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Cyclodextrin-Based Peptide Self-Assemblies (Spds) That Enhance Peptide-Based Fluorescence Imaging and Antimicrobial Efficacy.

ABSTRACT: As a result of their high specificity for their corresponding biological targets, peptides have shown significant potential in a range of diagnostic and therapeutic applications. However, their widespread use has been limited by their minimal cell permeability and stability in biological milieus. We describe here a hepta-dicyanomethylene-4H-pyran appended β-cyclodextrin (DCM₇-β-CD) that acts as a delivery enhancing "host" for 1-bromonaphthalene-modified peptides, as demonstrated with peptide probes P1-P4. Interaction between the fluorescent peptides P1-P3 and DCM₇-β-CD results in the hierarchical formation of unique supramolecular architectures, which we term supramolecular-peptide-dots (Spds). Each Spd (Spd-1, Spd-2, and Spd-3) was found to facilitate the intracellular delivery of the constituent fluorescent probes (P1-P3), thus allowing spatiotemporal imaging of an apoptosis biomarker (caspase-3) and mitosis. Spd-4, incorporating the antimicrobial peptide P4, was found to provide an enhanced therapeutic benefit against both Gram-positive and Gram-negative bacteria relative to P4 alone. In addition, a fluorescent Spd-4 was prepared, which revealed greater bacterial cellular uptake compared to the peptide alone (P4-FITC) in E. coli. (ATCC 25922) and S. aureus (ATCC 25923). This latter observation supports the suggestion that the Spd platform reported here has the ability to facilitate the delivery of a therapeutic peptide and provides an easy-to-implement strategy for enhancing the antimicrobial efficacy of known therapeutic peptides. The present findings thus serve to highlight a new and effective supramolecular delivery approach that is potentially generalizable to overcome limitations associated with functional peptides.

SUBMITTER: Jiao JB

PROVIDER: S-EPMC8009276 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Peptide nanoassemblies have garnered remarkable importance in the development of novel nanoscale biomaterials for drug delivery into tumor cells. Taking advantage of receptor mediated recognition of two known peptides, angiopep-2 (TFFYGGSRGKRNNFKTEEY) and A-COOP-K (ACGLSGLC10 VAK) that bind to the over-expressed receptors low density lipoprotein (LRP-1) and fatty acid binding protein (FABP3) respectively, we have developed new peptide conjugates by combining the anti-inflammatory, antitumor compound azelaic acid with angiopep-2, which efficiently self-assembled into nanofibers. Those nanofibers were then functionalized with the A-COOP-K sequence and formed supramolecular hierarchical structures that were found to entrap the chemotherapeutic drug doxorubicin efficaciously. Furthermore, the nanoassemblies were found to release the drug in a dose-dependent manner and showed a stepwise increase over a period of 2 weeks under acidic conditions. Two cell lines (U-87-MG and U-138-MG) were utilized as models for glioblastoma cells grown in the presence of serum and under serum-free conditions to mimic the growth conditions of natural tumors. The drug entrapped assemblies were found to inhibit the cell proliferation of both U-87 and U-138MG glioblastoma cells. Three dimensional spheroids of different sizes were grown to mimic the tumors and evaluate the efficacy of drug release and internalization. Our results indicated that the nanoassemblies were found to have higher internalization of DOX and were well-spread throughout the spheroids grown, particularly under serum-free conditions. The nanoassemblies also displayed blood-brain barrier penetration when tested with a multicellular in vitro model. Such self-assembled nanostructures with targeting ability may provide a suitable platform for the development of new peptide-based biomaterials that can provide more insights about the mechanistic approach for drug delivery for not only 2D cell cultures but also 3D tumoroids that mimic the tumor microenvironments.

Dataset Information

Cyclodextrin-Based Peptide Self-Assemblies (Spds) That Enhance Peptide-Based Fluorescence Imaging and Antimicrobial Efficacy.

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