Self Assembling Peptides For Targeted Drug Delivery Essay
Self Assembling Peptides For Targeted Drug Delivery Essay
Novel drug delivery systems is a field of which demands constant innovation. The healthcare industry is in continued search for delivery systems which can accurately deliver the drugs to target site with ideally no adverse effects. A poster-perfect drug delivery system is biocompatible and able deliver the active molecule at a constant rate, at the right dose, to the right site with no complications. Hence, the search for an idea drug carrier incorporates aspects of pharmacokinetics, pharmacodynamics, toxicological and immunological reactions, biorecognition and local biochemical interactions. Self Assembling Peptides For Targeted Drug Delivery Essay. In recent years, research in biochemical carriers for drug delivery has gained traction since these molecules can be adapted to meet most of the requirements of an ideal carrier and thus can be referred to as “smart” carriers. This includes liposomes, vectors, peptide drug adducts, dendrimers, micelles, microcapsules etc.
Molecular self-assembly can be defined as “spontaneous association of numerous individual entities into coherent organisation and well defined structures to maximize the benefit of the individual without external instruction”. The basic principle involves designing the molecules so that they interact and form numerous non-covalent bonds like hydrogen bonds, ionic bonds, Van der Waal’s interactions, etc leading to the formation of a stable structure into which a drug molecules can be incorporated. Peptides undergo self-assembly in nature leading to the formation of various peptide motifs like the α-helix and β- sheets.
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Peptides can be engineered specifically with these motifs which then interact to form various supramolecular assemblies including nanovesicles, nanotubes, nanofibers, nanoribbons and hydrogels which can be used for drug delivery and immunological applications. Widely explored biomedical applications for self-assembling peptides include formation of scaffolds for tissue engineering and drug and vaccine delivery.
Self-assembling peptide molecules are biocompatible and can act as intracellular transporters due to high permeability through bio membranes with high drug loading capacity and low drug leakage. They encapsulate hydrophobic drug molecules through interactions with amino acid side chains. Stability against enzymatic degradation can be conferred to the drug molecules and sustained release profiles can also be achieved. Self Assembling Peptides For Targeted Drug Delivery Essay.This can be done by designing the drug to respond to specific stimuli like pH, temperature or enzymes. In addition to acting as a carrier, peptide itself can have some therapeutic value. These peptides also demonstrate a sequence and structure specific impacts of the immune system which can be switched off for drug delivery and switched on for vaccine delivery. Targeted delivery can be achieved by including adhesin ligands, receptor specific ligands or peptide based antigens in the peptide design.
Dalargin is a low bioavailability drug which acts on the µ receptors and is effluxed and metabolized in the blood. This problem can be overcome by using a amphiphilic dalargin derivative where a palmitoyl moiety has been attached to the hydroxyl residue on tyrosine via an ester bond and then self-assembled into β-sheets fibrils on sonication. These nanofibrils show improved stability in blood and increased bioavailability in the CNS.
Sequences of poly-aspartic acid have shown increased binding to hydroxyapatite which can effectively deliver small drug molecules to the bones. This can be effectively used to treat osteoporosis or osteosarcoma where the complex mineralisation can be a barrier for conventional drug delivery techniques.
Active or passive targeting using self-assembling peptides for chemotherapeutic agents in an arena of much exploration. The RGD sequence in the peptide amphiphile has cell adhesion property and can mimic the extracellular matrix specifically binding to the transmembrane glycoproteins during tumour growth and metastasis, thus successfully entering the cell. This can prove to be a promising carrier for cytotoxic material into cancerous cells.
The examples stated above clearly demonstrate the potential of self-assembling peptides to target various physiological systems with minimal incompatibilities. With more concentrated research in the area, peptide therapeutics can boost the efficiency of drug therapy tremendously. Self Assembling Peptides For Targeted Drug Delivery Essay.
Peptide self-assembled nanostructures are very popular in many biomedical applications. Drug delivery is one of the most promising applications among them. The tremendous advantages for peptide self-assembled nanostructures include good biocompatibility, low cost, tunable bioactivity, high drug loading capacities, chemical diversity, specific targeting, and stimuli responsive drug delivery at disease sites. Peptide self-assembled nanostructures such as nanoparticles, nanotubes, nanofibers, and hydrogels have been investigated by many researchers for drug delivery applications. In this review, the underlying mechanisms for the self-assembled nanostructures based on peptides with different types and structures are introduced and discussed. Peptide self-assembled nanostructures associated promising drug delivery applications such as anticancer drug and gene drug delivery are highlighted. Furthermore, peptide self-assembled nanostructures for targeted and stimuli responsive drug delivery applications are also reviewed and discussed.
