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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.


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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.

Opportunities, New Targets, Models and Tools, and Delivering Therapy to the Brain

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.

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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.

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Multifunctional Nanoparticles for Successful Targeted Drug Delivery across the Blood-Brain Barrier

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Possible strategies to cross the blood–brain barrier | Italian Journal of Pediatrics | Full Text

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