Gemcitabine-Vitamin E Prodrug-Loaded Micelles for Pancreatic Cancer Therapy.

Pancreatic cancer (PC) is an aggressive cancer subtype presenting unmet clinical challenges. Conventional chemotherapy, which includes antimetabolite gemcitabine (GEM), is seriously undermined by a short half-life, its lack of targeting ability, and systemic toxicity. GEM incorporation in self-assembled nanosystems is still underexplored due to GEM's hydrophilicity which hinders efficient encapsulation. We hypothesized that vitamin E succinate-GEM prodrug (VES-GEM conjugate) combines hydrophobicity and multifunctionalities that can facilitate the development of Pluronic® F68 and Pluronic® F127 micelle-based nanocarriers, improving the therapeutic potential of GEM. Pluronic® F68/VES-GEM and Pluronic® F127/VES-GEM micelles covering a wide range of molar ratios were prepared by solvent evaporation applying different purification methods, and characterized regarding size, charge, polydispersity index, morphology, and encapsulation. Moreover, the effect of sonication and ultrasonication and the influence of a co-surfactant were explored together with drug release, stability, blood compatibility, efficacy against tumour cells, and cell uptake. The VES-GEM conjugate-loaded micelles showed acceptable size and high encapsulation efficiency (>95%) following an excipient reduction rationale. Pluronic® F127/VES-GEM micelles evidenced a superior VES-GEM release profile (cumulative release > 50%, pH = 7.4), stability, cell growth inhibition (<50% cell viability for 100 µM VES-GEM), blood compatibility, and extensive cell internalization, and therefore represent a promising approach to leveraging the efficacy and safety of GEM for PC-targeted therapies.

Nanodelivery systems for cutaneous melanoma treatment.

Cutaneous melanoma (CM) is a multifactorial disease whose treatment still presents challenges: the rapid progression to advanced CM, which leads to frequent recurrences even after surgical excision and, notably, the low response rates and resistance to the available therapies, particularly in the case of unresectable metastatic CM. Thereby, alternative innovative therapeutic approaches for CM continue to be searched. In this review we discuss relevant preclinical research studies, and provide a broad-brush analysis of patents and clinical trials which involve the application of nanotechnology-based delivery systems in CM therapy. Nanodelivery systems have been developed for the delivery of anticancer biomolecules to CM, which can be administered by different routes. Overall, nanosystems could promote technological advances in several therapeutic modalities and can be used in combinatorial therapies. Nevertheless, the results of these preclinical studies have not been translated to clinical applications. Thus, concerted and collaborative research studies involving basic, applied, translational, and clinical scientists need to be performed to allow the development of effective and safe nanomedicines to treat CM.

Liposome-based diagnostic and therapeutic applications for pancreatic cancer.

Pancreatic cancer is one of the harshest and most challenging cancers to treat, often labeled as incurable. Chemotherapy continues to be the most popular treatment yet yields a very poor prognosis. The main barriers such as inefficient drug penetration and drug resistance, have led to the development of drug carrier systems. The benefits, ease of fabrication and modification of liposomes render them as ideal future drug delivery systems. This review delves into the versatility of liposomes to achieve various mechanisms of treatment for pancreatic cancer. Not only are there benefits of loading chemotherapy drugs and targeting agents onto liposomes, as well as mRNA combined therapy, but liposomes have also been exploited for immunotherapy and can be programmed to respond to photothermal therapy. Multifunctional liposomal formulations have demonstrated significant pre-clinical success. Functionalising drug-encapsulated liposomes has resulted in triggered drug release, specific targeting, and remodeling of the tumor environment. Suppressing tumor progression has been achieved, due to their ability to more efficiently and precisely deliver chemotherapy. Currently, no multifunctional surface-modified liposomes are clinically approved for pancreatic cancer thus we aim to shed light on the trials and tribulations and progress so far, with the hope for liposomal therapy in the future and improved patient outcomes. STATEMENT OF SIGNIFICANCE: Considering that conventional treatments for pancreatic cancer are highly associated with sub-optimal performance and systemic toxicity, the development of novel therapeutic strategies holds outmost relevance for pancreatic cancer management. Liposomes are being increasingly considered as promising nanocarriers for providing not only an early diagnosis but also effective, highly specific, and safer treatment, improving overall patient outcome. This manuscript is the first in the last 10 years that revises the advances in the application of liposome-based formulations in bioimaging, chemotherapy, phototherapy, immunotherapy, combination therapies, and emergent therapies for pancreatic cancer management. Prospective insights are provided regarding several advantages resulting from the use of liposome technology in precision strategies, fostering new ideas for next-generation diagnosis and targeted therapies of pancreatic cancer.

