Targeting Glioblastoma Cells Expressing CD44 with Liposomes Encapsulating Doxorubicin and Displaying Chlorotoxin-IgG Fc Fusion Protein

Mahmud, Hafizah; Kasai, Tomonari; Khayrani, Apriliana Cahya; Asakura, Mami; Oo, Aung Ko Ko; Du, Jie; Vaidyanath, Arun; El-Ghlban, Samah; Mizutani, Akifumi; Seno, Akimasa; Murakami, Hiroshi; Masuda, Junko; Seno, Masaharu

doi:10.3390/ijms19030659

Cited by 28 publications

(17 citation statements)

References 31 publications

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“…Extensive Cltx research is currently focused on use of the peptide as a drug/gene delivery agent in a multitude of diverse formulations including nanoparticles, liposomes, phage, etc. for glioblastoma, various additional tumor types, and other disease indications [19–21]. Since Cltx has compelling potential as a platform for specifically targeting glioma and other cancer cells, appropriate tumor stratification and patient selection are essential.…”

Section: Discussionmentioning

confidence: 99%

Neuropilin-1 drives tumor-specific uptake of chlorotoxin

et al. 2019

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Background Chlorotoxin (Cltx) isolated from scorpion venom is an established tumor targeting and antiangiogenic peptide. Radiolabeled Cltx therapeutic ( 131 I-TM601) yielded promising results in human glioma clinical studies, and the imaging agent tozuleristide, is under investigation in CNS cancer studies. Several binding targets have previously been proposed for Cltx but none effectively explain its pleiotropic effects; its true target remains ambiguous and is the focus of this study. Methods A peptide-drug conjugate (ER-472) composed of Cltx linked to cryptophycin as warhead was developed as a tool to probe the molecular target and mechanism of action of Cltx, using multiple xenograft models. Results Neuropilin-1 (NRP1), an endocytic receptor on tumor and endothelial cells, was identified as a novel Cltx target, and NRP1 binding by Cltx increased drug uptake into tumor. Metabolism of Cltx to peptide bearing free C-terminal arginine, a prerequisite for NRP1 binding, took place in the tumor microenvironment, while native scorpion Cltx with amidated C-terminal arginine did not bind NRP1, and instead acts as a cryptic peptide. Antitumor activity of ER-472 in xenografts correlated to tumor NRP1 expression. Potency was significantly reduced by treatment with NRP1 blocking antibodies or knockout in tumor cells, confirming a role for NRP1-binding in ER-472 activity. Higher cryptophycin metabolite levels were measured in NRP1-expressing tumors, evidence of NRP1-mediated enhanced drug uptake and presumably responsible for the superior antitumor efficacy. Conclusions NRP1 was identified as a novel Cltx target which enhances tumor drug uptake. This finding should facilitate tumor selection for chlorotoxin-based therapeutics and diagnostics. Electronic supplementary material The online version of this article (10.1186/s12964-019-0368-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Neuropilin-1 drives tumor-specific uptake of chlorotoxin

et al. 2019

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“…It has been shown that even after aggressive multimodal therapy including chemotherapy, radiation, surgery, and their combined treatments, the median survival rate is 14 months, which emphasizes the urgent need for developing an effective strategy to eradicate brain tumors [1,25]. The discovery of highly expressed novel markers of brain tumors and the application of these markers in several nanoformulations functionalized with targeting ligands has notably improved the treatment and elimination of brain tumors [8,[26][27][28][29][30][31]. Another recent and emerging anticancer approach that led to an explosion of clinical trials is immunotherapy, defined by targeting immune checkpoint receptors expressed on adaptive immune cells to improve immune surveillance [32].…”

Section: Glioblastoma (Gbm)mentioning

confidence: 99%

“…Additionally, these nerves also offer a potential route for direct access of medication into the CNS [5][6][7]. Recent studies have shown the potential existence of a functional pathway (sometimes called "nose-to-brain" transport) for drugs to pass into the CNS from structures deep in the nose innervated by cranial nerves [5,7,8].…”