1. Introduction
Molecular self-assembly is organizing molecules into a stable and well-defined structure under equilibrium conditions through noncovalent interactions spontaneously, which is a powerful tool in the synthesis of functional nanostructures as a bottom-up fabrication method for biomedical applications [1, 2]. Self-assembly with a variety of complex nano- and microstructures is founded in nature [3–6]. Mechanisms underlying self-assembly have been applied in many areas to prepare functional materials. In most cases, a thermodynamically stable structure is formed through enthalpic and entropic interactions that involve the basic assembling units and the reacting solvent molecules [7, 8]. Electrostatic interactions, hydrophobic interactions, hydrogen bonding, π–π stacking, and so on together make sure molecules are at stable low energy levels [9]. Self Assembling Peptides For Targeted Drug Delivery Essay. The self-assembly process also gives the flexibility of developing many functional materials with the desired tunable properties and structures by single molecule design and fabrication [5, 10, 11].
Recently, many self-assembly nanostructures have been synthesized from biomaterials including carbohydrates, nucleic acids, and peptides to achieve a better understanding of the self-assembly mechanism and utilize them for several biomedical applications such as tissue regeneration, drug delivery, and biosensors [12–17]. Many self-assembling systems have been developed for various biomedical applications; peptide self-assembled nanostructures remain one of the most promising directions for many reasons [18]. They are easily fabricated using solid-phase peptide methods where the peptide sequence could be specifically modified at molecular levels [19]. Custom molecular structures can be designed and synthesized through tuning the peptide basic units. Naturally occurring structures occurred in proteins such as α-helices and β-sheets that can be utilized for driving the self-assembly processes [20–22]. Moreover, the self-assembly process is also very important in the functions of cell-penetrating peptides that could play an important role in delivering the drugs inside the cell membrane and transporting genes into the nucleus [23].
Peptides consisting of natural or synthetic amino acids are basic repeating units for the construction of molecular assemblies. These simple structures help us better understand the complex biological systems and underlying mechanisms. Researchers have utilized various approaches in the synthesis of peptide building units while minimizing other possible by-products [24]. To self-assemble peptides into nanostructures, there are mainly three approaches: solid-phase peptide synthesis, ring-opening polymerization, and protein engineering [25]. The solid-phase peptide synthesis is utilized to precisely control the peptide structure with short or medium sequences. Although this method has very high yield, the synthetic sequence is less than 70 amino acids [26]. Researchers have also utilized protein engineering to fabricate peptides with longer sequences and more defined structure such as collagen and silk materials through expression in bacteria [27–29]. For large-scale production of polypeptides, people have utilized ring-opening polymerization. In this method, cyclic monomers are introduced to the end of the sequences to form a longer peptide. On the other hand, a lower accuracy of the peptide primary structure than other methods such as solid-phase peptide synthesis is noticed using this method [25]. Self Assembling Peptides For Targeted Drug Delivery Essay.
Several reviews have been focused on the morphologies, functions, or biomedical applications of peptide self-assembled nanostructures in tissue engineering rather than drug delivery applications [24, 30–32]. There is still a need for a comprehensive review on the peptide self-assembled nanostructures for drug delivery applications. In this paper, self-assembled peptide types and structures including dipeptide, cyclic peptide, amphiphilic peptide, α-helical peptide, and β-sheet peptide as basic building blocks are introduced. Meanwhile, some relevant peptide self-assembly mechanisms are also discussed. More importantly, peptide self-assembled nanostructures for anticancer drug delivery, gene drug delivery, and targeted and stimuli responsive drug delivery applications are reviewed and discussed.
2. Peptide Types and Structures for Self-Assembly
Peptides can be assembled into different nanostructures in Figure 1 including nanotubes, nanofibers, and nanovesicles based on their design and self-assembly conditions [33]. Different types and structures of peptides including dipeptides, cyclic peptides, amphiphilic peptides, α-helical peptides, and β-sheet peptides have been utilized to self-assemble into nanostructures.