Stem cell membrane-coated abiotic nanomaterials for biomedical applications.

Nanoscale materials have been extensively employed for diagnostic and therapeutic purposes. However, the developed nanosystems still suffer from some limitations, namely the rapid elimination by the immune system, lack of targeting to specific cells, and insufficient biocompatibility. Therefore, novel strategies based upon a biomimetic approach have received attention to improving the pharmacokinetics and safety profile of nanosystems. One promising strategy is the application of a biomimetic coating consisting of cell membranes derived from different cell types onto nanoparticle cores. Stem cells have been investigated to develop targeted nanodevices owing to their excellent intrinsic tissue-specific homing features, protecting them from the immune system to reach the sites of inflammation. This targeting ability is conferred by a surface repertoire of stem cell-associated biomolecules. Such nanoscopical materials offer sustained circulation and boosted drug accumulation at target sites, augmenting therapeutic efficacy and safety. Additionally, the coating of nanoparticles with cell membranes acts as a camouflage mechanism to increase their circulation time. The current review explores the particular features of stem cell membrane coating as multifunctional biomimetic surface functionalization agents to camouflage nanoparticle cores. Biomedical applications of engineered stem cell membrane-coated nanoparticles, challenges in clinical translation, and their future prospects are addressed.

Naringenin: A potential flavonoid phytochemical for cancer therapy.

Naringenin is an important phytochemical which belongs to the flavanone group of polyphenols, and is found mainly in citrus fruits like grapefruits and others such as tomatoes and cherries plus medicinal plants derived food. Available evidence demonstrates that naringenin, as herbal medicine, has important pharmacological properties, including anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, and anti-cancer activities. Collected data from in vitro and in vivo studies show the inactivation of carcinogens after treatment with pure naringenin, naringenin-loaded nanoparticles, and also naringenin in combination with anti-cancer agents in various malignancies, such as colon cancer, lung neoplasms, breast cancer, leukemia and lymphoma, pancreatic cancer, prostate tumors, oral squamous cell carcinoma, liver cancer, brain tumors, skin cancer, cervical and ovarian cancer, bladder neoplasms, gastric cancer, and osteosarcoma. Naringenin inhibits cancer progression through multiple mechanisms, like apoptosis induction, cell cycle arrest, angiogenesis hindrance, and modification of various signaling pathways including Wnt/ß-catenin, PI3K/Akt, NF-ĸB, and TGF-ß pathways. In this review, we demonstrate that naringenin is a natural product with potential for the treatment of different types of cancer, whether it is used alone, in combination with other agents, or in the form of the naringenin-loaded nanocarrier, after proper technological encapsulation.

Macrophage Cell Membrane-Cloaked Nanoplatforms for Biomedical Applications.

Biomimetic approaches utilize natural cell membrane-derived nanovesicles to camouflage nanoparticles to circumvent some limitations of nanoscale materials. This emergent cell membrane-coating technology is inspired by naturally occurring intercellular interactions, to efficiently guide nanostructures to the desired locations, thereby increasing both therapeutic efficacy and safety. In addition, the intrinsic biocompatibility of cell membranes allows the crossing of biological barriers and avoids elimination by the immune system. This results in enhanced blood circulation time and lower toxicity in vivo. Macrophages are the major phagocytic cells of the innate immune system. They are equipped with a complex repertoire of surface receptors, enabling them to respond to biological signals, and to exhibit a natural tropism to inflammatory sites and tumorous tissues. Macrophage cell membrane-functionalized nanosystems are designed to combine the advantages of both macrophages and nanomaterials, improving the ability of those nanosystems to reach target sites. Recent studies have demonstrated the potential of these biomimetic nanosystems for targeted delivery of drugs and imaging agents to tumors, inflammatory, and infected sites. The present review covers the preparation and biomedical applications of macrophage cell membrane-coated nanosystems. Challenges and future perspectives in the development of these membrane-coated nanosystems are addressed.

Phytochemical-loaded liposomes for anticancer therapy: an updated review.

The major obstacles observed in current chemotherapy are severe adverse effects, narrow therapeutic indexes and multidrug resistance. Anticancer phytochemicals are extracted and purified from natural plants, providing alternative therapeutic approaches with recognized biomedical benefits. However, poor bioavailability, high dose requirements and non-specific targeting have made those molecules less effective. To tackle those issues, liposomal nanovesicles for phytochemical delivery are taken into consideration for improving the therapeutic effectiveness by increasing transportation across cell barriers and conferring attractive cancer-specific targeting capabilities. In the present review, the liposomal approaches of anticancer phytochemicals are discussed, and recent advances in these formulations applied to cancer phytotherapy are further reviewed by an informed approach.

