Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders

Sharma, Anjali; Sharma, Rishi; Zhi, Zhang; Liaw, Kevin; Kambhampati, Siva P.; Porterfield, Joshua E.; Lin, Ku Chien; DeRidder, Louis; Kannan, Sujatha; Kannan, Rangaramanujam M.

doi:10.1126/sciadv.aay8514

Cited by 58 publications

(41 citation statements)

References 41 publications

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“…Dendrimers were prepared by dissolving in water at 0.1 mg/ml. Measurements were performed in at 25°C with a scattering angle of 173° according to previously published protocol 50 …”

Section: Methodsmentioning

confidence: 99%

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Liaw

Reddy

Sharma

et al. 2020

Bioengineering & Transla Med

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Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16–20 months and a 5‐year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony‐stimulating factor 1 (CSF‐1) signaling pathway of tumor‐associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer‐mediated immunotherapy to deliver CSF‐1R inhibitor BLZ945 (D‐BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D‐BLZ targeted to TAMs decreases pro‐tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer‐drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off‐target effects.

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“…Dendrimers were prepared by dissolving in water at 0.1 mg/ml. Measurements were performed in at 25°C with a scattering angle of 173° according to previously published protocol 50 …”

Section: Methodsmentioning

confidence: 99%

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Liaw

Reddy

Sharma

et al. 2020

Bioengineering & Transla Med

Self Cite

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“…Being a green reaction, thiol-ene click chemistry has been widely used in the efficient growth of dendrimers. [23][24][25][26][27] We utilized thiol-ene click here as a tool to ascertain the robustness of monomer 1 towards synthesis of PUDs by functionalizing the dendritic surface via different methods. Accordingly, 4 was synthesized via two different routes as shown in Scheme 4.…”

Section: Synthesis Of Branching Monomermentioning

confidence: 99%

A Model for Late-Stage Modification of Polyurethane Dendrimers Using Thiol-Ene Click Chemistry

Poudel

Taylor²

2021

Preprint

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Protecting group free, one-pot multicomponent Curtius reaction was utilized to afford diurethane G-1 dendron. In our synthetic approach, G-1 dendron can undergo late-stage modification using thiol-ene click reaction, which was then attached to the core to furnish a dendrimer. In another approach, the G-1 dendron was attached to the core and so formed dendrimer was surface functionalized using thiol-ene click chemistry. Either way, we can synthesize the dendrimer.

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“…PAMAM-G4-OH can inherently target activated microglia and macrophages (Mi/Ma) at inflammatory regions and shows outstanding compatibility with different therapeutic drugs, including N-acetyl-L-cysteine, sinomenine, minocycline, dexamethasone and fluocinolone acetonide [ 139 , 142 , 143 , 144 , 145 , 146 ]. In a recent report, generation 2 PEG-based dendrimer functionalized with highly dense hydroxyl surface terminals (PEGOL-60) was synthesized, which exhibited superior performance to PAMAM-G4-OH, especially in selective targetability to neuroinflammation [ 147 ]. Dendrimers with a PEG backbone benefit from enhanced biocompatibility, aqueous solubility, stability and reduced immunogenicity.…”

Section: Dendrimersmentioning

confidence: 99%

Dendrimers as Modulators of Brain Cells

2020

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Nanostructured hyperbranched macromolecules have been extensively studied at the chemical, physical and morphological levels. The cellular structural and functional complexity of neural cells and their cross-talk have made it rather difficult to evaluate dendrimer effects in a mixed population of glial cells and neurons. Thus, we are at a relatively early stage of bench-to-bedside translation, and this is due mainly to the lack of data valuable for clinical investigations. It is only recently that techniques have become available that allow for analyses of biological processes inside the living cells, at the nanoscale, in real time. This review summarizes the essential properties of neural cells and dendrimers, and provides a cross-section of biological, pre-clinical and early clinical studies, where dendrimers were used as nanocarriers. It also highlights some examples of biological studies employing dendritic polyglycerol sulfates and their effects on glia and neurons. It is the aim of this review to encourage young scientists to advance mechanistic and technological approaches in dendrimer research so that these extremely versatile and attractive nanostructures gain even greater recognition in translational medicine.

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Dense hydroxyl polyethylene glycol dendrimer targets activated glia in multiple CNS disorders

Cited by 58 publications

References 41 publications

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

Targeted systemic dendrimer delivery of CSF‐1R inhibitor to tumor‐associated macrophages improves outcomes in orthotopic glioblastoma

A Model for Late-Stage Modification of Polyurethane Dendrimers Using Thiol-Ene Click Chemistry

Dendrimers as Modulators of Brain Cells

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