Do Lipid-based Nanoparticles Hold Promise for Advancing the Clinical Translation of Anticancer Alkaloids?
Ontology highlight
ABSTRACT: Since the commercialization of morphine in 1826, numerous alkaloids have been isolated and exploited effectively for the betterment of mankind, including cancer treatment. However, the commercialization of alkaloids as anticancer agents has generally been limited by serious side effects due to their lack of specificity to cancer cells, indiscriminate tissue distribution and toxic formulation excipients. Lipid-based nanoparticles represent the most effective drug delivery system concerning clinical translation owing to their unique, appealing characteristics for drug delivery. To the extent of our knowledge, this is the first review to compile in vitro and in vivo evidence of encapsulating anticancer alkaloids in lipid-based nanoparticles. Alkaloids encapsulated in lipid-based nanoparticles have generally displayed enhanced in vitro cytotoxicity and an improved in vivo efficacy and toxicity profile than free alkaloids in various cancers. Encapsulated alkaloids also demonstrated the ability to overcome multidrug resistance in vitro and in vivo. These findings support the broad application of lipid-based nanoparticles to encapsulate anticancer alkaloids and facilitate their clinical translation. The review then discusses several limitations of the studies analyzed, particularly the discrepancies in reporting the pharmacokinetics, biodistribution and toxicity data. Finally, we conclude with examples of clinically successful encapsulated alkaloids that have received regulatory approval and are undergoing clinical evaluation.
Project description:Resolvins are a novel class of lipid-derived endogenous molecules (autacoids) with potent immunomodulating properties, which regulate the resolution phase of an active immune response. These modulating factors are locally produced, influencing the function of cells and/or tissues, which are produced on demand and subsequently metabolized in the same cells and/or tissues. This review is focused on certain lipid autacoids with putative relevance for ophthalmology in general and for dry eye more specifically. We also briefly investigate the concept of aliamides and the role of palmitoylethanolamide in ophthalmology, and analyze in more detail the putative role and the preclinical and clinical development of resolvins as emerging treatments for dry eye and related disorders, with a focus on one of the lead resolvin derivatives - RX-10045.
Project description:Neurorestorative therapies for stroke aim to reverse disability by reparative mechanisms (rather than to thrombolyse or to neuroprotect). A substantial and persuasive body of pre-clinical evidence has come from the evaluation of antibodies against Nogo-A (a myelin-associated inhibitor of plasticity) in rat models of stroke. Particularly impressive is the benefit of this therapy in models of permanent middle cerebral artery occlusion (MCAO) when given to elderly animals after a one week delay, in adult rats with co-morbidities, and in adult rats when treatment is delayed by up to 9 weeks after stroke (although antibodies against Nogo-A did not reverse disability in mice after proximal MCAO with reperfusion). We predict that antibodies against Nogo-A will improve outcome further when combined with suitable additional rehabilitation, and also that antibodies against Nogo-A will improve outcome in animal models of haemmorhagic stroke that affect the same brain regions as ischemic stroke caused by MCAO. Antibodies against Nogo-A have been shown to be safe in Phase I clinical trials for acute spinal cord injury, and this may eventually facilitate a trial in stroke.
Project description:Gold nanoparticles display unique physicochemical features, which can be useful for therapeutic purposes. After two decades of preclinical progress, gold nanoconstructs are slowly but steadily transitioning into clinical trials. Although initially thought to be "magic golden bullets" that could be used to treat a wide range of diseases, current consensus has moved toward a more realistic approach, where gold nanoformulations are being investigated to treat specific disorders. These therapeutic applications are dictated by the pharmacokinetics and biodistribution profiles of gold nanoparticles. Here, we analyze the current clinical landscape of therapeutic gold nanoconstructs, discuss the shared characteristics that allowed for their transition from bench to bedside, and examine existing hurdles that need to be overcome before they can be approved for clinical use.
Project description:Silica nanoparticles have entered clinical trials for a variety of biomedical applications, including oral drug delivery, diagnostics, plasmonic resonance and photothermal ablation therapy. Preliminary results indicate the safety, efficacy and viability of silica nanoparticles under these clinical scenarios.
