Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges

Parrasia, Sofia; Szabó, Ildikò; Zoratti, Mario; Biasutto, Lucia

doi:10.1021/acs.molpharmaceut.2c00523

Cited by 29 publications

(30 citation statements)

References 495 publications

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“…Nanocapsules modified with Ang peptides may have improved ability to penetrate the BBB and deliver genetic drugs to the brain. The TAT peptide is a potent cell-penetrating peptide that can enter the nucleus of most live cells through the plasma membrane . TAT can stimulate internalization through an unsaturated and receptor/transporter-independent mechanism, allowing it to cross BBB biofilm barriers and access dense tumor tissues readily.…”

Section: Resultsmentioning

confidence: 99%

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

Liu,

Cao,

Wang

et al. 2023

ACS Nano

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Radiotherapy is a mainstay of glioblastoma (GBM) treatment; however, the development of therapeutic resistance has hampered the efficacy of radiotherapy, suggesting that additional treatment strategies are needed. Here, an in vivo loss-of-function genome-wide CRISPR screen was carried out in orthotopic tumors in mice subjected to radiation treatment to identify synthetic lethal genes associated with radiotherapy. Using functional screening and transcriptome analyses, glutathione synthetase (GSS) was found to be a potential regulator of radioresistance through ferroptosis. High GSS levels were closely related to poor prognosis and relapse in patients with glioma. Mechanistic studies demonstrated that GSS was associated with the suppression of radiotherapy-induced ferroptosis in glioma cells. The depletion of GSS resulted in the disruption of glutathione (GSH) synthesis, thereby causing the inactivation of GPX4 and iron accumulation, thus enhancing the induction of ferroptosis upon radiotherapy treatment. Moreover, to overcome the obstacles to broad therapeutic translation of CRISPR editing, we report a previously unidentified genome editing delivery system, in which Cas9 protein/sgRNA complex was loaded into Angiopep-2 (Ang) and the trans-activator of the transcription (TAT) peptide dual-modified extracellular vesicle (EV), which not only targeted the blood–brain barrier (BBB) and GBM but also permeated the BBB and penetrated the tumor. Our encapsulating EVs showed encouraging signs of GBM tissue targeting, which resulted in high GSS gene editing efficiency in GBM (up to 67.2%) with negligible off-target gene editing. These results demonstrate that a combination of unbiased genetic screens, and CRISPR-Cas9-based gene therapy is feasible for identifying potential synthetic lethal genes and, by extension, therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

Liu,

Cao,

Wang

et al. 2023

ACS Nano

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“…Small peptides are having various advantages, such as ease in synthesis, good penetrability even into the BBB, small size, rapid tumor access, ease in linking to a spacer through amide bonds, and high clearance rate [93]. Some of the major examples of peptides used widely for PDT-mediated anti-cancer therapy include:…”

Section: Peptide-mediated Targetingmentioning

confidence: 99%

Porphyrinoid Photosensitizers for Targeted and Precise Photodynamic Therapy: Progress in Fabrication

Sivakumar¹,

Raju²,

Kamal³

et al. 2023

Drug Formulation Design

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This chapter focuses on basic facts and details of photodynamic therapy (PDT). PDT’s ability to cause cytotoxicity has led to its applications for a variety of medical conditions other than cancer treatment. This adaptable technology has some advantages in treating severe illness situations such as cancer, alopecia, angina pectoris, and periodontitis. It stands out even more because of the interaction of three elements: light, a photosensitizer (PS), and cellular oxygen. By preventing PS accumulation in normal vegetative cells, targeted photodynamic therapy plays an important role in achieving better accumulation of PS in a specific area. This section discusses various types of targeting methods, such as active targeting, passive targeting, and peptide-mediated targeting. Aid in both diagnosing and curing diseases, gaining widespread acceptance. It is a promising therapeutic approach with a lot of potential.

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“…However, a number of cell-specific PTDs can be identified [ 202 ] mainly via the use of peptide phage display libraries [ 191 , 192 ].…”

Section: Deliverable Recombinant Protein Delivery Mediated By Ptd Tec...mentioning

confidence: 99%

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

et al. 2023

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Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness.

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Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges

Cited by 29 publications

References 495 publications

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma

Porphyrinoid Photosensitizers for Targeted and Precise Photodynamic Therapy: Progress in Fabrication

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

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