Biology subjects

Dam, K. U.

Publications and source records attributed to Dam, K. U..

3 recordsLinked to original sources

bioRxiv2026

Ang2 and TAT targeting of leptomeningeal disease by the intravenous and intrathecal routes: a comparative analysis

Leptomeningeal disease (LD) refers to the metastasis of cells to the leptomeningeal membranes in the central nervous system (CNS), and it is a deadly complication of several different types of cancer, including breast cancer (BC) and pediatric medulloblastoma (MB). Angiopep-2 (Ang2) and transactivating transcriptional activator (TAT) peptides have been reported to transport therapeutic cargos into the CNS. Here, compared the LD-targeting capability of Ang2 vs TAT by intrathecal (intracisternal magna, ICM) vs intravenous (IV) routes of administration. We first generated two xenograft models of LD by directly infusing breast cancer cells (MDA-MB231) or medulloblastoma cells (HDMB03) via the ICM route, characterizing models for survival, tumor growth patterns, and presence of hydrocephalus. Second, we administered fluorescently labeled Ang2 or TAT peptides either IV or ICM into tumor bearing mice to examine ligand localization. We discovered that the median survival of both models was negatively related to the number of the cells infused. While HDMB03 cells tended to metastasize preferentially to the brain region, MDA-MB231 cells tended to metastasize preferentially to the spinal cord. Compared to the healthy control, MB-LD yielded a 7.3-fold increase and BC-LD a 26.5-fold increase in ventricular volume. Furthermore, targeting achieved by TAT was significantly higher than targeting achieved by Ang2 in thoracic spine for the MB-LD model. For BC-LD, TAT targeting was superiot to Ang2 in the olfactory bulbs, brain stem, thoracic spine, and lumbar spine regions. Significantly, these data provide evidence that ICM will be a preferable route of administration over IV for maximally targeting LD.

bioengineering↗

bioRxiv2026

Intrathecal infusion of hypertonic fluid enables CSF Flow Enhancement (CFE) to facilitate nanoparticle delivery to the brain and spinal cord

Intrathecal (IT) drug delivery, i.e., the infusion of substances directly into cerebrospinal fluid (CSF) by lumbar, ventricular, or cisternal access points, is one method that can be used to bypass the blood brain barrier (BBB), however, IT-administered substances also suffer from rapid turnover and poor tissue penetration. Although nanoparticles and colloids can circulate within the subarachnoid space to sustain the levels of encapsulated drug in CSF, their access to deep tissue regions remains incomplete. Here, we present a new method for enhancing CNS delivery of IT-administered nanoparticles. CSF Flow Enhancement (CFE) refers to the manipulation of CSF production, distribution, and clearance for therapeutic purposes. We tested the overarching hypothesis that infusion of hypertonic fluid adjacent to the choroid plexus would enhance fluid production and movement to improve the CNS delivery of IT-administered nanoparticles. Model polystyrene nanoparticles (100nm) were solubilized in aCSF of increasing tonicity (1-9X tonicity) and infused into the cisterna magna, after which tissues were removed to examine delivery to CNS tissues and peripheral organs. Our results demonstrate that an infusion of up to 4X hypertonic aCSF in 10uL is well tolerated and yields significant improvements in CNS localization of co-administered nanoparticles, more than doubling the delivery of nanoparticles to the ventral surfaces of the brain and sometimes dramatic (up to 10-fold) increases in delivery to specific tissue regions and surfaces of the CNS. Significantly, we provide early evidence that modulation of tonicity can define the parenchymal fate of IT administered colloids: while nanoparticles were not detected in the brain parenchyma of mice that received a standard infusion, parenchymal delivery was observed for the 2X condition, and extensive perivascular infiltration of nanoparticles was observed for the 4X condition. Lastly, we show that the delivery improvements achieved by CFE are generalizable across multiple sizes of polystyrene nanoparticle (20, 40, or 100nm). Collectively, this work describes a tonicity-based approach for achieving CFE by the intrathecal route, which we posit is a useful and potentially generalizable approach for improving CNS drug delivery.

bioengineering↗

bioRxiv2019

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice After Gonadotoxic Chemotherapy

Many reproductive age women with cancer who receive chemotherapy are exposed to gonadotoxic agents and risk diminished ovarian reserve, sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid (HFF), when added to our stem cell differentiation system, enhances the steroidogenic potential of differentiating stem cells and increases the subpopulation of cells that express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormone synthesis and produces functional stem cell-derived oocytes. Additionally, these cells also ameliorate subfertility in nude mice, as demonstrated by the delivery of multiple litters of healthy pups from stem cell-derived oocytes. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat the endocrinologic and reproductive sequelae of premature ovarian insufficiency. One Sentence SummaryWe show that orthotopic injection of sorted, differentiated iPSCs in ovaries of subfertile mice restores reproductive hormone synthesis and fertility.

cell biology↗