Abstract
Background: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). Neuroblastoma (NB) is one of the most common cancers of childhood derived from the neural crest cells. The survival rate for patients with GBM and high-risk NB is poor; therefore, novel therapeutic approaches are needed. Increasing evidence suggests a dual role of redox-active compounds in both tumorigenesis and cancer treatment. Therefore, in this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed. Methods: We synthesized non-symmetric bola dendrimers and assessed their radical scavenging potency as well as redox capability. The influence of dendrimers on viability of rat primary cerebellar neurons (CGC) and normal human astrocytes (NHA) was determined by propidium iodide staining and cell counting. Cytotoxicity against human GBM cell lines, T98G and LN229, and NB cell line SH-SY5Y was assessed by cell counting and colony forming assay. Results: Testing of CGC and NHA viability allowed to establish a range of optimal dendrimers structure and concentration for further evaluation of their impact on two human GBM and one human NB cell lines. According to ABTS, DPPH, FRAP, and CUPRAC antioxidant tests, the most toxic for normal cells were dendrimers with high charge and an excess of antioxidant residues (Trp and PABA) on both sides of the bola structure. At 5 μM concentration, most of the tested dendrimers neither reduced rat CGC viability below 50–40%, nor harmed human neurons (NHA). The same dose of compounds 16 or 22, after 30 min treatment decreased the number of SH-SY5Y and LN229 cells, but did not affect the number of T98G cells 48 h post treatment. However, either compound significantly reduced the number of colonies formed by SH-SY5Y, LN229, and T98G cells measured 14 days after treatment. Conclusions: Peptide dendrimers with non-symmetric bola structure are excellent scaffolds for design of molecules with pro/antioxidant functionality. Design of molecules with an excess of positive charges and antioxidant residues rendered molecules with high neurotoxicity. Single, 30 min exposition of the GBM and NB cell lines to the selected bola dendrimers significantly suppressed their clonogenic potential
Highlights
We have studied a group of dendrimers bearing p-aminobenzoic residue (PABA) and found out that in addition to p-aminobenzoic acid (PABA) an indole moiety significantly enhanced antioxidant capacity of these dendrimers, providing novel compounds that were able to significantly protect glutamate stressed rat cerebellar granule cells (CGC) [12]
The present research was inspired by the previous observation that a group of dendrimers functionalized with several p-aminobenzoic residues (PABA), supplemented with an indole moiety provided novel antioxidant compounds that were able significantly protect glutamate-stressed rat CGC [12]
On the basis of the previous research on positive impact of dendrimers containing antioxidant moieties on viability of neurons, it was of interest to see if such residues can modulate selectivity of dendrimers towards glioblastoma in comparison of the normal cell lines
Summary
Despite significant progress that has been made recently in development of therapeutic strategies in cancer therapy, glioblastoma (GBM) remains the most common malignant tumor of the central nervous system (CNS) with five-year relative survival of 6.8% [1]. Since introduction of a new lead compounds is rather seldom worldwide, the rapidly growing field of nanomedicine offers new solutions to improve the pharmacodynamics and pharmacokinetics of the existing drugs and, at medical level, the effectiveness of chemotherapy [3] This involves development of various nanocarriers [4,5,6,7] or combining both therapeutic and diagnostic capability in the theranostic agents [8,9]. In this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed
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