Liposomal cytarabine as cancer therapy: From chemistry to medicine

Cancer is the second leading cause of death worldwide. The main modality to fight against cancer is surgery, radiotherapy, and chemotherapy, and more recently targeted therapy, gene therapy and immunotherapy, which play important roles in treating cancer patients. In the last decades, chemotherapy has been well developed. Nonetheless, administration of the drug is not always successful, as limited drug dosage can reach the tumor cells.. In this context, the possibility to use an encapsulated anti-cancer drug may potentially solve the problem. Liposomal cytarabine is a formulation with pronounced effectiveness in lymphomatous meningitis and reduced cardiotoxicity if compared to liposomal anthracyclines. Thus, the future liposomal cytarabine use could be extended to other diseases given its reduction in cytotoxic side effects compared to the free formulation. This review summarizes the chemistry and biology of liposomal cytarabine, with exploration of its clinical implications.N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal) for the strategic project ref. UID/BIM/04293/2013 and "NORTE2020 - Programa Operacional Regional do Norte" (NORTE-01-0145-FEDER-000012). M. Martorell would like to thank the support offered by CONICYT PIA/APOYO CCTE AFB170007

Managing CNS Tumors: The Nanomedicine Approach

Albeit the rapidly evolving knowledge about tumor biochemistry enables various new drug molecules to be designed as treatments, malignant central nervous system (CNS) tumors remain untreatable due to the failure to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, drug delivery in CNS tumors must be properly addressed, as otherwise, novel therapies will continue to fail. In this regard, nanomedicine poses an appealing platform for efficient drug delivery to the CNS, since it may be targeted to improve the drug availability in the site of action, which would be translated into lower drug doses and fewer side effects. Hence, the accumulation of data about the CNS physiology and their relevant receptors, the widening therapeutic armamentarium of drugs potentially useful in CNS chemotherapy and the alternative routes for administration may envisage nanomedicines as a forthcoming routine approach. Indeed, on the basis of the promising results gathered from preclinical studies of nanomedicine-based therapy both systemically and locally administered, some nanomedicines have already been approved for clinical trials in a variety of CNS tumor conditions to serve as the first steps in the translation of nanotherapy to clinic. Their outcome will steer research directions for further improvements

Improving the Brain Delivery of Chemotherapeutic Drugs in Childhood Brain Tumors

The central nervous system (CNS) may be considered as a sanctuary site, protected from systemic chemotherapy by the meninges, the cerebrospinal fluid (CSF) and the blood-brain barrier (BBB). Consequently, parenchymal and CSF exposure of most antineoplastic agents following intravenous (IV) administration is lower than systemic exposure. In this review, we describe the different strategies developed to improve delivery of antineoplastic agents into the brain in primary and metastatic CNS tumors. We observed that several methods, such as BBB disruption (BBBD), intra-arterial (IA) and intracavitary chemotherapy, are not routinely used because of their invasiveness and potentially serious adverse effects. Conversely, intrathecal (IT) chemotherapy has been safely and widely practiced in the treatment of pediatric primary and metastatic tumors, replacing the neurotoxic cranial irradiation for the treatment of childhood lymphoma and acute lymphoblastic leukemia (ALL). IT chemotherapy may be achieved through lumbar puncture (LP) or across the Ommaya intraventricular reservoir, which are both described in this review. Additionally, we overviewed pharmacokinetics and toxic aspects of the main IT antineoplastic drugs employed for primary or metastatic childhood CNS tumors (such as methotrexate, cytosine arabinoside, hydrocortisone), with a concise focus on new and less used IT antineoplastic agents

Nanomedicine for the Treatment of Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma, or NHL, is the predominant category of lymphoma. NHL is a type of lymphoid hematopoietic malignancy which approximately 70,000 Americans are diagnosed with annually, with the number of diagnoses growing annually. For decades, chemotherapy was the standard treatment of care, but since the discovery in 1997, monoclonal antibodies are increasingly used as an alternate form of therapy. Nonetheless, almost 20,000 Americans succumb to NHL annually, which highlights the translational gap between preclinical research and the market. Although a lot of progress has been made in therapy options by immunotherapy and combination chemotherapy, the ingenuity of nanomedicine may bridge the translational difficulties while serving as a novel form of therapy capable of eradicating solid tumors. The versatility of nanoparticles allows for personalized approach to NHL, as opposed to generalized medicine, since the subtypes of lymphoma are pathologically very different from one another

Medicamentos procedentes de la nanotecnología

El origen de la nanotecnología resulta indiscutiblemente ligado al científico norteamericano Richard Feynman (Nueva York,1918), laureado con el premio Nobel de Física en 1965. En 1974, el científico japonés, Norio Taniguchi, fue el primero en usar el término nanotecnología para describir los procesos semiconductores que ocurren en el orden de un nanómetro. No fue hasta la década de los años 80 del siglo XX, la era dorada de la nanotecnología, cuando se realizaron una serie de importantes descubrimientos e invenciones que generaron un gran impacto en el desarrollo de la nanotecnología. Desde sus inicios, la nanotecnología se ha aplicado a numerosos campos, entre ellos las ciencias de la salud, donde ha dado lugar a nuevas disciplinas denominadas nanomedicina y nanofarmacia. Cada vez existe más variedad de productos farmacéuticos basados en la nanotecnología en el mercado, debido al progresivo aumento de las enfermedades crónicas para las que no existen tratamientos definitivos y las formulaciones nanoterapeúticas presentan grandes ventajas frente a las convencionales. El objetivo de esta revisión bibliográfica es conocer y clasificar los principales medicamentos procedentes de la nanotecnología, así como, observar sus ventajas frente a los medicamentos convencionales y analizar las nuevas perspectivas de futuro en el uso de estas formulaciones. Actualmente, una gran variedad de productos farmacéuticos basados en nanotecnología se ha introducido con éxito en el mercado siendo prescritos a diario a un elevado número de pacientes. Los nanofármacos más conocidos se clasifican en función del tipo de nanoformulación. Estos grupos son: nanocristales, liposomas y nanopartículas basadas en lípidos, nanopartículas poliméricas, nanopartículas basadas en proteínas y nanopartículas metálicas.Universidad de Sevilla. Grado en Farmaci

Development of Cytarabine Prodrugs and Delivery Systems for Leukemia Treatment

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin’s lymphoma. The drug has a short plasma half-life, low stability, and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been extensively explored to enhance the half-life, stability, and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in phase 3 trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt®) has been approved for the treatment of lymphomatous meningitis. Areas covered in this review: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy. What reader will gain: This review provides in-depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provide insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability. Take home message: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents