Delivery Of Neural Stem Cells Research Articles

Magnetic Nanoparticles and Methylprednisolone Based Physico-Chemical Bifunctional Neural Stem Cells Delivery System for Spinal Cord Injury Repair.

Neural stem cells (NSCs) transplantation is an attractive and promising treatment strategy for spinal cord injury (SCI). Various pathological processes including the severe inflammatory cascade and difficulty in stable proliferation and differentiation of NSCs limit its application and translation. Here, a novel physico-chemical bifunctional neural stem cells delivery system containing magnetic nanoparticles (MNPs and methylprednisolone (MP) is designed to repair SCI, the former regulates NSCs differentiation through magnetic mechanical stimulation in the chronic phase, while the latter alleviates inflammatory response in the acute phase. The delivery system releases MP to promote microglial M2 polarization, inhibit M1 polarization, and reduce neuronal apoptosis. Meanwhile, NSCs tend to differentiate into functional neurons with magnetic mechanical stimulation generated by MNPs in the static magnetic field, which is related to the activation of the PI3K/AKT/mTOR pathway. SCI mice achieve better functional recovery after receiving NSCs transplantation via physico-chemical bifunctional delivery system, which has milder inflammation, higher number of M2 microglia, more functional neurons, and axonal regeneration. Together, this bifunctional NSCs delivery system combined physical mechanical stimulation and chemical drug therapy is demonstrated to be effective, which provides new treatment insights into clinical transformation of SCI repair.

Research progress of neural stem cells as a source of dopaminergic neurons for cell therapy in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease, the most characteristic pathological feature is the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compactus (SNpc) of the mesencephalon, along with reduced dopamine content in the striatum. Researchers have been searching for drugs and therapies to treat PD in decades. However, no approach could stop the progression of the disease, and even some of them caused adverse clinical side effects. PD has a well-defined lesion. Therefore, it is considered to be one of the most curable central nervous system diseases by cell replacement treatment. Fetal ventral mesencephalic tissue transplantation has been used to treat patients with PD and obtained positive treatment results. However, ethical issues, such as limited donor tissue, and side effects including graft-induced dyskinesias, limit its clinical applications. Neural stem cell (NSC) transplantation is a viable therapy choice because it possesses multipotency, self-renewal ability, and differentiation into DA neurons, which may substitute for lost DA neurons and slow down the neurodegenerative process in PD. Studies that investigated the delivery of NSCs by using animal models of PD revealed survival, migration, and even amelioration of behavioral deficits. Here, the research progress of NSCs or NSC-derived DA neurons in treating PD was reviewed, and the practicability of present manufacturing processes for clinical testing was considered. This review is expected to offer ideas for practical strategies to solve the present technical and biological problems related to the clinical application of NSCs in PD.

Helical hydrogel micromotors for delivery of neural stem cells and restoration of neural connectivity

Traumatic injuries and neurodegenerative disorders can lead to irreversible neuronal damage and destruction of neural circuits connectivity. Stem cell therapy holds promise as a treatment for neuronal damage and neurodegenerative diseases. However, previous trials have been limited in implantation precision and neuron connection restoration. The ability to transport neural stem cells to a targeted area and the effectiveness in restoring neuron connection needs to be noticed. In this study, we proposed an integrated micromotor for the untethered transportation of neurons and explored its capacity to repair functional neuronal connections. We developed the alginate hydrogel micromotor with a capillary microfluidic chip to encapsulate cells and nanoparticles. In vivo, the micromotors facilitated neuron regeneration in the hindlimb of Xenopus laevis. This miniaturized machine supported the growth of neural stem cells, and precisely transported them by external magnetic fields. Enzyme-responsive cell release in the targeted regions was allowed, facilitating reconstruction of neural connection. Furthermore, an in vivo trial was included to verify the effectiveness of micromotors, which was a prerequisite for establishing functional neuronal networks. This unique platform has the potential to inspire new avenues in targeted cell therapies.

Therapeutic effect of a hydrogel-based neural stem cell delivery sheet for mild traumatic brain injury

Objective: There are no effective clinically applicable treatments for neuronal dysfunction after mild traumatic brain injury (TBI). Here, we evaluated the therapeutic effect of a new delivery method of mouse neural stem cell (mNSC) spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after mild TBI. Methods: mNSCs were isolated from the subventricular zone and subgranular zone by a hydrogel-based culture system. GFP-transduced mNSCs were generated into spheroids and wrapped into a sheet for transplantation. Male C57BL/6J mice were randomly divided into four groups: sham operation, TBI, TBI with mNSC spheroids, and TBI with mNSC spheroid sheet transplantation covering the damaged cortex. Histopathological and immunohistochemical features and cognitive function were evaluated 7, 14, and 28 days after transplantation following TBI. Results: Hydrogel-based culture systems and mNSC isolation were successfully established from the adult mice. Essential transcription factors for NSCs, such as SOX2, PAX6, Olig2, nestin, and doublecortin (DCX), were highly expressed in the mNSCs. A transplanted hydrogel-based mNSC spheroid sheet showed good engraftment and survival ability, differentiated into TUJ1-positive neurons, promoted angiogenesis, and reduced neuronal degeneration. Also, TBI mice treated with mNSC spheroid sheet transplantation exhibited a significantly increased preference for a new object, suggesting improved cognitive function compared to the mNSC spheroids or no treatment groups. Conclusion: Transplantation with a hydrogel-based mNSC spheroid sheet showed engraftment, migration, and stability of delivered cells in a hostile microenvironment after TBI, resulting in improved cognitive function via reconstruction of the damaged cortex. Statement of Significance: This study presents the therapeutic effect of a new delivery method of mouse neural stem cells spheroids using a hydrogel, in terms of improvement in damaged cortical lesions and cognitive impairment after traumatic brain injury. Collagen/fibrin hydrogel allowed long-term survival and migratory ability of NSCs spheroids. Furthermore, transplanted hydrogel-based mNSCs spheroids sheet showed good engraftment, migration, and stability of delivered cells in a hostile microenvironment, resulting in reconstruction of the damaged cortex and improved cognitive function after TBI. Therefore, we suggest that a hydrogel-based mNSCs spheroids sheet could help to improve cognitive impairment after TBI.

Lipid Microcapsules Promoted Neural Stem Cell Survival in the Infarcted Area of Mice with Ischemic Stroke by Inducing Autophagy.

Intracerebral transplantation of neural stem cells (NSCs) for ischemic stroke treatment has been demonstrated to be inefficient, with only <5% of delivered cells being retained. Microcapsules may be a good carrier for NSC delivery; however, the current microcapsules do not fully meet the demands for cell survival after transplantation. In the present study, we designed a strategy for the encapsulation of NSCs in a novel lipid-alginate (L-A) microcapsule based on a two-step method. The protective effect of a L-A microcapsule on oxygen-glucose deprivation (OGD) was investigated by using the CCK8 test, the LDH release test, and flow cytometry. Mechanisms underlying the prosurvival effect were investigated by detecting autophagy markers like P62, LC3-I, and LC3-II, and autophagy flux analysis was also performed. Lastly, the ability of the L-A microcapsule to support NSCs delivery for ischemic stroke was investigated in the middle cerebral artery occlusion (MCAO) model. We found that L-A microcapsules exerted a good protective effect against OGD compared with control and alginate microcapsules. The L-A microcapsules were found to promote cell survival by not only providing a "physical" barrier but also altering autophagy markers like P62 and LC3-II, which enhanced autophagy flux. This novel microcapsule was confirmed to be suitable for NSC delivery in vivo, which alleviated transplanted NSC apoptosis, reduced the infarct volume, decreased brain edema, improved neurological deficit scores, and lastly, improved survival rate. The findings of this study may provide a new method for stem cell delivery, raising the prospect that intracerebral cell transplantation may be used to treat, for instance, ischemic stroke, traumatic brain injury, and so on.

Ultrasound‐targeted microbubbles destruction assists dual delivery of beta‐amyloid antibody and neural stem cells to restore neural function in transgenic mice of Alzheimer's disease

To explore the feasibility, efficacy and safety of ultrasound targeted microbubbles destruction (UTMD) assisted dual delivery of beta-amyloid (Aβ) antibody loaded by microbubbles (MBAβ ) and neural stem cells (NSCs) on Alzheimer's disease (AD). 27 APP/PS1 double transgenic mice (Tg mice) and 33 wild-type mice were used. Wild-type mice were insonated by diagnostic ultrasound with microbubbles (MB) for 5 min to observe the blood brain barrier (BBB) opening. The survival situation of engrafted NSCs crossing the opened BBB mediated by UTMD in AD mice was evaluated by in vivo imaging system. We further explored the combination therapy of UTMD mediated Aβ antibody and NSCs dual delivery. Tg mice in each group were exposed to diagnostic ultrasound for 5 min once a week for four times, with MB, MBAβ , and/or NSCs administration. Cognition and memory functions were explored by Morris water maze test, Aβ plaques deposition was evaluated by immunohistochemical, and brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN) expression were detected by western blot and immunofluorescence. BBB was opened mediated by diagnostic ultrasound with MB and the duration of opening was about 10 h. The transplanted NSCs survived in Tg mice for no more than 72 h. Compared with control group, the mice in combined delivery of NSCs and Aβ antibody by UTMD group improved memory function and spatial learning with shorter latency to find the platform, longer distance traveled and longer time spent in targeted quadrant, and more crossing times (P < 0.05). Besides, the combination delivery group promoted the clearance of Aβ plaques compared with control group both in hippocampus (P < 0.01) and cortex (P < 0.05). Moreover, the expression of BDNF in combination delivery group was significantly higher than that in control group and US mediated MB group (P < 0.05). No significant change of SYN was observed in each group. UTMD assisted dual delivery of Aβ antibody and NSCs to AD mice brain could help to clear Aβ plaques, increase the expression of BDNF and restore the impaired neural function. This finding may offer potential insight into treatment of AD. This article is protected by copyright. All rights reserved.

Neural stem cell delivery using brain-derived tissue-specific bioink for recovering from traumatic brain injury

Traumatic brain injury is one of the leading causes of accidental death and disability. The loss of parts in a severely injured brain induces edema, neuronal apoptosis, and neuroinflammation. Recently, stem cell transplantation demonstrated regenerative efficacy in an injured brain. However, the efficacy of current stem cell therapy needs improvement to resolve issues such as low survival of implanted stem cells and low efficacy of differentiation into respective cells. We developed brain-derived decellularized extracellular matrix (BdECM) bioink that is printable and has native brain-like stiffness. This study aimed to fabricate injured cavity-fit scaffold with BdECM bioink and assessed the utility of BdECM bioink for stem cell delivery to a traumatically injured brain. Our BdECM bioink had shear thinning property for three-dimensional (3D)-cell-printing and physical properties and fiber structures comparable to those of the native brain, which is important for tissue integration after implantation. The human neural stem cells (NSCs) (F3 cells) laden with BdECM bioink were found to be fully differentiated to neurons; the levels of markers for mature differentiated neurons were higher than those observed with collagen bioink in vitro. Moreover, the BdECM bioink demonstrated potential in defect-fit carrier fabrication with 3D cell-printing, based on the rheological properties and shape fidelity of the material. As F3 cell-laden BdECM bioink was transplanted into the motor cortex of a rat brain, high efficacy of differentiation into mature neurons was observed in the transplanted NSCs; notably increased level of MAP2, a marker of neuronal differentiation, was observed. Furthermore, the transplanted-cell bioink suppressed reactive astrogliosis and microglial activation that may impede regeneration of the injured brain. The brain-specific material reported here is favorable for NSC differentiation and suppression of neuroinflammation and is expected to successfully support regeneration of a traumatically injured brain.

Neural Stem Cells for Early Ischemic Stroke

Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.

Endothelial cell secreted VEGF-C enhances NSC VEGFR3 expression and promotes NSC survival

Although delivery of neural stem cell (NSC) as a therapeutic treatment for intracerebral hemorrhage (ICH) provides promise, NSC delivery typically has extremely low survival rates. Here, we investigate endothelial cell (EC) and pericyte (PC) interactions with NSC, where our results demonstrate that EC, and not PC, promote NSC cell proliferation and reduce cytotoxicity under glucose deprivation (GD). Additionally, NSC proliferation was increased upon treatment with EC conditioned media, inhibited with antagonism of VEGFR3. In an NSC + EC co-culture we detected elevated levels of VEGF-C, not seen for NSC cultured alone. Exogenous VEGF-C induced NSC upregulation of VEGFR3, promoted proliferation, and reduced cytotoxicity. Finally, we delivered microbeads containing NSC + EC into a murine ICH cavity, where VEGF-C was increasingly present in the injury site, not seen upon delivery NSC encapsulated alone. These studies demonstrate that EC-secreted VEGF-C may promote NSC survival during injury, enhancing the potential for cell delivery therapies for stroke.

Enhancing the regenerative potential of stem cell-laden, clinical-grade implants through laminin engineering

Protected delivery of neural stem cells (NSCs; a major transplant population) within bioscaffolds has the potential to improve regenerative outcomes in sites of spinal cord injury. Emergent research has indicated clinical grade bioscaffolds (e.g. those used as surgical sealants) may be repurposed for this strategy, bypassing the long approval processes and difficulties in scale-up faced by laboratory grade materials. While promising, clinical scaffolds are often not inherently regenerative. Extracellular molecule biofunctionalisation of scaffolds can enhance regenerative features such as encapsulated cell survival/distribution, cell differentiation into desired cell types and nerve fibre growth. However, this strategy is yet to be tested for clinical grade scaffolds. Here, we show for the first time that Hemopatch™, a widely used, clinically approved surgical matrix, supports NSC growth. Further, functionalisation of Hemopatch™ with laminin promoted homogenous distribution of NSCs and their daughter cells within the matrix, a key regenerative criterion for transplant cells.

ECM hydrogel improves the delivery of PEG microsphere-encapsulated neural stem cells and endothelial cells into tissue cavities caused by stroke

Intracerebral implantation of neural stem cells (NSCs) to treat stroke remains an inefficient process with <5% of injected cells being retained. To improve the retention and distribution of NSCs after a stroke, we investigated the utility of NSCs’ encapsulation in polyethylene glycol (PEG) microspheres. We first characterized the impact of the physical properties of different syringes and needles, as well as ejection speed, upon delivery of microspheres to the stroke injured rat brain. A 20 G needle size at a 10 μL/min flow rate achieved the most efficient microsphere ejection. Secondly, we optimized the delivery vehicles for in vivo implantation of PEG microspheres. The suspension of microspheres in extracellular matrix (ECM) hydrogel showed superior retention and distribution in a cortical stroke caused by photothrombosis, as well as in a striatal and cortical cavity ensuing middle cerebral artery occlusion (MCAo). Thirdly, NSCs or NSCs + endothelial cells (ECs) encapsulated into biodegradable microspheres were implanted into a large stroke cavity. Cells in microspheres exhibited a high viability, survived freezing and transport. Implantation of 110 cells/microsphere suspended in ECM hydrogel produced a highly efficient delivery that resulted in the widespread distribution of NSCs in the tissue cavity and damaged peri-infarct tissues. Co-delivery of ECs enhanced the in vivo survival and distribution of ∼1.1 million NSCs. The delivery of NSCs and ECs can be dramatically improved using microsphere encapsulation combined with suspension in ECM hydrogel. These biomaterial innovations are essential to advance clinical efforts to improve the treatment of stroke using intracerebral cell therapy.

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia.

Neural stem cell (NSC) therapy is an emerging innovative treatment for stroke, traumatic brain injury and neurodegenerative disorders. As compared to intracranial delivery, intra-arterial administration of NSCs is less invasive and produces a more diffuse distribution of NSCs within the brain parenchyma. Further, intra-arterial delivery allows the first-pass effect in the brain circulation, lessening the potential for trapping of cells in peripheral organs, such as liver and spleen, a complication associated with peripheral injections. Here, we detail the methodology, in both mice and rats, for delivery of NSCs through the common carotid artery (mouse) or external carotid artery (rat) to the ipsilateral hemisphere after an ischemic stroke. Using GFP-labeled NSCs, we illustrate the widespread distribution achieved throughout the rodent ipsilateral hemisphere at 1 d, 1 week and 4 weeks after postischemic delivery, with a higher density in or near the ischemic injury site. In addition to long-term survival, we show evidence of differentiation of GFP-labeled cells at 4 weeks. The intra-arterial delivery approach described here for NSCs can also be used for administration of therapeutic compounds, and thus has broad applicability to varied CNS injury and disease models across multiple species.

