This approach is mainly based on the use of nanosized technology for drug release in the brain. This delivery system uses a wide variety of nanoscale drug delivery platforms mainly including lipid- and polymer-based nanoparticles NPs that assure a controlled and improved release of their cargo by protecting loaded drugs from being metabolized [ 25 ]. The main efforts today are mainly focused on increasing the ability of NPs to effectively target the therapeutic site, thus minimizing the doses of drugs released at undesired sites [ 26 ].
Considering that NPs have shown to be effective drug carriers, the feasibility of using them for enabling a more effective delivery to organs has been investigated using laronidase surface-functionalized lipid-core nanocapsules L-MLNC for the treatment of MPS I.
Another recent study has addressed the feasibility of loading arylsulfatase B onto poly butyl cyanoacrylate PBCA nanoparticles to affect neurological manifestations such as spinal cord compression in MPS VI by delivery of therapeutic enzyme across the BBB [ 28 ]. Moreover, it has been demonstrated that g7-NPs, thanks to the intra- and intercellular vesicular transport, can target specific cells in the brain and are also able to reach the CNS by intraperitoneal, intranasal, and oral administrations [ 30 ]. Results showed the g7-NPs ability to cross the BBB and to widely localize in all brain parenchyma, demonstrating the applicability of NPs for therapeutic brain delivery of high molecular weight molecules and thus encouraging their potential application to enzyme delivery to the brain [ 31 ].
This technique consists of transferring recombinant DNA with therapeutic function directly into the cells of specific organs. It represents a promising solution for those neurodegenerative conditions where the neuropathology is spread throughout the entire brain and therefore a global CNS gene delivery is required for an effective treatment [ 32 ].
However, when translated to adult animal models, problems with immune response were encountered; although the use of systemically delivered AAV vectors in murine models of MPS I, IIIA, IIIB, and VI has demonstrated a reduction in the corresponding substrates in the CNS [ 34 ], it remains difficult to translate these achievements to larger animal models because of differences in biology, anatomy, and size. These differences make it necessary to accurate scale the dosage, and efficacy and toxicity tests due to their longer life-span. For all these reasons, intracerebral gene therapy can open up a new horizon in this field.
The technique consists of directly injecting viral gene transfer into the brain parenchyma or ventricular system. Studies in certain small rodent and large canine and feline animal models of LSDs have shown functional improvement and reduction in lysosomal storage [ 35 ]. This approach constitutes a potential alternative method for therapeutic brain targeting and is based on the direct transport into the CSF enabled by the presence of the neural pathways connecting the nasal mucosa and the brain [ 38 ].
Such a nose-to-brain pathway allows rapid delivery of the therapeutic molecules to the CNS within minutes, bypassing the BBB.
- The Use of Psychological Testing for Treatment Planning and Outcomes Assessment: Volume 3: Instruments for Adults (The Use of Psychological Testing for Treatment Planning and Outcomes Assessment).
- Messerschmitt Me 262.
- Silver Bay.
- The Five in a Row Cookbook.
- Castiglione 1796: Napoleon Repulses Wurmsers First Attack!
Absorption occurs by transcellular and paracellular passive absorption, carrier-mediated transport, and absorption through transcytosis. Lipid-based NPs have been studied for intranasal drug delivery and this non-invasive strategy approach has been used to assess the efficacy of treatment of neurological manifestation in MPS I disease. Nevertheless, several restrictions for its use exist, such as the existence of upper limits of the concentrations that can be achieved in different regions of the brain and spinal cord, the reduction of the drug delivery efficiency with increasing molecular weight of the drug, and large variability in nasal absorption caused by irritation of the nasal mucosal or common nasal pathology, such as with the common cold, etc.
Treatment of MPS is mostly challenging because delivery of therapeutic drug molecules to the brain is frequently obstructed by the presence of the BBB which constitutes the main obstacle for the treatment of those forms of MPS characterized by neurological involvement.
