Harnessing Immense Clinical Potential of Targeted Intracellular Delivery

More than 20 years ago, our team discovered and patented that hydroxyl dendrimer-drug compositions target reactive microglia and macrophages without targeting ligands. Validated in over 60 models across six species including primates. The targeting is hydroxyl surface functional density dependent and 'disease-directed' — driven only by the extent of injury, independent of receptor expression.

Dendrimer-drug conjugates clear intact through the kidney, with minimal liver uptake and metabolism. We utilize the small size (~4nm), high hydroxyl surface density enabled by the dendritic architecture — navigating disease pathology exquisitely to enable specific disease-cell targeting.

• Brain tumor macrophage targeting — exquisite selective uptake from systemic administration
• Blood-brain barrier crossing — without special ligands or conjugates
• Cerebral palsy & neonatal brain injury — postnatal neuroinflammation therapy validated in rabbit and primate models
• Retinal degeneration / AMD / DME — targeted DDC therapy with 67% reduction in intravitreal injection need (Phase 2)
• Severe COVID-19 — Phase 2a trial attenuating inflammation and neurological injury markers
• Necrotizing enterocolitis — cognitive impairment prevention via microglial inhibition (Sci Transl Med cover)

Systemic hydroxyl dendrimers rapidly and selectively distribute into tumor and tumor-associated macrophages (TAMs). Minimal uptake in healthy brain tissue. Zhang F et al., Biomaterials 2015; Liaw et al., Bioeng. Trans. Med. 2020

Mechanism of CNS targeting: dendrimers cross the injured BBB, diffuse rapidly in tissue, and are selectively taken up by inflamed activated cells. >1 OH/nm² hydroxyl density required. Nance et al., Biomaterials 2015; Zhang et al., J. Neuroinflammation 2015

Building on unique disease physics enabled by high hydroxyl densities, our group designed and patented glucose-based dendrimers (GD2) to interact with dysregulated glucose metabolism on injured neuronal cells. These dendrimers navigate the brain's intricate architecture, interacting with GLUT receptors and glucose transporters on dysregulated neurons and adipocytes.

GD2 robustly accumulates in overactive neurons while avoiding non-excitable or resting cells — responding dynamically to disease-relevant hyperexcitability. The platform can be conjugated with different drugs and delivered through multiple administration routes for rapid, noninvasive brain access.

• Selective & Precise: Accumulates in overactive neurons, avoids resting cells — unparalleled targeting accuracy
• Activity-Dependent Uptake: Entry driven by neuronal activity dynamically
• Epilepsy — anticonvulsant delivery to hyperexcitable seizure circuits
• Traumatic Brain Injury — neuroprotectant delivery to injured neurons
• Depression & Pain — neuromodulator delivery via activity-dependent uptake
• US Patent #18/854,897 — Dendrimer compositions for targeted delivery to neurons (April 2024)

Our laboratory has developed dendrimer-based delivery platforms to transform how macromolecules and biologics are deployed against neurological and ophthalmic disorders. By leveraging the unique architecture and modularity of dendrimers, we have engineered systems capable of preserving the extracellular activity of biologics while ensuring targeted delivery into target cells — adding entirely new mechanisms of action.

• Dendrimer–Antibody Conjugates (DACs) — merge targeting specificity of antibodies with nanoscale trafficking precision of dendrimers
• Dendrimer–Peptide Conjugates — stable, bioactive delivery for signaling modulation and receptor targeting
• Dendrimer–RNA Therapeutics — siRNA, microRNA, and ASO conjugates enabling sequence-specific gene expression modulation while overcoming degradation barriers
• Dendrimer–Cas9 Conjugates — non-viral, neuron-accessible platform for CRISPR-based gene editing in vivo

Systemically-administered hydroxyl dendrimers target reactive microglia and macrophages and/or neurons at the site of pathology, crossing the blood-brain barrier effectively. Validated in over 60 preclinical models representing various CNS and retinal disorders producing remarkable efficacy in AMD, diabetic retinopathy, epilepsy, depression, pain, cerebral palsy, Rett syndrome, Alzheimer's disease, and more.

The precise cell-targeting and rapid off-target clearance produces a broad therapeutic window, superior safety compared to free drug — significantly improving the chances of clinical success, as shown in Phase 1 and Phase 2 trials.