Neural stem cell delivery via porous collagen scaffolds promotes neuronal differentiation and locomotion recovery in spinal cord injury

Neural stem cell (NSC) grafts have demonstrated significant effects in animal models of spinal cord injury (SCI), yet their clinical translation remains challenging. Significant evidence suggests that the supporting matrix of NSC grafts has a crucial role in regulating NSC effects. Here we demonstrate that grafts based on porous collagen-based scaffolds (PCSs), similar to biomaterials utilized clinically in induced regeneration, can deliver and protect embryonic NSCs at SCI sites, leading to significant improvement in locomotion recovery in an experimental mouse SCI model, so that 12 weeks post-injury locomotion performance of implanted animals does not statistically differ from that of uninjured control animals. NSC-seeded PCS grafts can modulate key processes required to induce regeneration in SCI lesions including enhancing NSC neuronal differentiation and functional integration in vivo, enabling robust axonal elongation, and reducing astrogliosis. Our findings suggest that the efficacy and translational potential of emerging NSC-based SCI therapies could be enhanced by delivering NSC via scaffolds derived from well-characterized clinically proven PCS.

Minimally Invasive Delivery of Microbeads with Encapsulated, Viable and Quiescent Neural Stem Cells to the Adult Subventricular Zone

Stem cell therapies demonstrate promising results as treatment for neurological disease and injury, owing to their innate ability to enhance endogenous neural tissue repair and promote functional recovery. However, delivery of undifferentiated and viable neuronal stem cells requires an engineered delivery system that promotes integration of transplanted cells into the inflamed and cytotoxic region of damaged tissue. Within the brain, endothelial cells (EC) of the subventricular zone play a critical role in neural stem cell (NSC) maintenance, quiescence and survival. Therefore, here, we describe the use of polyethylene glycol microbeads for the coincident delivery of EC and NSC as a means of enhancing appropriate NSC quiescence and survival during transplantation into the mouse brain. We demonstrate that EC and NSC co-encapsulation maintained NSC quiescence, enhanced NSC viability, and facilitated NSC extravasation in vitro, as compared to NSC encapsulated alone. In addition, co-encapsulated cells delivered to an in vivo non-injury model reduced inflammatory response compared to freely injected NSC. These results suggest the strong potential of a biomimetic engineered niche for NSC delivery into the brain following neurological injury.

Neurosurgical grade biomaterial, DuraGenTM, offers a promising matrix for protected delivery of neural stem cells in clinical cell therapies

Transplantation of neural stem cells (NSCs) into sites of neurological injury is being investigated in clinical trials around the world. These important self-renewing and multipotent precursors can generate the major central nervous system cell types – neurons, astrocytes and oligodendrocytes, and have a major role in ‘restorative cell therapeutics’. However, high stem cell death in host tissue (>∼90%) following surgical delivery procedures is a critical barrier to clinical translation. Polymer-based encapsulating biomaterials offer protective matrices to improve stem cell survival but the majority of studies use laboratory based …

Quantitative Evaluation of Intraventricular Delivery of Therapeutic Neural Stem Cells to Orthotopic Glioma.

Neural stem cells (NSCs) are inherently tumor-tropic, which allows them to migrate through normal tissue and selectively localize to invasive tumor sites in the brain. We have engineered a clonal, immortalized allogeneic NSC line (HB1.F3.CD21; CD-NSCs) that maintains its stem-like properties, a normal karyotype and is HLA Class II negative. It is genetically and functionally stable over time and multiple passages, and has demonstrated safety in phase I glioma trials. These properties enable the production of an “off-the-shelf” therapy that can be readily available for patient treatment. There are multiple factors contributing to stem cell tumor-tropism, and much remains to be elucidated. The route of NSC delivery and the distribution of NSCs at tumor sites are key factors in the development of effective cell-based therapies. Stem cells can be engineered to deliver and/or produce many different therapeutic agents, including prodrug activating enzymes (which locally convert systemically administered prodrugs to active chemotherapeutic agents); oncolytic viruses; tumor-targeted antibodies; therapeutic nanoparticles; and extracellular vesicles that contain therapeutic oligonucleotides. By targeting these therapeutics selectively to tumor foci, we aim to minimize toxicity to normal tissues and maximize therapeutic benefits. In this manuscript, we demonstrate that NSCs administered via intracerebral/ventricular (IVEN) routes can migrate efficiently toward single or multiple tumor foci. IVEN delivery will enable repeat administrations for patients through an Ommaya reservoir, potentially resulting in improved therapeutic outcomes. In our preclinical studies using various glioma lines, we have quantified NSC migration and distribution in mouse brains and have found robust migration of our clinically relevant HB1.F3.CD21 NSC line toward invasive tumor foci, irrespective of their origin. These results establish proof-of-concept and demonstrate the potential of developing a multitude of therapeutic options using modified NSCs.

