Effect of lipidated gonadotropin-releasing hormone peptides on receptor mediated binding and uptake into prostate cancer cells in vitro

Stephenson, Rachel J.; Varamini, Pegah; Butcher, Neville J.; Minchin, Rodney F.; Tóth, István

doi:10.1016/j.nano.2014.06.015

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…The addition of hydrophobic moieties (such as lipids) has been shown to increase nonspecific binding to the surface of cells, which could account for the higher level of cell-binding observed for 12 (Figure ). Here, nonspecific binding observed for peptide 12 could be associated with the affinity of the vaccine candidates for non-C-type lectin receptors (including Toll-like receptors) where previous studies on lipidated peptides have confirmed this finding . The mannan inhibition study indicated that receptor-mediated uptake through a mannan-inhibited receptor (e.g., MR) is likely.…”

Section: Results and Discussionsupporting

confidence: 51%

Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties

Sedaghat¹,

Stephenson²,

Giddam³

et al. 2016

Bioconjugate Chem.

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Present on the surface of antigen presenting cells (APCs), the mannose receptor (MR) has long been recognized as a front-line receptor in pathogen recognition. During the past decade many attempts have been made to target this receptor for applications including vaccine and drug development. In the present study, a library of vaccine constructs comprising fluorescently labeled mannosylated lipid-dendrimers that contained the ovalbumin CD4(+) epitope, OVA(323-339), as the model peptide antigen were synthesized using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in APCs. Uptake studies performed on F4/80(+) and CD11c(+) cells showed significant uptake and/or binding for lipopeptides containing mannose, and also the lipopeptide without mannose when compared to the control peptides (peptide with no lipid and peptide with no mannose and no lipid). Furthermore, mannan inhibition assays demonstrated that uptake of the mannosylated and lipidated peptides was receptor mediated. To address the specificity of receptor uptake, surface plasmon resonance studies were performed using biacore technology and confirmed high affinity of the mannosylated and lipidated vaccine constructs toward the MR. These studies confirm that both mannose and lipid moieties play significant roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development.

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Section: Results and Discussionsupporting

confidence: 51%

Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties

Sedaghat¹,

Stephenson²,

Giddam³

et al. 2016

Bioconjugate Chem.

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“…Figure 3-12 shows the RP-HPLC trace for construct 15 as an example. The peak of product (15, Figure 3-12) and the lipopeptide starting material (11, Figure 3-12) are multivalent because the lipids are present as a diastereomeric mixture in accordance to previous reports [255]. Construct 15 also contained a mixture of both α-and β-stereochemistries for the mannose units (Figure 3-11).…”

Section: Conjugation Of Mannosylated Peptide Azides To Lipopeptide Alsupporting

confidence: 73%

“…However, 16 that did not have any mannose units in its structure had a higher uptake than 13 or 14. The addition of hydrophobic moieties (such as lipids) has been shown to increase non-specific binding to the surface of cells, which could account for the higher level of cell-binding observed for 16 (Figure 4-1) [255]. The non-specific binding observed for peptide 16 could be associated with the affinity of the vaccine candidates for non-CLRs (including TLRs) as previous studies on lipidated peptides have confirmed this finding [178].…”

