The design and synthesis of a photo-controlled, peptide-based potential drug carrier

Our focus in this study is on the design and synthesis of a light-responsive peptide-based nanocarrier in order to develop effective and biocompatible drug delivery systems. The synthesized nanocarrier is basically composed of peptide amphiphiles comprising a micelle forming a Pro-Pro-Pro-Lys-Lys-Lys peptide sequence with an attached anthracene fluorophore Anthracene containing an inner core of the micelle can serve as a storage site for poorly water-soluble drugs. Moreover, anthracenes that come in close proximity with the formation of micellar structures can undergo photodimerization upon irradiation at 365 nm, which disrupts the micelle structures formed by the self-assembly of the peptide amphiphiles. Therefore, if a drug is encapsulated within the hydrophobic core of this peptidic carrier system, its release can be induced by the controlled exposure of the anthracene moiety to UV light

Structure-based design, synthesis and anticancer effect of cyclic Smac-polyarginine peptides

The second mitochondria-derived activator of caspase (Smac/DIABLO) is a pro-apoptotic protein that released from mitochondria into the cytosol when cells undergo apoptosis. Smac promotes caspase activation by binding the inhibitors of apoptosis proteins (IAP), particularly XIAP and eliminating their inhibitory activity. Although the seven N-terminal amino acids AVPIAQK (SmacN7) of Smac protein is able to elicit an anticancer response by itself, it is neither cell-permeable nor stable in the cellular environment. Thus, the use of SmacN7 derivatives and mimetics is an alluring field for cancer therapy. In this study, heptamer Smac peptide was fused to a well-known octaarginine cell-penetrating peptide for promoting its intracellular access. Both therapeutic Smac part and cell-penetrating octaarginine parts of the peptide sequence constrained in a cyclic structure so as to enhance the apoptosis-inducing potential of the SmacN7 peptide. Biological assays interestingly showed that cyclic peptides P4, P5 and P7 gave rise to a significant level of cytotoxicity and apoptosis mediated cell death in multiple myeloma tumor cells (MM) comparing to linear peptide

Synthesis and evaluation of tumor-homing peptides for targeting prostate cancer

High toxicity caused by chemotherapeutic drugs and the acquisition of drug resistance by cancer cells are the major drawbacks in cancer therapy. A promising approach to overcome the posed barriers is conjugating tumor-homing peptides to drugs or nanocarriers. Such high-affinity peptides can specifically target surface markers overexpressed by cancer cells, ensuring a rapid and cancer-specific uptake of the drugs. Since prostate-specific membrane antigen (PSMA) is overexpressed by aggressive prostate cancer cells, targeting this surface protein with peptide conjugates can lead to the development of effective strategies against prostate cancer. In this study, we aimed to determine which PSMA-binding peptide among peptides 563, 562 and 9-mer, show the highest selectivity towards PSMA using 22Rv1 prostate cancer cells, a cell line with moderate PSMA levels. Tumor-homing peptides were synthesized by fluorenylmethoxycarbonyl-based solid-phase peptide synthesis (Fmoc-SPPS) strategy, and evaluated for their prostate cancer cell-specific targeting efficiencies by flow cytometry. Our results showed that the PSMA-binding capacity of peptide 563 was superior to those of 562, 9-mer, and 5-mer; therefore, can be utilized as a potent-targeting agent not only in the treatment of high PSMA positive but also moderate PSMA positive prostate cancer tumors

The Synthesis of Peptide-Conjugated Poly(2-Ethyl-2-Oxazoline)-bpoly(L-Lactide) (PEtOx-B-PLA) Polymeric Systems Through the Combination of Controlled Polymerization Techniques and Click Reactions

To optimize the therapeutic effect of pharmaceutical agents, drug delivery systems tailored from FDA-approved polymers like poly(L-lactide) (PLA) is an effective strategy. Because of their hydrophobic character, these systems greatly suffer from reduced circulation time thus, amphiphilic block copolymers became favourable to overcome this limitation. Of them, poly(oxazoline)-b-poly(L-lactide) are of choice as poly(oxazoline) (PEtOx) is compatibile, biodegradable, while exhibiting minimum cytotoxicity. To tailor selective drug targeting drug delivery systems, whereby their selectivity for tumour tissues is maximised, these polymers should be decorated with so-called tumour-homing agents, such as antibodies, peptides and so forth. To this respect, we designed a new block copolymer, allyl-poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) allyl-(PEtOx-b-PLA) and its subsequent conjugation to tumour-homing peptides, peptide-18 and peptide-563 at the terminal position. In this manuscript, we report our synthetic route to obtain this building block and its conjugation to tumour-homing agents

The synthesis of peptide-conjugated poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) (PEtOx-b-PLA) polymeric systems through the combination of controlled polymerization techniques and click reactions

To optimize the therapeutic effect of pharmaceutical agents, drug delivery systems tailored from FDA-approved polymers like poly(L-lactide) (PLA) is an effective strategy. Because of their hydrophobic character, these systems greatly suffer from reduced circulation time thus, amphiphilic block copolymers became favorable to overcome this limitation. Of them, poly(oxazoline)-b-poly(L-lactide) are of choice as poly(oxazoline) (PEtOx) is compatible, biodegradable, while exhibiting minimum cytotoxicity. To tailor selective drug targeting drug delivery systems, whereby their selectivity for tumor tissues is maximized, these polymers should be decorated with so-called tumor-homing agents, such as antibodies, peptides and so forth. To this respect, we designed a new block copolymer, allyl-poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) allyl-(PEtOx-b-PLA) and its subsequent conjugation to tumor-homing peptides, peptide-18, and peptide-563 at the terminal position. In this manuscript, we report our synthetic route to obtain this building block and its conjugation to tumor-homing agents

