Lipid Nanocarriers for Oligonucleotide Delivery to the Brain

Glioblastoma (GBM) is the most malignant form of all primary brain tumors, and it is responsible for around 200,000 deaths each year worldwide. The standard therapy for GBM treatment includes surgical resection followed by temozolomide-based chemotherapy and/or radiotherapy. With this treatment, the median survival rate of GBM patients is only 15 months after its initial diagnosis. Therefore, novel and better treatment modalities for GBM treatment are urgently needed. Mounting evidence indicates that non-coding RNAs (ncRNAs) have critical roles as regulators of gene expression. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are among the most studied ncRNAs in health and disease. Dysregulation of ncRNAs is observed in virtually all tumor types, including GBMs. Several dysregulated miRNAs and lncRNAs have been identified in GBM cell lines and GBM tumor samples. Some of them have been proposed as diagnostic and prognostic markers, and as targets for GBM treatment. Most ncRNA-based therapies use oligonucleotide RNA molecules which are normally of short life in circulation. Nanoparticles (NPs) have been designed to increase the half-life of oligonucleotide RNAs. An additional challenge faced not only by RNA oligonucleotides but for therapies designed for brain-related conditions, is the presence of the blood-brain barrier (BBB). The BBB is the anatomical barrier that protects the brain from undesirable agents. Although some NPs have been derivatized at their surface to cross the BBB, optimal NPs to deliver oligonucleotide RNA into GBM cells in the brain are currently unavailable. In this review, we describe first the current treatments for GBM therapy. Next, we discuss the most relevant miRNAs and lncRNAs suggested as targets for GBM therapy. Then, we compare the current drug delivery systems (nanocarriers/NPs) for RNA oligonucleotide delivery, the challenges faced to send drugs through the BBB, and the strategies to overcome this barrier. Finally, we categorize the critical points where research should be the focus in order to design optimal NPs for drug delivery into the brain; and thus move the Oligonucleotide RNA-based therapies from the bench to the clinical setting.

Download Full-text

Lipid nanocarriers for neurotherapeuticals: Introduction, challenges, blood-brain barrier and promises of delivery approaches

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210706104240 ◽

2021 ◽

Vol 20 ◽

Author(s):

Mohammed Aslam ◽

Md. Noushad Javed ◽

Hala Hasan Deeb ◽

Michel Kaisar Nicola ◽

Aamir Mirza ◽

...

Keyword(s):

Blood Brain Barrier ◽

Targeted Delivery ◽

Water Soluble ◽

Brain Barrier ◽

Synthetic Drugs ◽

Blood Brain ◽

Water Soluble Drugs ◽

Lipid Nanocarriers ◽

Disor Ders ◽

The Brain

: Significant efforts are being made in research to discover newer neurotherapeuticals, but the rate of reported neurological disorders has been increasing at an alarming speed. Neurothera-peuticals delivery in the brain is still posing a significant challenge, owing to the blood-brain barrier and blood-cerebrospinal fluid barrier. These physiological barriers restrict the passage of systemically available fractions of neurotherapeuticals into the brain, owing to low permeability and drug localization factors. Neurotherapeuticals encapsulating lipid carriers favor a significant increase in bioavailability of poorly water-soluble drugs by enhancing solubility in the gastroin-testinal tract and favoring stability. Due to their small size and lipid-based composition, these carriers offer enhanced permeability across the semi-permeable blood-brain barrier to effective-ly transport encapsulated loads, such as synthetic drugs, nutraceuticals, phytoconstituents, herb-al extracts, and peptides, reducing incidences of off-target mediated adverse impacts and tox-icity. The most significant advantage of such lipid-based delivery systems is non–invasive na-ture and targeting of neurotherapeuticals to the central nervous system. Critical attributes of li-pid-based carriers modulate release rates in rate-controlled manners, enable higher penetration through the blood-brain barrier, and bypass the hepatic first-pass metabolism, leading to higher CNS bioavailability neurotherapeuticals. The current review discusses a brief and introductory account of the limitations of neurothera-peuticals, pharmacological barriers, challenges in brain-targeted delivery, and the potential of nanotechnology-processed lipid-based carriers in the clinical management of neuronal disor-ders.

Download Full-text