an advanced stage, resulting in the death of half of these patients. Thus, the prognosis of advanced or recurrent/metastatic HNC, especially HNC squamous cell carcinoma (HNSCC), is notably poorer than the prognosis of patients diagnosed with localized HNC. This review explores the epidemiology and etiologic factors of HNC, the histopathology of this heterogeneous cancer, and the diagnosis methods and treatment approaches currently available. Moreover, special interest is given to the novel therapies used to treat HNC subtypes with worse prognosis, exploring immunotherapies and targeted/multi-targeted drugs undergoing clinical trials, as well as light-based therapies (i.e., photodynamic and photothermal therapies).

Nanoformulation of Seaweed Eisenia bicyclis in Albumin Nanoparticles Targeting Cardiovascular Diseases: In Vitro and In Vivo Evaluation.

Natural products, especially those derived from seaweeds, are starting to be seen as effective against various diseases, such as cardiovascular diseases (CVDs). This study aimed to design a novel oral formulation of bovine albumin serum nanoparticles (BSA NPs) loaded with an extract of Eisenia bicyclis and to validate its beneficial health effects, particularly targeting hypercholesterolemia and CVD prevention. Small and well-defined BSA NPs loaded with Eisenia bicyclis extract were successfully prepared exhibiting high encapsulation efficiency. Antioxidant activity and cholesterol biosynthesis enzyme 3-hydroxy-3 methylutaryl coenzyme A reductase (HMGR) inhibition, as well as reduction of cholesterol permeation in intestinal lining model cells, were assessed for the extract both in free and nanoformulated forms. The nanoformulation was more efficient than the free extract, particularly in terms of HMGR inhibition and cholesterol permeation reduction. In vitro cytotoxicity and in vivo assays in Wistar rats were performed to evaluate its safety and overall effects on metabolism. The results demonstrated that the Eisenia bicyclis extract and BSA NPs were not cytotoxic against human intestinal Caco-2 and liver HepG2 cells and were also safe after oral administration in the rat model. In addition, an innovative approach was adopted to compare the metabolomic profile of the serum from the animals involved in the in vivo assay, which showed the extract and nanoformulation's impact on CVD-associated key metabolites. Altogether, these preliminary results revealed that the seaweed extract and the nanoformulation may constitute an alternative natural dosage form which is safe and simple to produce, capable of reducing cholesterol levels, and consequently helpful in preventing hypercholesterolemia, the main risk factor of CVDs.

Melanoma Management: From Epidemiology to Treatment and Latest Advances.

Melanoma is the deadliest skin cancer, whose morbidity and mortality indicators show an increasing trend worldwide. In addition to its great heterogeneity, melanoma has a high metastatic potential, resulting in very limited response to therapies currently available, which were restricted to surgery, radiotherapy and chemotherapy for many years. Advances in knowledge about the pathophysiological mechanisms of the disease have allowed the development of new therapeutic classes, such as immune checkpoint and small molecule kinase inhibitors. However, despite the incontestable progress in the quality of life and survival rates of the patients, effectiveness is still far from desired. Some adverse side effects and resistance mechanisms are the main barriers. Thus, the search for better options has resulted in many clinical trials that are now investigating new drugs and/or combinations. The low water solubility of drugs, low stability and rapid metabolism limit the clinical potential and therapeutic use of some compounds. Thus, the research of nanotechnology-based strategies is being explored as the basis for the broad application of different types of nanosystems in the treatment of melanoma. Future development focus on challenges understanding the mechanisms that make these nanosystems more effective.

How to Treat Melanoma? The Current Status of Innovative Nanotechnological Strategies and the Role of Minimally Invasive Approaches like PTT and PDT.

Melanoma is the most aggressive type of skin cancer, the incidence and mortality of which are increasing worldwide. Its extensive degree of heterogeneity has limited its response to existing therapies. For many years the therapeutic strategies were limited to surgery, radiotherapy, and chemotherapy. Fortunately, advances in knowledge have allowed the development of new therapeutic strategies. Despite the undoubted progress, alternative therapies are still under research. In this context, nanotechnology is also positioned as a strong and promising tool to develop nanosystems that act as drug carriers and/or light absorbents to potentially improve photothermal and photodynamic therapies outcomes. This review describes the latest advances in nanotechnology field in the treatment of melanoma from 2011 to 2022. The challenges in the translation of nanotechnology-based therapies to clinical applications are also discussed. To sum up, great progress has been made in the field of nanotechnology-based therapies, and our understanding in this field has greatly improved. Although few therapies based on nanoparticulate systems have advanced to clinical trials, it is expected that a large number will come into clinical use in the near future. With its high sensitivity, specificity, and multiplexed measurement capacity, it provides great opportunities to improve melanoma treatment, which will ultimately lead to enhanced patient survival rates.

