Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology

Hersh, Andrew; Alomari, Safwan; Tyler, Betty

doi:10.3390/ijms23084153

Cited by 101 publications

(56 citation statements)

References 296 publications

(329 reference statements)

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“…The problem of delivering drugs to the brain is important because the blood–brain barrier is impermeable to most compounds. However, nanoparticles (<1000 nm), including dendrimers, may pass through or bypass the BBB depending on how the compound is administered, as detailed in the Hersh et al, 2022 review [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis and Activity of New N1-Alkyl Tryptophan Functionalized Dendrimeric Peptides against Glioblastoma

et al. 2022

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Background: Due to resistance to conventional therapy, a blood–brain barrier that results in poor drug delivery, and a high potential for metastasis, glioblastoma (GBM) presents a great medical challenge. Since the repertoire of the possible therapies is very limited, novel therapeutic strategies require new drugs as well as new approaches. The multiple roles played by L-tryptophan (Trp) in tumorigenesis of GBM and the previously found antiproliferative properties of Trp-bearing dendrimers against this malignancy prompted us to design novel polyfunctional peptide-based dendrimers covalently attached to N1-alkyl tryptophan (Trp) residues. Their antiproliferative properties against GBM and normal human astrocytes (NHA) and their antioxidant potential were tested. Methods: Two groups of amphiphilic peptide dendrimers terminated with N1-butyl and N1-aminopentane tryptophan were designed. The influence of dendrimers on viability of NHA and human GBM cell lines, displaying different genetic backgrounds and tumorigenic potentials, was determined by the MTT test. The influence of compounds on the clonogenic potential of GBM cells was assessed by colony-formation assay. Dendrimers were tested for radical scavenging potency as well as redox capability (DPPH, ABTS, and FRAP models). Results: Several peptide dendrimers functionalized with N1-alkyl-tryptophan at 5 µM concentration exhibited high selectivity towards GBM cells retaining 85–95% viable NHA cells while killing cancer cells. In both the MTT and colony-formation assays, compounds 21 (functionalized with N1-butyl-Trp and (+)8 charged) and 25 (functionalized with N1-aminopentane-Trp and (+)12 charged) showed the most promise for their development into anticancer drugs. According to ABTS, DPPH, and FRAP antioxidant tests, dendrimers functionalized with N1-alkylated Trp expressed higher ROS-scavenging capacity (ABTS and DPPH) than those with unsubstituted Trp. Conclusions: Peptide dendrimers functionalized with N1-alkyl-tryptophan showed varying toxicity to NHA, while all were toxic to GBM cells. Based on their activity towards inhibition of GBM viability and relatively mild effect on NHA cells the most advantageous were derivatives 21 and 25 with the respective di-dodecyl and dodecyl residue located at the C-terminus. As expected, peptide dendrimers functionalized with N1-alkyl-tryptophan expressed higher scavenging potency against ROS than dendrimers with unsubstituted tryptophan.

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Section: Discussionmentioning

confidence: 99%

Design, Synthesis and Activity of New N1-Alkyl Tryptophan Functionalized Dendrimeric Peptides against Glioblastoma

et al. 2022

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“…Nanogels have been confirmed to be efficient in crossing the blood-brain barrier for optimal targeted brain cancer therapies ( Stawicki et al, 2021 ). Furthermore, nanoparticles can be designed by incorporation of ligands to trigger either carrier-mediated transport or receptor-mediated transcytosis across the blood brain barrier ( Saraiva et al, 2016 ; Hersh et al, 2022 ). Singh et al (2021) developed nanogels functionalized with diphtheria toxin receptor ligand which enabled receptor-mediated transcytosis (transcellular transport) of nanogels through the blood brain barrier into the tumor cells.…”

Section: Nanogels For Cancer Therapymentioning

confidence: 99%

Nanogels as target drug delivery systems in cancer therapy: A review of the last decade

et al. 2022

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Cancer is an important cause of morbidity and mortality worldwide, irrespective of the level of human development. Globally, it was estimated that there were 19.3 million new cases of cancer and almost 10 million deaths from cancer in 2020. The importance of prevention, early detection as well as effective cancer therapies cannot be over-emphasized. One of the important strategies in cancer therapy is targeted drug delivery to the specific tumor sites. Nanogels are among the several drug delivery systems (DDS) being explored as potential candidates for targeted drug delivery in cancer therapy. Nanogels, which are new generation, versatile DDS with the possession of dual characteristics of hydrogels and nanoparticles have shown great potential as targeted DDS in cancer therapy. Nanogels are hydrogels with a three-dimensional (3D) tunable porous structure and a particle size in the nanometre range, from 20 to 200 nm. They have been visualized as ideal DDS with enormous drug loading capacity, and high stability. Nanogels can be modified to achieve active targeting and enhance drug accumulation in disease sites. They can be designed to be stimulus-responsive, and react to internal or external stimuli such as pH, temperature, light, redox, thus resulting in the controlled release of loaded drug. This prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. Drugs with severe adverse effects, short circulation half-life, and easy degradability by enzymes, such as anti-cancer drugs, and proteins, are suitable for delivery by chemically cross-linked or physically assembled nanogel systems. This systematic review summarizes the evolution of nanogels for targeted drug delivery for cancer therapy over the last decade. On-going clinical trials and recent applications of nanogels as targeted DDS for cancer therapy will be discussed in detail. The review will be concluded with discussions on safety and regulatory considerations as well as future research prospects of nanogel-targeted drug delivery for cancer therapy.

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“…Additional mechanisms influencing GSC chemoresistance include expression of drug efflux transporters. Drug delivery to tumor cells is limited by the tight microvascular network constituting the blood–brain barrier, and those drugs capable of intratumoral accumulation can be removed by ATP-binding cassette transporters [ 226 ]. Overexpression of these multi-drug resistance transporters on GSC cell membranes mediate chemoresistance to a range of therapeutics [ 210 , 227 ].…”

Section: Resistance Mechanisms To Therapymentioning

confidence: 99%

“…Additionally, the blood–brain barrier poses a formidable challenge to the delivery of anti-tumor therapeutics [ 226 ]. Uptake of drugs is limited by tight junctions and adherens junctions, as well as multidrug efflux transporters along the barrier.…”

Section: Targeted Therapymentioning

confidence: 99%

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Hersh

Gaitsch

Alomari

et al. 2022

Cancers

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Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

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Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology

Cited by 101 publications

References 296 publications

Design, Synthesis and Activity of New N1-Alkyl Tryptophan Functionalized Dendrimeric Peptides against Glioblastoma

Design, Synthesis and Activity of New N1-Alkyl Tryptophan Functionalized Dendrimeric Peptides against Glioblastoma

Nanogels as target drug delivery systems in cancer therapy: A review of the last decade

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

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