This review describes the application of liposomal phyto-chemotherapy as a promising therapeutic and technological intervention against cancer that has the potential to enhance the effectiveness of cancer therapy, reduce the associated side effects and improve the clinical outcomes of cancer patients.

Ethosomes as Nanocarriers for the Development of Skin Delivery Formulations.

The use of nanotechnology has been extensively explored for developing efficient drug delivery systems towards topical and transdermal applications. Ethosomes constitute a vesicular nanocarrier containing a relatively high concentration of ethanol (20-45%). Ethanol is a well-known permeation enhancer, which confers ethosomes unique features, including high elasticity and deformability, allowing them to penetrate deeply across the skin and enhance drug permeation and deposition. The improved composition of ethosomes offer, thereby, significant advantages in the delivery of therapeutic agents over particularly the conventional liposomes regarding different pathologies, including acne, psoriasis, alopecia, skin infections, hormonal deficiencies, among others. This review provides a comprehensive overview of the ethosomal system and an assessment of its potential as an efficient nanocarrier towards the skin delivery of active ingredients. Special attention is given to the composition of ethosomes and the mechanism of skin permeation, as well as their potential applications in different pathologies, particularly skin pathologies (acne, psoriasis, atopic dermatitis, skin cancer and skin infections). Some examples of ethosome-based formulations for the management of skin disorders are also highlighted. Besides the need for further studies, particularly in humans, ethosomal-based formulations hold great promise in the skin delivery of active ingredients, which increasingly asserts oneself as a viable alternative to the oral route.

Naringenin Nano-Delivery Systems and Their Therapeutic Applications.

Naringenin (NRG) is a polyphenolic phytochemical belonging to the class of flavanones and is widely distributed in citrus fruits and some other fruits such as bergamot, tomatoes, cocoa, and cherries. NRG presents several interesting pharmacological properties, such as anti-cancer, anti-oxidant, and anti-inflammatory activities. However, the therapeutic potential of NRG is hampered due to its hydrophobic nature, which leads to poor bioavailability. Here, we review a wide range of nanocarriers that have been used as delivery systems for NRG, including polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanosuspensions, and nanoemulsions. These nanomedicine formulations of NRG have been applied as a potential treatment for several diseases, using a wide range of in vitro, ex vivo, and in vivo models and different routes of administration. From this review, it can be concluded that NRG is a potential therapeutic option for the treatment of various diseases such as cancer, neurological disorders, liver diseases, ocular disorders, inflammatory diseases, skin diseases, and diabetes when formulated in the appropriate nanocarriers.

Plant-mediated green synthesis of metal-based nanoparticles for dermopharmaceutical and cosmetic applications.

The skin is the primordial barrier that protects the human body against environmental factors. Due to the arise of dermatological pathologies, the development of efficient delivery systems for topical applications has received increased interest. The highest challenge consists of increasing the penetration of the active ingredients through the skin barrier, alongside to the need of obtaining enough skin retention to achieve therapeutic concentrations. Metals, specially noble metals, have been used for years to treat and prevent health issues, among them dermatological disorders. Nanoparticles have been extensively used for topical applications given their advantages, namely by enhancing solubility of apolar drugs, the possibility of controlled release, the higher stability and the capability to target specific areas and delivery of high concentrations of active ingredients. In order to take advantage of the before mentioned unique properties of nanoparticles and the biological activities of metals, various metal-based nanoparticles (MNPs) have been synthesized in the past few years, such as silver (AgNPs), gold (AuNPs), zinc (ZnNPs), zinc oxide (ZnONPs), copper (CuNPs) and copper oxide (CuONPs) nanoparticles. These MNPs are flexible structures that allow the control of physical characteristics, with enhanced surface properties, which provides a high applicability in dermopharmacy and cosmetics. The conventional methods for synthesizing nanoparticles (physical and chemical approaches) are associated with major drawbacks, being the most concerning the high cost (in resources, energy, time and space) and human/environmental toxicity. Hence, the need to develop an alternative synthesis pathway was imposed, giving rise to the green synthesis methodology. In general, green synthesis consist of using biological sources (plants, bacteria or fungi) to synthesize ecological benign, non-hazard and biocompatible nanoparticles. With the development of green synthesis, starting materials have been used more frequently, among them plants. Plant-mediated green synthesis of nanoparticles is based on the use of plant extracts to synthesize nanoparticles, and their outstanding advantages have paved the way for exciting developments on nanoparticle synthesis to the detriment of complex and toxicity-associated chemical and physical synthesis. MNPs produced by plant-mediated synthesis also demonstrate notorious biological activities, i.e., anticancer, antioxidant, anti-inflammatory, antimicrobial, wound healing and antiaging activities. However, safety assessment of phyto MNPs (phyto-MNPs) holds significant importance due to the lack of toxicological studies and the conception issues that some of the available studies show. In general, current studies suggest the biocompatibility and safety of phyto-MNPs, together with significantly improved and relevant biological activities towards dermopharmaceutical and cosmetic applications. Against this backdrop, there is still a long way to run until the application of phyto-MNPs in the medical, pharmaceutical and cosmetic fields, but studies so far show a very high potential towards their clinical translation for dermopharmaceutical and cosmetics applications. This review focuses on phyto-MNPs synthesized resorting to various plant extracts, including their production, characterization and the biological activities that support their topical application for dermopharmaceutical and cosmetic purposes.