Biological Thermal Performance of Organic and Inorganic Aerogels as Patches for Photothermal Therapy.

Aerogels are materials with unique properties, among which are low density and thermal conductivity. They are also known for their exquisite biocompatibility and biodegradability. All these features make them attractive for biomedical applications, such as their potential use in photothermal therapy (PTT). This technique is, yet, still associated with undesirable effects on surrounding tissues which emphasizes the need to minimize the exposure of healthy regions. One way to do so relies on the use of materials able to block the radiation and the heat generated. Aerogels might be potentially useful for this purpose by acting as insulators. Silica- and pectin-based aerogels are reported as the best inorganic and organic thermal insulators, respectively; thus, the aim of this work relies on assessing the possibility of using these materials as light and thermal insulators and delimiters for PTT. Silica- and pectin-based aerogels were prepared and fully characterized. The thermal protection efficacy of the aerogels when irradiated with a near-infrared laser was assessed using phantoms and ex vivo grafts. Lastly, safety was assessed in human volunteers. Both types presented good textural properties and safe profiles. Moreover, thermal activation unveils the better performance of silica-based aerogels, confirming the potential of this material for PTT.

New iron(III) anti-cancer aminobisphenolate/phenanthroline complexes: Enhancing their therapeutic potential using nanoliposomes.

Malignant melanoma is an aggressive and deadly form of skin cancer and novel and improved therapeutic options are needed. A promising strategy involves the use of metallodrugs combined with liposomes for targeted delivery to cancer cells. In this work, a family of iron(III) complexes was synthesized bearing a trianionic aminobisphenolate ligand (L) and phenanthroline-type co-ligands (NN). Four ternary iron complexes of general formula [Fe(L)(NN)] were obtained: [Fe(L)(amphen)] (1), [Fe(L)(phen)] (2), [Fe(L)(Clphen)] (3), and [Fe(L)(Mephen)] (4), as well as a fifth complex [Fe(L)(NEt3)(H2O)] (5) without the bidentate co-ligand. All complexes were characterized by analytic and spectroscopic techniques and demonstrated to be stable in aqueous environment. Complexes 1 and 2 were able to bind DNA and presented high cytotoxic activity towards human cancer cells. Complex 1 (IronC) was selected for incorporation into different liposomal formulations, which were fully characterized and screened against murine melanoma cells. The IronC liposomal formulation with the highest incorporation efficiency (∼95%) and a low IC50 value (7.1 ± 0.7 µM) was selected for in vivo evaluation. In a syngeneic murine melanoma model the liposomal formulation of IronC yielded the highest impairment on tumour progression when compared with the control, temozolomide, and with the iron complex in free form.

Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model.

Colorectal cancer is the second leading cause of cancer-related mortality. Many current therapies rely on chemotherapeutic agents with poor specificity for tumor cells. The clinical success of cisplatin has prompted the research and design of a huge number of metal-based complexes as potential chemotherapeutic agents. In this study, two zinc(II) complexes, [ZnL2] and [ZnL(AcO)], where AcO is acetate and L is an organic compound combining 8-hydroxyquinoline and a benzothiazole moiety, were developed and characterized. Analytical and spectroscopic studies, namely, NMR, FTIR, and UV-Vis allowed us to establish the complexes' structures, demonstrating the ligand-binding versatility: tetradentate in [ZnL(AcO)] and bidentate in [ZnL2]. Complexes were screened in vitro using murine and human colon cancer cells cultured in 2D and 3D settings. In 2D cells, the IC50 values were <22 µM, while in 3D settings, much higher concentrations were required. [ZnL(AcO)] displayed more suitable antiproliferative properties than [ZnL2] and was chosen for further studies. Moreover, based on the weak selectivity of the zinc-based complex towards cancer cell lines in comparison to the non-tumorigenic cell line, its incorporation in long-blood-circulating liposomes was performed, aiming to improve its targetability. The resultant optimized liposomal nanoformulation presented an I.E. of 76% with a mean size under 130 nm and a neutral surface charge and released the metal complex in a pH-dependent manner. The antiproliferative properties of [ZnL(AcO)] were maintained after liposomal incorporation. Preliminary safety assays were carried out through hemolytic activity that never surpassed 2% for the free and liposomal forms of [ZnL(AcO)]. Finally, in a syngeneic murine colon cancer mouse model, while free [ZnL(AcO)] was not able to impair tumor progression, the respective liposomal nanoformulation was able to reduce the relative tumor volume in the same manner as the positive control 5-fluorouracil but, most importantly, using a dosage that was 3-fold lower. Overall, our results show that liposomes were able to solve the solubility issues of the new metal-based complex and target it to tumor sites.