WP1-22 DuraGen™ as an encapsulating material for neural stem cell delivery

ObjectivesAchieving neural regeneration after spinal cord injury (SCI) represents a significant challenge. Neural stem cell (NSC) therapy offers replacement of damaged cells and delivery of pro-regenerative factors, but &gt;95% of cells die when transplanted to sites of neural injury. Biomaterial scaffolds provide cellular protective encapsulation to improve cell survival. However, current available scaffolds are overwhelmingly not approved for human use, presenting a major barrier to clinical translation. Surgical biomaterials offer the unique benefit of being FDA-approved for human implantation. Specifically, a neurosurgical grade material, DuraGen™, used predominantly for human duraplasty has many attractive features of an ideal biomaterial scaffold. Here, we have investigated the use of DuraGen™ as a 3D cell encapsulation device for potential use in combinatorial, regenerative therapies.MethodsPrimary NSCs were seeded into optimised sheets of DuraGen™. NSC growth and fate within DuraGen™ were assessed using 3D microscopic fluorescence imaging techniques.ResultsDuraGen™ supports the survival (ca 95% viability, 12 days) and 3D growth of NSCs. NSC phenotype, proliferative capacity and differentiation into astrocytes, neurons and oligodendrocytes were unaffected by DuraGen™.ConclusionsA ‘combinatorial therapy’, consisting of NSCs protected within a DuraGen™ matrix, offers a potential clinically translatable approach for neural cell therapy.

(Invited) Self-healing Polysaccharide-based Hydrogels as Injectable Carriers for Neural Stem Cells

Self-healing injectable hydrogels can be formulated as three-dimensional carriers for the treatment of neurological diseases with desirable advantages, such as avoiding the potential risks of cell loss during injection, protecting cells from the shearing force of injection. However, the demands for biocompatible self-healing injectable hydrogels to meet above requirements and to promote the differentiation of neural stem cells (NSCs) into neurons remain a challenge. Herein, we developed a biocompatible selfhealing polysaccharide-based hydrogel system as a novel injectable carrier for the delivery of NSCs. N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) are the main backbones of the hydrogel networks, denoted as CEC-l-OSA hydrogel (“l” means “linked-by”). Owing to the dynamic imine cross-links formed by a Schiff reaction between amino groups on CEC and aldehyde groups on OSA, the hydrogel possesses the ability to self-heal into a integrity after being injected from needles under physiological conditions. The CEC-l-OSA hydrogel in which the stiffness mimicking nature brain tissues (100~1000 Pa) can be finely tuned to support the proliferation and neuronal differentiation of NSCs. The multi-functional, injectable, and self-healing CEC-l-OSA hydrogels hold great promises for NSC transplantation and further treatment of neurological diseases.

Intraperitoneal Administration of Neural Stem Cell-Nanoparticle Conjugates Targets Chemotherapy to Ovarian Tumors.

Ovarian cancer is particularly aggressive once it has metastasized to the abdominal cavity (stage III). Intraperitoneal (IP) as compared to intravenous (IV) administration of chemotherapy improves survival for stage III ovarian cancer, demonstrating that concentrating chemotherapy at tumor sites has therapeutic benefit; unfortunately, IP therapy also increases toxic side effects, thus preventing its completion in many patients. The ability to target chemotherapy selectively to ovarian tumors while sparing normal tissue would improve efficacy and decrease toxicities. We have previously shown that tumor-tropic neural stem cells (NSCs) dramatically improve the intratumoral distribution of nanoparticles (NPs) when given intracerebrally near an orthotopic brain tumor or into a flank xenograft tumor. Here, we show that NPs either conjugated to the surface of NSCs or loaded within the cells are selectively delivered to and distributed within ovarian tumors in the abdominal cavity following IP injection, with no evidence of localization to normal tissue. IP administration is significantly more effective than IV administration, and NPs carried by NSCs show substantially deeper penetration into tumors than free NPs. The NSCs and NPs target and localize to ovarian tumors within 1 h of administration. Pt-loaded silica NPs (SiNP[Pt]) were developed that can be transported in NSCs, and it was found that the NSC delivery of SiNP[Pt] (NSC-SiNP[Pt]) results in higher levels of Pt in tumors as compared to free drug or SiNP[Pt]. To the best of our knowledge, this work represents the first demonstration that cells given IP can target the delivery of drug-loaded NPs.