Interactions of Nanoscale Self-Assembled Peptide-Based Assemblies with Glioblastoma Cell Models and Spheroids

Abstract

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.

Nanocrystals for Deep-Tissue In Vivo Luminescence Imaging in the Near-Infrared Region

“…It is crucial to achieve clear and finely delineated visualization of the margins. The Angiopep-2 peptide (ANG), a 19-amino acid polypeptide, was utilized due to its specific affinity toward the low-density lipoprotein receptor-related protein, which is known to be overexpressed in glioma cells. − Based on this, Ren et al developed a dye-brush polymer (Dye-BP) modified NaErF 4 :​2.5%Ce@NaYbF 4 (0.9 nm)@NaLuF 4 downconversion nanocrystals, referred to as Er-DCNP-Dye-BP, for fluorescence-guided surgery of brain tumors (Figure a) . Modification with Dye-BP enabled a remarkable 675-fold luminescence enhancement of 1525 nm under 808 nm excitation, surpassing the performance of NaErF 4 nanoparticles.…”

Electrospun Drug-Loaded and Gene-Loaded Nanofibres: The Holy Grail of Glioblastoma Therapy?

“…Due to their ability to form a wide range of nanostructures, self-assembling peptide hydrogels are used [ 55 ]. Lebedenko et al [ 56 ] developed new peptide conjugates by amalgamating the anti-inflammatory antitumour compound azelaic acid with angiopep-2, which efficiently self-assembled into nanofibres. Functionalizing of the two nanofibres was then performed using two known peptides with receptor-mediated recognition, known as A-COOP-K sequence forming supramolecular hierarchical structures, that efficiently encapsulated the chemotherapeutic agent doxorubicin (DOX).…”

“…From an economic point of view, the low yield of electrospinning equipment also affects the reproducibility and the ability to scale up manufacturing processes, and tremendous is effort required to resolve this issue, for example, issues with regard to electrospinning processing parameters, such as electrostatic charges, loss of sample, design optimization and the compatibility of these drug- and gene-loaded nanofibres post-implantation. These shortcomings limit these nanofibres to preclinical studies, making it imperative for a viable strategy to be developed to progress these fabricated nanofibres from bench/academic research to clinical trials [ 56 ]. It is also imperative to publish negative data when studies enter in vivo trials, as this may help other scientists tailor ongoing research to increase the chance of success of these drug-loaded and gene-loaded nanofibres in treating GBM or any other types of disease.…”