Section: Introductionmentioning

confidence: 99%

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

et al. 2020

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Although the global prevalence of neurological disorders such as Parkinson's disease, Alzheimer's disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs' entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices. Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neurodegenerative disease, leading to the development of bradykinesia and tremors of cardinal motor functions ( Figure 2) [3]. PD models specifically show a decrease in dopamine transporters, which are responsible for dopamine uptake by dopaminergic neurons and progression of neuronal communications. Reduced Figure 1. Schematic demonstrating various transport systems that shuttle molecules across the BBB. Very small amount of water-soluble compounds cross through the tight junctions (paracellular), whereas lipid-soluble agents traverse via the transcellular lipophilic pathway. Selective transport systems exist for glucose, amino acids, nucleosides, and other substances, in addition to specific receptor-mediated endocytosis for certain proteins such as insulin and transferrin. (AZT = azathioprine). List of CNS Diseases Parkinson's Disease (PD)PD, occurring primarily in the substantia nigra, is the second-most common neuro...

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“…The authors verified the superiority of M-CTX-Fc by comparing U251MG-P1 cells (CD44+) with CD44-negative cells (SKBR3) in cellular uptake, in vitro cytotoxicities and in vivo tumor growth inhibition. Since CD44 positivity represent stemness of a cancer cell line along with other markers such as OCT3/4, SOX2, KLF4, and Nanog, this approach may contribute to the retardation of tumor growth by restricting cancer stem cell population (34).…”

Section: Active Targetingmentioning

confidence: 99%

Macromolecular Drug Carriers for Targeted Glioblastoma Therapy: Preclinical Studies, Challenges, and Future Perspectives

2018

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Glioblastoma, the most common, aggressive brain tumor, ranks among the least curable cancers—owing to its strong tendency for intracranial dissemination, high proliferation potential, and inherent tumor resistance to radiation and chemotherapy. Current glioblastoma treatment strategies are further hampered by a critical challenge: adverse, non-specific treatment effects in normal tissue combined with the inability of drugs to penetrate the blood brain barrier and reach the tumor microenvironment. Thus, the creation of effective therapies for glioblastoma requires development of targeted drug-delivery systems that increase accumulation of the drug in the tumor tissue while minimizing systemic toxicity in healthy tissues. As demonstrated in various preclinical glioblastoma models, macromolecular drug carriers have the potential to improve delivery of small molecule drugs, therapeutic peptides, proteins, and genes to brain tumors. Currently used macromolecular drug delivery systems, such as liposomes and polymers, passively target solid tumors, including glioblastoma, by capitalizing on abnormalities of the tumor vasculature, its lack of lymphatic drainage, and the enhanced permeation and retention (EPR) effect. In addition to passive targeting, active targeting approaches include the incorporation of various ligands on the surface of macromolecules that bind to cell surface receptors expressed on specific cancer cells. Active targeting approaches also utilize stimulus responsive macromolecules which further improve tumor accumulation by triggering changes in the physical properties of the macromolecular carrier. The stimulus can be an intrinsic property of the tumor tissue, such as low pH, or extrinsic, such as local application of ultrasound or heat. This review article explores current preclinical studies and future perspectives of targeted drug delivery to glioblastoma by macromolecular carrier systems, including polymeric micelles, nanoparticles, and biopolymers. We highlight key aspects of the design of diverse macromolecular drug delivery systems through a review of their preclinical applications in various glioblastoma animal models. We also review the principles and advantages of passive and active targeting based on various macromolecular carriers. Additionally, we discuss the potential disadvantages that may prevent clinical application of these carriers in targeting glioblastoma, as well as approaches to overcoming these obstacles.

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Targeting Glioblastoma Cells Expressing CD44 with Liposomes Encapsulating Doxorubicin and Displaying Chlorotoxin-IgG Fc Fusion Protein

Cited by 28 publications

References 31 publications

Neuropilin-1 drives tumor-specific uptake of chlorotoxin

Neuropilin-1 drives tumor-specific uptake of chlorotoxin

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Macromolecular Drug Carriers for Targeted Glioblastoma Therapy: Preclinical Studies, Challenges, and Future Perspectives

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