Project description:Radiation has been utilized for a long time for the treatment of cancer patients. However, radiotherapy (RT) has many constraints, among which non-selectivity is the primary one. The implementation of nanoparticles (NPs) with RT not only localizes radiation in targeted tissue but also provides significant tumoricidal effect(s) compared to radiation alone. NPs can be functionalized with both biomolecules and therapeutic agents, and their combination significantly reduces the side effects of RT. NP-based RT destroys cancer cells through multiple mechanisms, including ROS generation, which in turn damages DNA and other cellular organelles, inhibiting of the DNA double-strand damage-repair system, obstructing of the cell cycle, regulating of the tumor microenvironment, and killing of cancer stem cells. Furthermore, such combined treatments overcome radioresistance and drug resistance to chemotherapy. Additionally, NP-based RT in combined treatments have shown synergistic therapeutic benefit(s) and enhanced the therapeutic window. Furthermore, a combination of phototherapy, i.e., photodynamic therapy and photothermal therapy with NP-based RT, not only reduces phototoxicity but also offers excellent therapeutic benefits. Moreover, using NPs with RT has shown promise in cancer treatment and shown excellent therapeutic outcomes in clinical trials. Therefore, extensive research in this field will pave the way toward improved RT in cancer treatment.
Project description:Nanotechnology takes the lead in providing new therapeutic options for cancer patients. In the last decades, lipid-based nanoparticles-solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, and lipid-polymer hybrid nanoparticles-have received particular interest in anticancer drug delivery to solid tumors. To improve selectivity for target cells and, thus, therapeutic efficacy, lipid nanoparticles have been functionalized with antibodies that bind to receptors overexpressed in angiogenic endothelial cells or cancer cells. Most papers dealing with the preclinical results of antibody-conjugated nanoparticles claim low systemic toxicity and effective tumor inhibition, which have not been successfully translated into clinical use yet. This review aims to summarize the current "state-of-the-art" in anticancer drug delivery using antibody-functionalized lipid-based nanoparticles. It includes an update on promising candidates that entered clinical trials and some explanations for low translation success.
Project description:Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans worldwide. Because a vaccine is not available and the currently small number of existing drugs are less than ideal due to lack of specificity and emerging drug resistance, the need for new therapeutic strategies is urgent. Natural products and their derivatives are being used and explored as therapeutics and interest in developing such products as antileishmanials is high. The enzyme arginase, the first enzyme of the polyamine biosynthetic pathway in Leishmania, has emerged as a potential therapeutic target. The flavonols quercetin and fisetin, green tea flavanols such as catechin (C), epicatechin (EC), epicatechin gallate (ECG), and epigallocatechin-3-gallate (EGCG), and cinnamic acid derivates such as caffeic acid inhibit the leishmanial enzyme and modulate the host's immune response toward parasite defense while showing little toxicity to the host. Quercetin, EGCG, gallic acid, caffeic acid, and rosmarinic acid have proven to be effective against Leishmania in rodent infectivity studies. Here, we review research on these natural products with a focus on their promise for the development of treatment strategies as well as unique structural and pharmacokinetic/pharmacodynamic features of the most promising agents.
Project description:Colon cancer poses a complex and substantial global health challenge, necessitating innovative therapeutic approaches. Chalcones, a versatile class of compounds with diverse pharmacological properties, have emerged as promising candidates for addressing colon cancer. Their ability to modulate pivotal signaling pathways in the development and progression of colon cancer makes them invaluable as targeted therapeutics. Nevertheless, it is crucial to recognize that although chalcones exhibit promise, further pre-clinical studies are required to validate their efficacy and safety. The journey toward effective colon cancer treatment is multifaceted, involving considerations such as optimizing the sequencing of therapeutic agents, comprehending the resistance mechanisms, and exploring combination therapies incorporating chalcones. Furthermore, the integration of nanoparticle-based drug delivery systems presents a novel avenue for enhancing the effectiveness of chalcones in colon cancer treatment. This review delves into the mechanisms of action of natural chalcones and some derivatives. It highlights the challenges associated with their use in pre-clinical studies, while also underscoring the advantages of employing chalcone-based nanoparticles for the treatment of colon cancer.
Project description:Nanocarrier systems are widely used for drug delivery applications, but limitations such as the use of synthetic surfactants, leakage of toxic drugs, and a poor encapsulation capacity remain as challenges. We present a new hybrid nanocarrier system that utilizes natural materials to overcome these limitations and improve the safety and efficacy of drug delivery. The system comprises a biopolymeric shell and a lipid core, encapsulating the lipophilic anticancer drug paclitaxel. Bovine serum albumin and dextran, in various molecular weights, are covalently conjugated via Maillard reaction to form the shell which serves as a stabilizer to maintain nanoparticle integrity. The properties of the system, such as Maillard conjugate concentration, protein/polysaccharide molar ratio, and polysaccharide molecular weight, are optimized to enhance nanoparticle size and stability. The system shows high stability at different pH conditions, high drug loading capacity, and effective in vitro drug release through the trigger of enzymes and passive diffusion. Serine proteases are used to digest the protein portion of the nanoparticle shell to enhance the drug release. This nanocarrier system represents a significant advancement in the field of nanomedicine, offering a safe and effective alternative for the delivery of lipophilic drugs.