The Pt(IV) coupled drug delivery system shows efficacy in the treatment of glioblastoma


A recent study published in Observer Edition Magazine demonstrated a novel method for delivering anticancer drugs conjugated to modified cell-penetrating peptides across the blood-brain barrier (BBB) ​​in mice for the treatment of glioblastoma (GBM).

Stady: The brain-infiltrated macrocyclic peptide Pt(IV) shows preclinical efficacy in glioblastoma. Image credit: April stock/Shutterstock

background

Like most tumors, brain tumors develop due to abnormal cell proliferation. It can be cancerous or non-cancerous. There are two types of primary brain tumors: glioma (made up of glial cells) and non-glial (developing near nerves, blood vessels, or glands). Gliomas are brain tumors that arise from glial cells. Glioblastoma (GBM) is the most common, malignant (cancerous) and fatal tumor of all gliomas; Most patients with GBM live for about 15 months after diagnosis. The 5-year survival rate for GBM is less than 5%.

A major challenge in treating brain cancer is the ability to deliver therapeutic agents across the BBB – a network of blood vessels and cells that protects the brain from harmful substances. It has been observed that anticancer drugs are unable to penetrate the blood-blood barrier in effective therapeutic amounts. Drugs with proven anticancer efficacy do not show a significant effect on brain cancer outcome, possibly due to the selective penetrability of the BBB.

Standard cancer management includes surgical removal of the tumor, followed by radiotherapy and temozolomide (TMZ) chemotherapy. In the first year after diagnosis, most patients experience a recurrence of the tumor. Cisplatin is commonly used to treat various types of tumors for its ability to destroy deoxyribonucleic acid (DNA) by or within cross-links.

However, cisplatin and other platinum-based drugs are not considered effective in treating GBM because they cannot penetrate the BBB. For similar reasons, current anticancer drugs have few therapeutic benefits for patients with GBM. It has been suggested that enhancing BBB permeability could be of tremendous value as it could facilitate greater concentrations of drugs within the tumor.

It is possible to increase the amounts of drugs delivered to the GBM using direct intraventricular injection and implantable drugs, such as Gliadel chips, which can be inserted directly into the tumor resection cavity immediately after surgery.

The BBB can be made transiently permeable using hypertoxic solutions or targeted ultrasound. Instead, non-invasive central nervous system (CNS) delivery methods are promising, and many of these approaches are currently in preclinical trials. Among these are BBB-penetrating nanoparticles, lipid formulations, and peptide-based delivery systems, for example, cell-penetrating peptides (CPPs).

Drug-conjugated peptides are emerging as important therapeutic agents in the treatment of various diseases, including cancer. Peptides are effective in brain tumors because they have an inherent ability to cross membranes and penetrate tissues.

In the former, the researchers created M13-CPP derivative Transportan 10 (TP10), which was made by adding the full perfluorinated macrocycle to the latter. This change enables greater penetration with 3D BBB spheroids in the laboratory It causes accumulation in the mouse brain in vivo. Pt(IV)-M13 facilitates the transfer of platinum into healthy rat brain tissue, after conjugation to cis-, cis-, and transit-[Pt (NH3)2Cl2(OH)2]which is a prodrug Pt(IV) form of cisplatin.

Platinum can be easily detected by inductively coupled plasma mass spectrometry (ICP-MS) – a technique that can identify trace levels of the metal in biological tissues.

the study

In the current study, the researchers examined platinum transport by the Pt(IV)-M13 group in a BBB-spheroid model, in the laboratoryas well as in healthy brain and tumor of a mouse GBM-xenograft model.

Here, preparation and initial characterization of a drug-conjugated peptide [Pt(IV)-M13] conducted. The cytotoxicity of Pt(IV) was assessed by comparing its effects on GBM cell lines cultured as neurospheres with that of Pt(IV) without conjugate and cisplatin. A three-dimensional BBB spheroid model simulating the BBB was used for the analysis, in the laboratory, Penetration of drugs and peptides across the BBB.

Quantitative analysis of platinum amounts in GBM tumor-bearing mice was performed using ICP-MS to determine the BBB platinum penetration and biodistribution properties.

The Pt(IV)-M13 conjugate was administered to tumor-bearing nude mice to examine the pharmacokinetics of platinum accumulation in healthy brain and tumor tissues. ICP-MS analysis of brain tissue and tumor tissue over time was performed. A reference fixed dosing schedule of 5 mg/kg of cisplatin was chosen to assess the pharmacokinetics of the peptide conjugate.

Drug-bound peptides were analyzed using confocal immunofluorescence microscopy to detect the DNA damage marker – γH2AX. Concurrent administration of Pt(IV) prodrug with cisplatin was performed at the maximum tolerated dose (MTD) of 5 mg/kg—with increasing doses.

Using a four-week treatment schedule with an initial dose of 5–30 mg of a drug-conjugated peptide, the effects of the highest tolerable dose (15 mg/kg, twice weekly) on tumor growth were evaluated in GBM animal models. The researchers conducted an MRI study during treatment (20 days after tumor implantation) to compare tumor growth behavior between groups as the control group started to reach predetermined growth goals.

the findings

found that when compared to Pt(IV) alone, conjugation of the prodrug Pt(IV) with M13 peptide significantly increased the cytotoxicity of Pt(IV) and reduced neurosphere growth in GBM cell lines. embodied in the laboratory The drug-conjugated peptide effectively killed GBM cells.

Moreover, platinum uptake was limited in BBB spheroids treated with the prodrug cisplatin or Pt(IV) alone. However, platinum uptake increased in the BBB spheroid model when Pt(IV) prodrugs were conjugated with M13 peptides. This means that the drug-conjugated peptide efficiently crosses the BBB spheroids.

Treatment with drug-conjugated peptides significantly increased platinum uptake compared to cisplatin in healthy brain tissue and eight-fold higher in tumor tissue. According to this study, conjugation of M13 to a Pt(IV) prodrug resulted in enhanced platinum uptake across the BBB and elevated platinum concentrations in the brain and tumor. Meanwhile, the lungs and kidneys, the two primary sites of platinum drug accumulation, showed no significant differences.

Five hours after injection of the drug-conjugated peptide Pt(IV)-M13, platinum accumulation in the brain and healthy tissues reached its maximum. There was no significant weight gain associated with administration of the drug-conjugated peptide. The data also found that mice tolerated increasing doses of Pt(IV)-M13 well.

Moreover, neither the dose nor the time point showed significant differences, indicating that these doses are safe for nude mice and suitable for exploratory survival studies.

also found that elevated platinum levels, when combined with Pt(IV)-M13 treatment, promoted DNA damage in tumours, which is thought to contribute to the observed improvement in survival. The authors showed, for the first time, that conjugation of the drug cisplatin (Pt(IV)) to a large epitope (M13) cell-penetrating peptide was effective.

These results indicated that conjugation of cisplatin with a cyclic macrocytic penetrating peptide (M13) enables effective doses in mice—three times higher for MTDs than cisplatin alone, and thus, confers significant survival advantages.

conclusion

The results indicated that systemic injection of Pt(IV) compound conjugated to a brain penetrating macrocyclic peptide could bring up brain platinum levels and prolong survival in mouse GBM models.

Macrocyclic-stapled CPPs show promising results when used as a drug delivery vehicle for brain tumor treatment across the BBB. Furthermore, Pt(IV)-M13 is a promising strategy for systemic delivery of GBM chemotherapies to the brain, which overcomes the challenges posed by the BBB, which currently impedes most oncology therapies.



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