2.1. Dipeptide
Recently, researchers have claimed that short peptides have the ability to self-assemble into many different nanostructures that can minimize the difficulty and cost of the fabrication process and simultaneously enhance the stability [35, 36]. Among them, dipeptide self-assembled nanostructures are investigated intensively for various biomedical applications including drug delivery. Diphenylalanine, Phe-Phe (FF), the first reported dipeptide that has been used for the self-assembly of different nanostructures, is a core motif of the amyloid-β polypeptide segment [37]. It has been recognized as the core recognition motif to drive self-assembly in Alzheimer’s disease. Many studies have been carried out to self-assemble FF dipeptides into different nanostructures including nanoparticles, nanotubes, nanovesicles, and nanowires, shown in Figure 2 [34, 38–42]. Self Assembling Peptides For Targeted Drug Delivery Essay. FF self-assembled nanotubes have been demonstrated to be thermally stable, which is one of the most unique properties for bioinspired materials [43]. The high yield of FF dipeptides self-assembled nanotubes was achieved through vapor deposition method, which could tune the density and length of nanotubes by controlling the monomer supply [38]. FF self-assembled nanotubes were also obtained through dissolving the dipeptides in water by sonication followed by heating. Meanwhile, FF self-assembled nanowires were achieved in water at high ionic strength. Both FF dipeptides self-assembled nanotubes and nanowires are interconvertible. These two nanostructures have been studied for mechanical applications including biosensors, nanodevices, and conducting nanomaterials [44, 45].
Hydrophobic dipeptides such as LL, LI, and LF can also self-assemble into nanotubes through hydrogen bonding. The water molecules filled nanotubes from the dipeptide WG showed negative thermal expansion, which later was utilized to form nanoporous structures from dipeptides FF, LS, IV, VI, VA, and AV [46–48]. These dipeptide self-assembled nanoporous materials have been demonstrated to absorb and store many different gasses including carbon dioxide, methane, and hydrogen [49–51]. Introducing a thiol group in FF dipeptides can change their formation from tubular to spherical nanostructures. Nanospheres, nanoplates, nanofibrils, and hydrogels were further developed from the self-assembly of several aromatic homodipeptides [52, 53]. These dipeptide self-assembled nanostructures can be applied for a casting mold to fabricate conductive nanowires and for many different biomedical applications including biosensing, tissue engineering, bioimaging, and drug delivery [53–55]. Self Assembling Peptides For Targeted Drug Delivery Essay.
Modified dipeptides also could be used as templates for self-assembling nanostructures with tunable biological functions [56]. The modified dipeptides containing an N-terminal ω-amino acid could self-assemble into nanotubes in the solid state and in aqueous solutions [57]. The morphological studies revealed the self-assembly of uniform and well-organized nanotubes with various dimensions. These modified dipeptide self-assembled nanostructures are significantly different from the solid-state or solution methods, which demonstrated that the self-assembly mechanisms in these two strategies are different [58]. Therefore, water molecules with hydrogen bonding capacities could have an important function in the self-assembly or even stabilization of the nanotubes.
Except for the dipeptides self-assembled nanostructures, there are also many other short linear peptides self-assembled nanostructures for biomedical applications including drug delivery [59, 60]. For example, KLVFF, a short peptide from amyloid-beta peptides self-assembly mechanism from Alzheimer’s disease, could also self-assemble into nanofibrous structures and then hydrogel format in a concentrated phosphate buffered saline solution. The experimental results from physical and chemical characterizations have demonstrated that the linear short peptides can self-assemble into β-sheet structures and then form nanofibrillar hydrogel structures through electrostatic interactions [59]. Moreover, the short linear peptides DFNK and DFNKF both have been demonstrated to self-assemble into nanofibril structures based on the effects of pH values. These peptides have aromatic and charged side chains in the peptide sequences [60]. Self Assembling Peptides For Targeted Drug Delivery Essay.
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2.2. Cyclic Peptide
Cyclic peptides with alternating D type and L type amino acids that could self-assemble into nanotubes were determined theoretically as early as 1974 [61]. However, the first self-assembled nanotube using cyclo-(L-Gln-D-Ala-L-Glu-D-Ala)2 cyclic peptides was achieved in 1993 based on that theory [62]. The cyclic peptide self-assembly is formed through aggregating cyclic peptides as basic building blocks to a flat conformation structure where the amino and carbonyl side chains are arranged perpendicular to the ring [63]. The cyclic peptide self-assembled nanotubes were self-assembled and stabilized by hydrogen bonding between amide groups shown in Figure 3 [64]. Due to the alternating D type and L type amino acids, the peptide side chains could be formulated on the outside area that can create a nanotube structure. There are many cyclic peptide sequences that can be used for the self-assembly, including alternating D type and L type α-amino acids, alternating α– and β-amino acids, β-amino acids, and δ-amino acids [62, 63, 65, 66]. Self Assembling Peptides For Targeted Drug Delivery Essay.