A robust optimization approach for the breast cancer targeted design of PEtOx-b-PLA polymersomes

© 2021 Elsevier B.V.The equipping of nanoparticles with the peptide moiety recognizing a particular receptor, enables cell or tissue-specific targeting, therefore the optimization of the targeted nanoparticles is a key factor in the formulation design process. In this paper, we report the optimization concept of Doxorubicin encapsulating PEtOx-b-PLA polymersome formulation equipped with Peptide18, which is a breast cancer recognizing tumor homing peptide, and the unveiling of the cell-specific delivery potential. The most dominant formulation parameters, which are the polymer to Doxorubicin mass ratio (w/w) and the aqueous to organic phase ratio (v/v), were optimized using Central Composite Design (CCD) based Response Surface Methodology. The characteristics of optimum polymersome formulation were determined as the hydrodynamic diameter of 146.35 nm, the PDI value of 0.136, and the encapsulation efficiency of 57.11% and TEM imaging, which are in agreement with the DLS data, showed the spherical morphology of the polymersomes. In order to demonstrate the breast cancer-specific delivery of targeted polymersomes, the flow cytometry and confocal microscopy analyses were carried out. The targeted polymersomes were accumulated 8 times higher in AU565 cells compared to MCF10A cells and the intracellular Doxorubicin was almost 10 times higher in AU565 cells. The CCD-mediated optimized targeted polymersomes proposed in this report holds the promise of targeted therapy for breast cancer and can be potentially used for the development of novel treatments

Poly(2-ethyl-2-oxazoline-co-ethyleneimine)-block-poly(epsilon-caprolactone) based micelles: synthesis, characterization, peptide conjugation and cytotoxic activity

Here we present self-assembled polymeric micelles as potential delivery systems for therapeutic agents with highly tunable properties. The major goal of this study is to design breast and prostate cancer specific targeting peptide modified PEtOx-co-PEI-b-PCL block copolymer based micelles as a targetable carrier system in cancer treatment. For this, a series of micelles based on poly(2-ethyl-2-oxazoline)-co-polyethyleneimine-block-poly(epsilon-caprolactone) [P(EtOx-co-EI)-b-PCL] copolymers with two different proportions of PEI (30% and 60% hydrolysis degrees of PEtOx) were successfully prepared. The block copolymers were synthesized using a combination of living cationic ring-opening polymerization and a copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. Then, peptide 18 and peptide 563 were conjugated to P(EtOx-co-EI)-b-PCL through a thiol-ene click-type reaction to obtain the desired tumor-targeting. The structural properties of the copolymers were confirmed by H-1 NMR, FT-IR, UV-Vis spectrometry and GPC. Peptide and non-peptide-conjugated micelles with particle sizes between 82 +/- 0.6 and 170 +/- 10.7 nm were obtained by self-assembly with two different chain lengths of PEI blocks. The micelles containing the 60% PEI block showed increased zeta potential values. The cytotoxicity of the copolymers was evaluated under in vitro conditions. Overall, our results indicate that the micelles prepared with peptide-conjugated block copolymers can be used as potential nanocarriers for targeted therapeutic delivery systems

Synthesis, biocompatibility and gene encapsulation of poly(2-Ethyl 2-Oxazoline)-dioleoyl phosphatidylethanolamine (PEtOx-DOPE) and post-modifications with peptides and fluorescent dye coumarin

Liposome surface modifications serve great potential applications of liposomes, for instance, increasing stability, bioactive liposome conjugates, and targeted drug, gene, and image agent delivery. In this study, novel targeted lipopolymers, peptide 18/peptide 563-poly(2-ethyl-2-oxazoline)-dioleoylphosphatidyl-ethanolamine (P18/P563-PEtOx-DOPE), have been demonstrated to be successfully synthesized. The structures of P18/P563-PEtOx-DOPE were confirmed by FT-IR spectroscopy, GPC, and(1)H-NMR. In this strategy, poly(2-ethyl 2-oxazoline)-modified liposomes were firstly constructed with molecular weights of 3,500 and 5,800 Da. Then, we chose PEtOx(5800)-DOPE because it has been obtained better particle size (88.74 +/- 0.6816) according to the DLS results. Then, peptides- and dye-PEtOx lipid-based nanovesicle (LN) were prepared by peptide-18, peptide-563, and 7-mercapto-4-methyl coumarin. Genetic material (pDNA) was encapsulated into the liposomes and evaluated the encapsulation of plasmid DNA with migration by using agarose gel electrophoresis.In vitrocytotoxicity experiment results on prostate cancer and breast cancer cell lines, parallelly with the healthy prostate (PNT1A) and breast (MCF10A) epithelial cell lines, cells showed insignificant toxic effects. Thus, we can suggest a novel PEtOx phospholipid thanks to this article and its integration with ligands, which great potential for gene transfer system