A Combination of Tri-Leucine and Angiopep-2 Drives a Polyanionic Polymalic Acid Nanodrug Platform Across the Blood–Brain Barrier

Israel, L.; Braubach, Oliver; Galstyan, Anna; Chiechi, Antonella; Shatalova, Ekaterina S.; Grodzinski, Zachary B.; Black, Keith L.; Ljubimova, Julia Y.; Holler, Eggehard

doi:10.1021/acsnano.8b06437

Cited by 43 publications

(115 citation statements)

References 57 publications

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“…Efficiency of BBB crossing of NCA was evaluated by a fluorescence-based quantification method developed in our lab. 10…”

Section: Immunohistochemistry and Bbb Crossing Efficiencymentioning

confidence: 99%

“…PMLA-based macromolecular nanoconjugates for fluorescence imaging and treatment of primary and metastatic brain tumors have been highlighted. [9][10][11][12][13][14][15] Starting from these conjugates, Gd 3+ DOTA derivatives have been developed to cross blood-brain barrier (BBB) and increase the contrast in MR imaging. In the nanodrugs and nano contrast agents, targeting was achieved by conjugation of specific antibodies.…”

Section: Introductionmentioning

confidence: 99%

“…Antibodies are replaced by Angiopep-2 (Ap2), a ligand specific for the LRP-1 transcytosis pathway across the BBB. 10,[16][17][18] The purpose of substituting previously involved BBBpenetrating antibodies by small peptides was to develop ("mini") contrast agents for fast and deep tissue penetration. Moreover, agents with low hydrodynamic diameters are likely to wash out through kidneys and minimize the implication to liver.…”

Section: Introductionmentioning

confidence: 99%

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Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma

Patil¹,

Galstyan²,

Grodzinski³

et al. 2020

IJN

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Background: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized singleand multi-arm ("star") gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model. Materials and Methods: Antibody-and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood-brain barrier was studied by fluorescent microscopy. Results: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2-9.4 nm and antibody-targeted NCAs had diameters in the range 15.8-20.5 nm. Zeta potentials were in the range of-5.4-−8.2 mV and −4.6-−8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30-60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement. Conclusion: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors.

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“…Efficiency of BBB crossing of NCA was evaluated by a fluorescence-based quantification method developed in our lab. 10…”

Section: Immunohistochemistry and Bbb Crossing Efficiencymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma

Patil¹,

Galstyan²,

Grodzinski³

et al. 2020

IJN

Self Cite

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“…This strategy has attracted much attention, yet the efficacy of drugs and the pharmacokinetics remain to be confirmed. With the development of nanotechnology and nanomedicine in the recent decades, various drug delivery vehicles, such as liposomes [21][22][23], hydrogels [24], micelles [25,26], polymers [27][28][29] and inorganic nanoparticles [30][31][32][33][34][35] have been developed to incorporate therapeutics and to deliver them into tumor sites and CNS.…”

Section: Ivyspringmentioning

confidence: 99%

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

Liu¹,

Zhao²,

Gao³

et al. 2019

Nanotheranostics

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Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a "one-bead one-compound" (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both in vitro and in vivo, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.

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“…17,18 However, efforts are still being made to improve active targeting by fully exploring the tumor features. [19][20][21][22] Currently, the most commonly used active targeting ligands include transferrin, 23 folic acid, 24 and Arg-Gly-Asp. 25,26 Unfortunately, these ligands are not specific to head and neck cancer and do not target the core area of tumors, namely, the hypoxic region, which is widely regarded as the main contributor of chemoresistance.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma

Song

Tang

et al. 2020

IJN

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Chemotherapy in head and neck squamous cell carcinoma (HNSCC) has many systemic side effects, as well as hypoxia-induced chemoresistance. To reduce side effects and enhance chemosensitivity are urgently needed. Methods: We synthesized a drug delivery system (named CECMa NPs) based on cisplatin (CDDP) and metformin (chemotherapeutic sensitizer), of which chlorin e6 (Ce6) and polyethylene glycol diamine (PEG) were synthesized as the shell, an anti-LDLR antibody (which can target to hypoxic tumor cells) was modified on the surface to achieve tumor targeting. Results: The NPs possessed a great synergistic effect of chemotherapy and phototherapy. After laser stimulation, both CDDP and metformin can be released in situ to achieve antitumor effects. Meanwhile, PDT and PTT triggered by a laser have anticancer effects. Furthermore, compared with free cisplatin, CECMa exhibits less systemic toxicity with laser irradiation in the xenograft mouse tumor model. Conclusion: CECMa effectively destroyed the tumors via hypoxia targeting multimodal therapy both in vitro and in vivo, thereby providing a novel strategy for targeting head and neck squamous cell carcinoma.

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A Combination of Tri-Leucine and Angiopep-2 Drives a Polyanionic Polymalic Acid Nanodrug Platform Across the Blood–Brain Barrier

Cited by 43 publications

References 57 publications

<p>Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma</p>

<p>Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma</p>

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

<p>Hypoxia-Targeting Multifunctional Nanoparticles for Sensitized Chemotherapy and Phototherapy in Head and Neck Squamous Cell Carcinoma</p>

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