Project description:Treatment of neurodegenerative diseases or other central nervous system (CNS) disorders has always been a significant challenge. The nature of the blood-brain barrier (BBB) limits the penetration of therapeutic molecules to the brain after oral or parenteral administration, which, in combination with hepatic metabolism and drug elimination and inactivation during its journey in the systemic circulation, decreases the efficacy of the treatment, requires high drug doses and often induces adverse side effects. Nose-to-brain drug delivery allows the direct transport of therapeutic molecules by bypassing the BBB and increases drug concentration in the brain. The present review describes mechanisms of nose-to-brain drug delivery and discusses recent advances in this area with especial emphasis on nanotechnology-based approaches.
Project description:Intranasal drug administration is a promising method for delivering drugs directly to the brain. Animal studies have described pathways and potential brain targets, but nose-to-brain delivery and treatment efficacy in humans remains debated. We describe the proposed pathways and barriers for nose-to-brain drug delivery in humans, drug properties that influence central nervous system delivery, clinically tested methods to enhance absorption, and the devices used in clinical trials. This review compiles the available evidence for nose-to-brain drug delivery in humans and summarizes the factors involved in nose-to-brain drug delivery.
Project description:Despite the enormity of the societal and health burdens caused by Alzheimer's disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood-brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder.
Project description:Chemotherapy-related cognitive deficits (CRCI) as one of the common adverse drug reactions during chemotherapy that manifest as memory, attention, and executive function impairments. However, there are still no effective pharmacological therapies for the treatment of CRCI. Natural compounds have always inspired drug development and numerous natural products have shown potential therapeutic effects on CRCI. Nevertheless, improving the brain targeting of natural compounds in the treatment of CRCI is still a problem to be overcome at present and in the future. Accumulated evidence shows that nose-to-brain drug delivery may be an excellent carrier for natural compounds. Therefore, we reviewed natural products with potential anti-CRCI, focusing on the signaling pathway of these drugs' anti-CRCI effects, as well as the possibility and prospect of treating CRCI with natural compounds based on nose-to-brain drug delivery in the future. In conclusion, this review provides new insights to further explore natural products in the treatment of CRCI.
Project description:NeuroAIDS (Neuro Acquired Immunodeficiency Syndrome) or HIV (Human Immunodeficiency Virus) associated neuronal abnormality is continuing to be a significant health issue among AIDS patients even under the treatment of combined antiretroviral therapy (cART). Injury and damage to neurons of the brain are the prime causes of neuroAIDS, which happens due to the ingress of HIV by direct permeation across the blood-brain barrier (BBB) or else via peripherally infected macrophage into the central nervous system (CNS). The BBB performs as a stringent barricade for the delivery of therapeutics drugs. The intranasal route of drug administration exhibits as a non-invasive technique to bypass the BBB for the delivery of antiretroviral drugs and other active pharmaceutical ingredients inside the brain and CNS. This method is fruitful for the drugs that are unable to invade the BBB to show its action in the CNS and thus erase the demand of systemic delivery and thereby shrink systemic side effects. Drug delivery from the nose to the brain/CNS takes very less time through both olfactory and trigeminal nerves. Intranasal delivery does not require the involvement of any receptor as it occurs by an extracellular route. Nose to brain delivery also involves nasal associated lymphatic tissues (NALT) and deep cervical lymph nodes. However, very little research has been done to explore the utility of nose to brain delivery of antiretroviral drugs in the treatment of neuroAIDS. This review focuses on the potential of nasal route for the effective delivery of antiretroviral nanoformulations directly from nose to the brain.
Project description:A valid option to bypass the obstacle represented by the blood-brain barrier (BBB) in brain delivery is the use of the unconventional intranasal route of administration. The treatment of depressive diseases, resulting from the depletion of a neurotransmitter in the inter-synaptic space, such as serotonin, is indirectly treated using molecules that can permeate the BBB unlike the latter. In the present article, a set of nanovectors were produced using a mucoadhesive biopolymer, i.e. alginate (Alg). Optimizing the reaction, polymeric nanoparticles having diameter of 30-70 nm were produced, and water stable multi-walled carbon nanotubes functionalized (MWCNT-COOH)/Alg complexes were obtained. These nanovectors were loaded with serotonin, evaluating drug loading/release. By means of Raman microscopy, the cellular internalization of the (MWCNT-COOH)/Alg complex was demonstrated. A complete biocompatibility on neuronal cells was proved for the whole set of nanovectors. Finally, a method of self-administration was tested, which involves the use of a household apparatus, such as an aerosol machine, observing a fine particulate, able to deliver the nanovectors through the nose.
Project description:Research on the neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) and its use as a therapeutic agent has grown over the past 30 years. Both in vitro and in vivo experiments have shown that PACAP exerts a strong neuroprotective effect in many central and peripheral neuronal diseases. Various delivery routes have been employed from intravenous (IV) injections to intracerebroventricular (ICV) administration, leading either to systemic or topical delivery of the peptide. Over the last decade, a growing interest in the use of intranasal (IN) administration of PACAP and other therapeutic agents has emerged as an alternative delivery route to target the brain. The aim of this review is to summarize the findings on the neuroprotective effect of PACAP and to discuss how the IN administration of PACAP could contribute to target the effects of this pleiotropic peptide.
Project description:Cachexia, a severe multifactorial condition that is underestimated and unrecognized in patients, is characterized by continuous muscle mass loss that leads to progressive functional impairment, while nutritional support cannot completely reverse this clinical condition. There is a strong need for more effective and targeted therapies for cachexia patients. There is a need for drugs that act on cachexia as a distinct and treatable condition to prevent or reverse excess catabolism and inflammation. Due to ghrelin properties, it has been studied in the cachexia and other treatments in a growing number of works. However, in the body, exogenous ghrelin is subject to very rapid degradation. In this context, the intranasal release of ghrelin-loaded liposomes to cross the blood-brain barrier and the release of the drug into the central nervous system may be a promising alternative to improve its bioavailability. The administration of nose-to-brain liposomes for the management of cachexia was addressed only in a limited number of published works. This review focuses on the discussion of the pathophysiology of cachexia, synthesis and physiological effects of ghrelin and the potential treatment of the diseased using ghrelin-loaded liposomes through the nose-to-brain route.
Project description:Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the brain is challenging due to their low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit peptides' clinical application and explain the interest in alternative routes of peptide administration, particularly nose-to-brain (N-to-B) delivery, which allows protein and peptide drugs to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure; the olfactory and trigeminal nerves provide a unique pathway to the brain and the external environment. This review highlights the intranasal delivery of drugs, focusing on peptide delivery, illustrating various clinical applications, nasal delivery devices, and the scope and limitations of this approach.
Project description:Cerebral ischemia (CI) results from inadequate blood flow to the brain. The difficulty of delivering therapeutic molecules to lesions resulting from CI hinders the effective treatment of this disease. The inflammatory response following CI offers a unique opportunity for drug delivery to the ischemic brain and targeted cells because of the recruitment of leukocytes to the stroke core and penumbra. In the present study, neutrophils and monocytes were explored as cell carriers after selectively carrying cRGD liposomes, which effectively transmigrated the blood-brain barrier, infiltrated the cerebral parenchyma, and delivered therapeutic molecules to the injured sites and target cells. Our results showed the successful comigration of liposomes with neutrophils/monocytes and that both monocytes and neutrophils were important for successful delivery. Enhanced protection against ischemic injury was achieved in the CI/reperfusion model. The strategy presented here shows potential in the treatment of CI and other diseases related to inflammation.