Self-assembled peptide-based nanostructures, comprised of naturally occurring amino acids, display excellent biocompatibility, biodegradability, flexible responsiveness, and synthetic feasibility and can be customized for various biomedical applications. However, the lack of...

Fluorescent nanostructures obtained from small organic molecules or generated from supramolecular assembly of various functional π- conjugated molecules have concerned significant importance due to their potential applications in colour tunable...

A newly synthesized short peptide PS1 at different concentrations self-assemble into different nanostructures with various morphologies. The spherical units formed at lower concentration, considered as a potential candidate for intracellular delivery.

Two newly synthesized peptides, PA1 and PA2 with fluorinated aromatic unit and dicarboxylate group as an anchoring moiety able to form a non-toxic, stable, coating by a simple drop-coating method, improving the antifouling property of the surface.

Development of drug carriers, which can chaperone xenobiotics directly to their site of action, is an essential step for the advancement of precision medicine. Cationic nanoparticles can be used as a drug delivery platform for various agents including chemotherapeutics, oligonucleotides, and antibodies. Self-assembly of short peptides facilitates the formation of well-defined nanostructures suitable for drug delivery, and varying the polarity of the self-assembly medium changes the nature of noncovalent interactions in such a way as to generate numerous unique nanostructures. Here, we have synthesized an ultrashort cell-penetrating tetrapeptide (sequence Lys-Val-Ala-Val), with Lys as a cationic amino acid, and studied the self-assembly property of the BOC-protected (L1) and -deprotected (L2) analogues. Spherical assemblies obtained from L1/L2 in a 1:1 aqueous ethanol system have the ability to encapsulate small molecules and successfully enter into cells, thus representing them as potential candidates for intracellular drug delivery. To verify the efficacy of these peptides in the facilitation of drug efficacy, we generated encapsulated versions of the chemotherapeutic drug doxorubicin (Dox). L1- and L2-encapsulated Dox (Dox-L1 and Dox-L2), similar to the unencapsulated drug, induced upregulation of regulator of G protein signaling 6 (RGS6) and Gβ5, the critical mediators of ATM/p53-dependent apoptosis in Dox-treated cancer cells. Further, Dox-L1/L2 damaged DNA, triggered oxidative stress and mitochondrial dysfunction, compromised cell viability, and induced apoptosis. The ability of Dox-L1 to mediate cell death could be ameliorated via knockdown of either RGS6 or Gβ5, comparable to the results obtained with the unencapsulated drug. These data provide an important proof of principle, identifying L1/L2 as drug delivery matrices.

Chemotherapeutic drugs remain the most efficacious treatment options for a many human cancers. However, the inability to deliver these drugs directly to cancerous cells often results in dose limiting and sometimes life-threatening adverse effects. Rather than developing new chemical moieties, researchers have begun focusing on the development of drug carriers, which are specifically designed to shuttle chemotherapeutics into malignant cells while sparing healthy cells. Charged nanoparticles have emerged as effective delivery platforms for several xenobiotic classes including anticancer agents, oligonucleotides and antibodies. Notably, peptide-based self-assembled nanostructures are of particular interest due to their biocompatibility, high drug loading capacity, and potential for customization for cellspecific targeting. We synthesized and studied the selfassembling properties of two charged, cell penetrating tri-peptides: H 2 NÀ ArgÀ LeuÀ PheÀ OMe (S1) with Arg as cationic amino acid and BocÀ PheÀ LeuÀ GluÀ OH (S2) with Glu as negatively charged amino acid. The fibrils and spherical selfassembled structures formed by S1 and S2, respectively, can encapsulate the chemotherapeutic drug Doxorubicin and facilitate intracellular drug delivery via endocytosis. Furthermore, S1-and S2-encapsulated Doxorubicin (Dox-S1, Dox-S2), like the unencapsulated drug, induced oxidative stress and mitochondrial dysfunction, activated the ATM/p53 signaling cascades, and triggered apoptosis in cancer cells. Thus, while the surface charge of molecular building blocks used to generate supramolecular assemblies influences the morphology of generated nanostructures, both cationic and anionic peptide-based assemblies are capable of functioning as drug delivery vehicles.

Adenosine triphosphate (ATP), one of the biological anions plays crucial roles in several biological processes including energy transduction, cellular respiration, enzyme catalysis and signaling. ATP is a bioactive phosphate molecule,...

Nanodrug delivery systems (NDDs) capable of conveying chemotherapeutics directly into malignant cells without harming healthy ones are of significant interest in the field of cancer therapy. However, the development of nanostructures with the requisite biocompatibility, inherent optical properties, cellular penetration ability, encapsulation capability, and target selectivity has remained elusive. In an effort to develop cell-selective NDDs, we have synthesized a cationic tripeptide Boc-Arg-Trp-Phe-OMe (PA1), which self-assembles into well-ordered spheres in 100% aqueous medium. The inherent fluorescence properties of the peptide PA1 were shifted from the ultraviolet to the visible region by the self-assembly. These fluorescent nanostructures are proteolytically stable, photostable, and biocompatible, with characteristic blue fluorescence signals that permit us to monitor their intracellular entry in real time. We also demonstrate that these tripeptide spherical structures (TPSS) have the capacity to entrap the chemotherapeutic drug doxorubicin (Dox), shuttle the encapsulated drug within cancerous cells, and initiate the DNA damage signaling cascade, which culminates in apoptosis. Next, we functionalized the TPSS with an epithelial-cell-specific epithelial cell adhesion molecule aptamer. Aptamer-conjugated PA1 (PA1−Apt) facilitated efficient Dox delivery into the breast cancer epithelial cell line MCF7, resulting in cell death. However, cells of the human cardiomyocyte cell line AC16 were resistant to the cell killing actions of PA1−Apt. Together, these data demonstrate that not only can the self-assembly of cationic tripeptides like PA1 be exploited for efficient drug encapsulation and delivery but their unique chemistry also allows for functional modifications, which can improve the selectivity of these versatile NDDs.