It is clear that nowadays there is an urgent need to direct research efforts to overcome the BBB and to develop new therapeutic strategies capable of successfully targeting the drug to the brain compartment. Although there are some interesting outcomes at present for brain-targeted drug delivery by mean of clinical invasive or technological non-invasive approaches using innovative drug delivery systems for crossing the BBB, these are still not well defined.
chapter and author info
Further studies are needed to better understand the BBB transport systems, to assess brain drug pharmacokinetics, and to improve the delivery and distribution of the drugs into specific areas of the brain. Nevertheless, it seems quite reasonable to think that the BBB is no longer an impenetrable barrier. This raises significant hopes, not just for patients affected by MPS but for all those suffering from LSDs and other conditions characterized by brain pathology. Mucopolysaccharidoses and other lysosomal storage diseases. Rheum Dis Clin N Am.
New advances in the transport of doxorubicin through the blood—brain barrier by a peptide vector-mediated strategy. Mol Pharmacol. Potential use of polymeric nanoparticles for drug delivery across the blood—brain barrier. Curr Med Chem. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery?
Curr Pharm Des. Lysosomal storage diseases and the blood—brain barrier. Structure and function of the blood—brain barrier. Neurobiol Dis. Begley DJ. ABC transporters and the blood—brain barrier. Neuronopathic lysosomal storage disorders: approaches to treat the central nervous system.
Multifunctional Nanoparticles for Successful Targeted Drug Delivery across the Blood-Brain Barrier
Transcytosis of macromolecules at the blood—brain barrier. Adv Pharmacol. Immunologic privilege in the central nervous system and the blood—brain barrier. J Cereb Blood Flow Metab. Pardridge WM. The blood—brain barrier: bottleneck in brain drug development. Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol. Enzyme-replacement therapy in mucopolysaccharidosis I.
N Engl J Med. Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder. Exp Neurol. Mol Genet Metab. Sorrentino NC, Fraldi A. Pediatr Endocrinol Rev. Genet Med.
Possible strategies to cross the blood–brain barrier | Italian Journal of Pediatrics | Full Text
Current approaches to enhance CNS delivery of drugs across the brain barriers. Intl J Nanomed. Pathways for small molecule delivery to the central nervous system across the blood—brain barrier. Perspect Medicin Chem. Brain drug targeting and gene technologies. Jpn J Pharmacol. Blood—brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody.
http://haktad.org/includes/app/vovo-iphone-8.html Expert Opin Drug Deliv. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov. Reengineering biopharmaceuticals for targeted delivery across the blood—brain barrier. Methods Enzymol. Evolving drug delivery strategies to overcome the blood brain barrier. Nanoparticles as blood—brain barrier permeable cns targeted drug delivery systems. The blood brain barrier BBB. Topics in medicinal chemistry, vol. Berlin: Springer Heidelberg; Barua S, Mitragotri S. Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects.
Nano Today. Laronidase-functionalized multiple-wall lipid-core nanocapsules: promising formulation for a more effective treatment of mucopolysaccharidosis type I. Pharm Res. Development of nanoparticle-bound arylsulfatase B for enzyme replacement therapy of mucopolysaccharidosis VI.
Insight on the fate of CNS-targeted nanoparticles. Part I: Rab5-dependent cell-specific uptake and distribution. J Control Release. Endocytosis of nanomedicines: the case of glycopeptide engineered PLGA nanoparticles. Targeted polymeric nanoparticles for brain delivery of high molecular weight molecules in lysosomal storage disorders. PLoS One. Gene therapy approaches for lysosomal storage disorders, a good model for the treatment of mendelian diseases.
Acta Paediatr. Gene therapy for neurologic manifestations of mucopolysaccharidoses. Exp Opin Drug Deliv. Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII. Gene Ther. CNS-directed gene therapy for lysosomal storage diseases. Acta Paediatr Suppl. Pan D. Cell- and gene-based therapeutic approaches for neurological deficits in mucopolysaccharidoses.
Adeno-associated virus-based gene therapy for CNS diseases. Hum Gene Ther. Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J Drug Target. Intranasal adeno-associated virus mediated gene delivery and expression of human iduronidase in the central nervous system: a noninvasive and effective approach for prevention of neurologic disease in mucopolysaccharidosis type I.