Section: Flow Cytometry Cell Uptake Studymentioning

confidence: 54%

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

Sedaghat¹

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The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of targeted vaccine design. Improved understanding of the role of carbohydrate recognition domains (CRDs) 4-7 in recognising glycosylated ligands present on the surface of pathogens such as C. albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about structural properties of the MR. During the last decade many attempts have been made to target this receptor for applications including vaccine and drug development.In the present study, a library of vaccine constructs comprising fluorescently-labelled mannosylated lipid dendrimers that contained the ovalbumin CD4 + epitope, OVA323-339, as the model peptide antigen were synthesised using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in antigen presenting cells.Mannosylated building blocks were prepared with a Lewis acid reaction and the reaction was successfully modified and monitored for a better yield. This was followed by solid phase synthesis of mannosylated peptides with an azide functional group and a fluorescent tag. Considering the presence of multi-components on the designed mannosylated peptide, different methods of preparation was used and a high yield of the final mannosylated peptides with an azide functional group and a fluorescent tag were prepared. Further, OVA323-339 lipopeptides with an alkyne functional group were prepared using microwave assisted peptide synthesis. Final vaccine structures were prepared by attaching azide and alkyne functional groups using click chemistry. The same methods were applied for the preparation of a library of control vaccine structures.In vitro uptake studies performed on macrophage (F4/80 + ) and dendritic (CD11c + ) cells showed significant uptake and/or binding for vaccine constructs containing mannose and lipid, and also for the lipopeptide vaccine construct without mannose when compared to the controls (containing no lipid, no mannose and no mannose or lipid). Further, in vitro mannan competition assays demonstrated that uptake of the mannosylated and lipidated vaccine constructs was MR mediated. To address the specificity of receptor uptake, surface plasmon resonance (SPR) was performed usingBiacore technology which confirmed a high affinity of the mannosylated and lipidated vaccine constructs towards the human recombinant MR in vitro when compared with vaccine constructs without mannose. These studies also confirmed that both mannose and lipid moieties play significant II roles in receptor-mediated uptake on APCs, potentially faci...

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“…For instance, applications of cyclic RGD peptides, cell-surface hormone receptors (LHRH receptor), and tumor vasculature antigens in chemotherapeutic delivery systems have shown promising results [163,164]. Intensive research into the development of selfassembled peptide delivery vehicles for active or passive targeting of chemotherapeutics has accelerated due to the peptides' desirable physicochemical properties and potential for tailoring to suit specific biological applications [26].…”

Section: Anticancer Drug Deliverymentioning

confidence: 99%

“…Developing peptidebased vaccines has been hampered by the need to display antigens in their native conformation and the use of immuno-adjuvants that only exhibit adjuvanting properties under specific circumstances [168]. Recently, several patents have been registered for the development of self-adjuvanting vaccines from self-assembled peptides [164,165]. These materials provide scaffolds that can accommodate multivalency and molecular specificity, and enable anable control over epitope position [169].…”

Section: Self-assembled Peptides For Vaccine Designmentioning

confidence: 99%

Recent advances in self-assembled peptides: Implications for targeted drug delivery and vaccine engineering

Eskandari

Guerin

Tóth

et al. 2017

Advanced Drug Delivery Reviews

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220

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Self-assembled peptides have shown outstanding characteristics for vaccine delivery and drug targeting. Peptide molecules can be rationally designed to self-assemble into specific nanoarchitectures in response to changes in their assembly environment including: pH, temperature, ionic strength, and interactions between host (drug) and guest molecules. The resulting supramolecular nanostructures include nanovesicles, nanofibers, nanotubes, nanoribbons, and hydrogels and have a diverse range of mechanical and physicochemical properties. These molecules can be designed for cell-specific targeting by including adhesion ligands, receptor recognition ligands, or peptide-based antigens in their design, often in a multivalent display. Depending on their design, self-assembled peptide nanostructures have advantages in biocompatibility, stability against enzymatic degradation, encapsulation of hydrophobic drugs, sustained drug release, shear-thinning viscoelastic properties, and/or adjuvanting properties. These molecules can also act as intracellular transporters and respond to changes in the physiological environment. Furthermore, this class of materials has shown sequence- and structure-dependent impacts on the immune system that can be tailored to non-immunogenic for drug targeting, and immunogenic for vaccine delivery. This review explores self-assembled peptide nanostructures (beta sheets, alpha helices, peptide amphiphiles, amino acid pairing, elastin like polypeptides, cyclic peptides, short peptides, Fmoc peptides, and peptide hydrogels) and their application in vaccine delivery and drug targeting.

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Effect of lipidated gonadotropin-releasing hormone peptides on receptor mediated binding and uptake into prostate cancer cells in vitro

Cited by 8 publications

References 38 publications

Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties

Synthesis of Mannosylated Lipopeptides with Receptor Targeting Properties

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

Recent advances in self-assembled peptides: Implications for targeted drug delivery and vaccine engineering

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