Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials - PubMed (original) (raw)

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Integrin-Targeting Peptides for the Design of Functional Cell-Responsive Biomaterials

Junwei Zhao et al. Biomedicines. 2020.

Abstract

Integrins are a family of cell surface receptors crucial to fundamental cellular functions such as adhesion, signaling, and viability, deeply involved in a variety of diseases, including the initiation and progression of cancer, of coronary, inflammatory, or autoimmune diseases. The natural ligands of integrins are glycoproteins expressed on the cell surface or proteins of the extracellular matrix. For this reason, short peptides or peptidomimetic sequences that reproduce the integrin-binding motives have attracted much attention as potential drugs. When challenged in clinical trials, these peptides/peptidomimetics let to contrasting and disappointing results. In the search for alternative utilizations, the integrin peptide ligands have been conjugated onto nanoparticles, materials, or drugs and drug carrier systems, for specific recognition or delivery of drugs to cells overexpressing the targeted integrins. Recent research in peptidic integrin ligands is exploring new opportunities, in particular for the design of nanostructured, micro-fabricated, cell-responsive, stimuli-responsive, smart materials.

Keywords: RGD peptides; cell adhesion; drug delivery; integrin ligands; peptide conjugates; regenerative medicine; smart nanomaterials; tissue engineering; tumor-targeting nanoparticles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Bent-inactive, and open-active integrin states, and focal adhesions formation that consents outside-in downstream signaling.

Figure 2

Figure 2

Examples of cyclopeptide integrin ligands: c[RGDfVG], and c[RGDfV], from which derive c[RGDfK], c[RGDf-N(Me)V], and c[(R)-βPheΨ(NHCO)AspΨ-(NHCO)Gly-Arg].

Figure 3

Figure 3

Examples of antagonist integrin ligands.

Figure 4

Figure 4

Examples of β-lactam based agonist or antagonist integrin ligands utilized for Structure-Activity Relationships (SAR) and modeling analysis of agonism vs. antagonism; the affinities (nM) for the specified integrins are also shown.

Figure 5

Figure 5

Integrin-targeted internalization of the Arg–Gly–Asp (RGD) peptide-drug conjugates via clathrin or caveolin mediated endocytosis.

Figure 6

Figure 6

Integrin-targeted organic nanoparticles (NPs). (A) liposomes; (B) polymeric micelles; (C) dendrimers; (D) chitosan NPs.

Figure 7

Figure 7

Preparation of AVPI/cRGD-NPs from micelles composed of PF127 (PEG100–PPO65–PEG100) and PF127-(N3)2, followed by polymerization of the silica core to embed the dye RhB. Peptide functionalization is achieved by click chemistry.

Figure 8

Figure 8

Integrin-targeted inorganic NPs and quantum dots (QDs): (A) magnetic NPs; (B) gold NPs; (C) QDs.

Figure 9

Figure 9

Blending strategy for surface functionalization. (A) Star PEO was blended on the surface. The surface density of star PEO and special distribution of RGD peptides can be controlled. (B) Preparation of cRGD-conjugated tumor-targeting drug delivery platform by blending of L121 and F127 and encapsulating docetaxel.

Figure 10

Figure 10

Electron beam lithography. Before immobilizing Lev-GRGDSPG and bFGF on the surface, pSS-co-PEGMA and PEG-AO were coated and cross-linked on passivated silicon wafers. Then HUVEC cells were cultured on the surface.

Figure 11

Figure 11

Photolithography strategy for surface functionalization. The photoinitiator-containing gel precursor solution was added on RGD peptides immobilized nanoporous alumina membrane to form a thin layer. Then it was covered by photomask and irradiated by UV light to get polymerization. Fibroblasts cells were seeded in the nanowells.

Figure 12

Figure 12

Nanolithography surfaces functionalization. PS-b-P2VP micelles were dip-coated on glass, forming Au-nanopatterned surfaces. c[RGDfK]-thiol was anchored on gold before cell culture.

Figure 13

Figure 13

The electrospin strategy for surface functionalization. A mixture of PLGA (poly(lactic-co-glycolic acid)) and PLGA-b-PEI-NH2 in DMF/THF was electrospun to produce nanofiber with free NH2-group, which can be used to conjugate RGD peptides. Fibroblasts were used to study cell adhesion, spreading, and proliferation.

Figure 14

Figure 14

3D printing for surface functionalization. 3D PLA microstructure was prepared via 3D printing technology; GelMA was obtained by methacrylation of gelatin; peptide-conjugated Gold NPs (RGNPs) were prepared by reduction of chloroauric acid before conjugating RGD peptides.

Figure 15

Figure 15

(A) Sketch of c[RGDfK]-zeolite SAM bound onto a glass substrate. Confocal images of the patterned c[RGDfK]-SAM after 30 min incubation with (a) glioma C6 and (b) primary endothelial cells T-293 (scale bar = 100 μm). (B) Sketch of urea-LDV-zeolite SAM. Confocal microscopy images of urea-LDV-SAM visualized after 15 min incubation with (c) Jurkat cells and (d) HEK-293 cells (scale bar = 50 μm). (C) SEM image of zeolite L crystals (white bar = 500 nm).

Figure 16

Figure 16

The thermoresponsive PIPAAm polymer undergoes expansion at 20 °C, and the RGD peptide remains hidden into the polymer. At 37 °C, the polymer shrinks and exposes the RGD peptide, promoting cell adhesion.

Figure 17

Figure 17

Enzyme-triggered polymers were immobilized on glass. The RGD peptide was blocked by Fmoc, amino acid, or polyethyleneglycol (PEG). Elastase can cleave the blocking group at a specific position thus exposing the RGD peptide, thereby improving cell adhesion.

Figure 18

Figure 18

Redox-switchable polymers. In the cyclic form, the RGD sequence is blocked and inactive; after redox, the RGD peptide is exposed.

Figure 19

Figure 19

Potential responsive polymers on the Au surface. When the surface is positively charged, positively charged RGD-containing molecule (Me3N+)-KRGDK is extended, and the RGD peptide is exposed and active. When the surfaced is negatively charged, (Me3N+)-KRGDK is hidden.

Figure 20

Figure 20

Photo-responsive polymers. AAP-RGD is isomerized from E- to Z-isomer under UV irradiation at 365 nm, resulting in dissociation of AAP-RGD from MV2+/AAP-RGD/CB[8] complex. When AAP-RGD is irradiated at 520 nm, the E-isomer is reobtained, and the MV2+/AAP-RGD/CB[8] complex can reform.

Figure 21

Figure 21

Electrochemically controlled polymers on the surface. The WGG-viologen-CB[8] complex is immobilized on the gold surface when viologen gets 2 electrons, and WGGRGDS is released from the complex.

Figure 22

Figure 22

Dynamically competitive polymers. Guest molecular naphthyl-RGDS is captured by β-CD, which is grafted on alginate. Cell adhesion and spreading can be controlled dynamically because the addition of Ada-RGES can reverse cell adhesion due to it competed with naphthyl-RGDS to form a complex with β-CD.

Figure 23

Figure 23

Smart interfaces for 3D cell culture. (A) Poly(acrylate)-PEG 3D gel containing RGD peptide and photocleavable domain. (B) ELP-HA hydrogel containing RGD sequence. (C) DexMA hydrogels functionalized RGD peptide.

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