Cyclodextrin-based delivery systems for in vivo-tested anticancer therapies.

Cyclodextrins (CDs) are naturally occurring macromolecules widely used as excipients on pharmaceutical formulations, evidencing a large spectrum of applications in the pharmaceutical industry. Their unique ability to act as molecular containers by entrapping a wide range of guest molecules in their internal cavity makes them a remarkable excipient to improve drug apparent solubility, stability, and bioavailability, and a valuable tool for the assembly of new drug delivery systems. These features are especially useful when it comes to chemotherapy, as most of the anticancer drugs present both low permeability and reduced water solubility. Therefore, guest-host inclusion complexes offer several potential advantages not only regarding the improvement of pharmaceutical formulations characteristics but also considering the reduction of drug toxic side effects. The combination of CDs with additional technologies and materials constitutes a potential strategy towards the development of advanced and multifunctional CD-based delivery systems. Paclitaxel, curcumin, camptothecin, doxorubicin, and cisplatin are among the most studied molecules with anticancer activities and have been successfully incorporated in such nanosystems. Exciting results using CDs and CD-based delivery systems have been obtained so far, paving the way towards the attainment of intelligent delivery systems to possibly address cancer therapeutics' unmet needs. In this review, a comprehensive exposition concerning in vivo-tested CD and CD-based delivery systems for anticancer therapy is undertaken. Additionally, the authors address the multivalent functionalities of CD-based delivery systems, namely the incorporation of active target ligands, stimuli-responsiveness components, surface functionalization, or further associations with other delivery systems, aiming at improved in vivo anticancer therapies. Graphical abstract.

Sarcoma treatment in the era of molecular medicine.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Micelleplex-based nucleic acid therapeutics: From targeted stimuli-responsiveness to nanotoxicity and regulation.

Cell-targeted nucleic acid (NA) therapeutics, either DNA- or RNA-based, have experienced considerable attention regarding their potential applications in gene expression modulation aiming at disease management. However, the therapeutic potential of NAs as selective, safe and multispecific biomolecules is principally hindered by their instability in biological fluids and deficient cellular uptake, urgently calling for intelligent design strategies such as NA loading in effective nanosystems. In this regard, NA delivery nanosystems which bypass biological hurdles and are capable of safeguarding the NA payload have been extensively explored so far. Micelleplexes consist of tailored and multifunctional micelle-like nanoassemblies of negatively-charged NAs complexed with cationic blocks, generally of polymeric nature, this way ensuring efficient NA protection and transportation, as well as enhanced cellular transfection and boosted intracellular trafficking. Herein, we review the biomedical applications of stable micelleplexes as robust and smart NA delivery nanosystems focusing on the fine-tuning of their properties toward stimuli-responsiveness and the nanosystem's versatility to accommodate distinct ligands for selective tissue-targeting purposes. Additionally, the nanosafety and regulatory considerations of micelleplexes will also be discussed toward the future clinical translation of micelleplexes for efficient NA delivery to cells, paving the way to next-generation micelleplex-based NA therapeutics.

Micelleplexes as nucleic acid delivery systems for cancer-targeted therapies.

Cancer remains one of the leading causes of death worldwide despite significant therapeutic advancements and improved detection methods. Nucleic acid (NA) therapeutics are receiving increasing attention for cancer management and cure. Indeed, ribonucleic acid (RNA) oligonucleotides (such as small interfering RNA (siRNA) and micro RNA (miRNA)), messenger RNA (mRNA) and deoxyribonucleic acid (DNA) (such as plasmidic DNA (pDNA) and minicircle DNA (mcDNA)), have demonstrated potential as novel therapeutic agents. The imposing prospects of NA-based therapeutics reside in their ability to act as key-players mediating cellular pathways and bestowing potent gene silencing properties, as in the case of RNA interference (RNAi) agents, or by promoting the expression of specific required proteins for disease management (pDNA, mcDNA and mRNA, for instance). However, efficient NA therapeutics delivery is seriously hampered by NA physicochemical features, low in vivo serum stability and compromised cellular internalization, which swiftly reduce their biological activities. Recently, nano-based systems emerged as suitable vehicles for NA delivery. This review covers NA-carrying micelleplexes as robust and multifunctional polymer-based NA delivery systems, as well as the specific in vivo challenges for successful NA delivery to cancer cells and their prospects to become clinical reality, followed by a critical analysis of the major in vivo micelleplex-based cancer-targeted strategies accomplished till the present day.

Nanomedicine in osteosarcoma therapy: Micelleplexes for delivery of nucleic acids and drugs toward osteosarcoma-targeted therapies.

Osteosarcoma(OS) represents the main cancer affecting bone tissue, and one of the most frequent in children. In this review we discuss the major pathological hallmarks of this pathology, its current therapeutics, new active biomolecules, as well as the nanotechnology outbreak applied to the development of innovative strategies for selective OS targeting. Small RNA molecules play a role as key-regulator molecules capable of orchestrate different responses in what concerns cancer initiation, proliferation, migration and invasiveness. Frequently associated with lung metastasis, new strategies are urgent to upgrade the therapeutic outcomes and the life-expectancy prospects. Hence, the prominent rise of micelleplexes as multifaceted and efficient structures for nucleic acid delivery and selective drug targeting is revisited here with special emphasis on ligand-mediated active targeting. Future landmarks toward the development of novel nanostrategies for both OS diagnosis and OS therapy improvements are also discussed.

Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence.

Resveratrol (RSV) is a polyphenol endowed with potential therapeutic effects in chronic diseases, particularly in cancer, the second leading cause of death worldwide in the twenty-first century. The advent of nanotechnology application in the field of drug delivery allows to overcome the constrains associated with the conventional anticancer treatments, in particular chemotherapy, reducing its adverse side effects, off target risks and surpassing cancer multidrug chemoresistance. Moreover, the use of nanotechnology-based carriers in the delivery of plant-derived anticancer agents, such as RSV, has already demonstrated to surpass the poor water solubility, instability and reduced bioavailability associated with phytochemicals, improving their therapeutic activity, thus prompting pharmaceutical developments. This review highlights the in vivo anticancer potential of RSV achieved by nanotherapeutic approaches. First, RSV physicochemical, stability and pharmacokinetic features are described. Thereupon, the chemotherapeutic and chemopreventive properties of RSV are underlined, emphasizing the RSV numerous cancer molecular targets. Lastly, a comprehensive analysis of the RSV-loaded nanoparticles (RSV-NPs) developed and administered in different in vivo cancer models to date is presented. Nanoparticles (NPs) have shown to improve RSV solubility, stability, pharmacokinetics and biodistribution in cancer tissues, enhancing markedly its in vivo anticancer activity. RSV-NPs are, thus, considered a potential nanomedicine-based strategy to fight cancer; however, further studies are still necessary to allow RSV-NP clinical translation.

Nanotechnology-based formulations for resveratrol delivery: Effects on resveratrol in vivo bioavailability and bioactivity.

Resveratrol (RES), also known as 3,5,4'-trihydroxystilbene, is a polyphenolic phytoalexin that has been widely researched in the past decade due to its recognized numerous biological activities. Despite the potential benefits of RES, its effective use is limited due to its poor solubility, photosensitivity and rapid metabolism, which strongly undermine RES bioavailability and bioactivity. Thereby, recently, nanotechnology appeared as a potential strategy to circumvent RES physicochemical and pharmacokinetics constrains. However, only few studies have addressed the crucial in vivo suitability of the developed delivery systems to improve RES efficacy. Facing this scenario, in the present review, it is intended to present and discuss the in vivo resveratrol bioavailability and bioactivity, following its encapsulation or conjugation in nanotechnology-based carriers, contemplating their pharmacokinetics effectiveness.