cRGD Peptide Research Articles

Fabrication of poly(PEGMA) surface with controllable thickness gradient and its mediation on the gradient adhesion of cells

AbstractThe gradient surface shows enormous potential in the development of tissue engineering, biosensor, microfluidic control, and particle sorting. In this work, a poly(polyethyleneglycol methacrylate) (poly(PEGMA)) gradient surface was prepared through surface‐initiated activators regenerated by electron transfer atom transfer radical polymerization (SI‐AGRET ATRP). The effect of various parameters on the thickness growth of poly(PEGMA) film were analyzed, among which the excessive reducing agent was utmost important. The reducing agents supported the regeneration of CuI and eliminated the disturbance of air, maintaining the "living polymerization" of poly(PEGMA) up to 73.1 nm under tested conditions. The physicochemical properties of the fabricated surfaces were characterized by ellipsometry, X‐ray photoelectron spectroscopy, water contact angle. The thickness slope of gradient poly(PEGMA) was controllable in a nanoscale range. The gradient surface was further grafted with CRGD (Cys‐Arg‐Gly‐Asp) peptides onto the poly(PEGMA‐co‐[glycidyl methacrylate]) blocks via the ring‐opening reaction between epoxy and amino groups, which showed a gradient change in water contact angle and adhesion of endothelial cells.

Multifunctional pathology-mapping theranostic nanoplatforms for US/MR imaging and ultrasound therapy of atherosclerosis.

Atherosclerotic thrombosis is the leading cause of most life-threatening cardiovascular diseases (CVDs), particularly as a result of rupture or erosion of vulnerable plaques. Rupture or erosion-prone plaques are quite different in cellular composition and immunopathology, requiring different treatment strategies. The current imaging technology cannot distinguish the types of vulnerable plaques, and thus empirical treatment is still applied to all without a tailored and precise treatment. Herein, we propose a novel strategy called "Multifunctional Pathology-mapping Theranostic Nanoplatform (MPmTN)" for the tailored treatment of plaques based on the pathological classification. MPmTNs are made up of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), containing contrast imaging materials Fe3O4 and perfluoropentane (PFP), and coated with specific plaque-targeted peptides PP1 and cyclic RGD. The PFP encapsulated inside the MPmTN can undergo a phase change from nanodroplets to gas microbubbles under therapeutic ultrasound (TUS) exposure. The acoustic and biological effects induced by TUS and disruption of microbubbles may further promote therapeutic effects. Hypothetically, MPmTN NPs can target the rupture-prone plaque via the binding of PP1 to class A scavenger receptors (SR-A) on macrophages, induce the apoptosis due to TUS exposure and thus reduce the chronic soakage of inflammatory cells. The MPmTN NPs can also target the erosion-prone plaque through the binding of cRGD to glycoprotein (GP) IIb/IIIa on activated platelets and promote platelet disaggregation under TUS exposure. Therefore, MPmTNs may work as a multifunctional pathology-mapping therapeutic agent. Our in vitro results show that the MPmTN with PP1 and cRGD peptides had a high binding affinity both for activated macrophages and blood clots. Under TUS exposure, the MPmTN could effectively induce macrophage apoptosis, destroy thrombus and exhibit good imaging properties for ultrasound (US) and MRI. In apoE-/- mice, MPmTNs can selectively accumulate at the plaque site and reduce the T2-weighted signal. The apoptosis of macrophages and disaggregation of activated platelets on the plaques were also confirmed in vivo. In summary, this study provides a potential strategy for a tailored treatment of vulnerable plaques based on their pathological nature and a multimodal imaging tool for the risk stratification and assessment of therapeutic efficacy.

CRGD peptide-conjugated polyethylenimine-based lipid nanoparticle for intracellular delivery of siRNA in hepatocarcinoma therapy

The effective delivery system plays an important role in the application of siRNA in the antitumor study. However, until now, researches on the delivery systems targeting hepatocarcinoma cells are still being explored. Here we designed and prepared a novel siRNA delivery system, cRGD-PSH-NP, which was based on a modified polyethyleneimine (PSH) and DSPE-PEG2000-cRGD. cRGD-PSH-NP loaded with survivin siRNA (cRGD-PSH-NP/S) was composed of egg phosphatidylcholine, cationic PSH, PEGylated lipids, survivin siRNA, and cRGD peptide as a targeting ligand. The formulations of cRGD-PSH-NP/S were optimized and characterized. In vitro investigations showed excellent gene silencing and antitumor activity compared with the unmodified nanoparticles in HepG2 cells. In vivo antitumor efficacy of cRGD-PSH-NP/S exhibited potent tumor inhibition (74.71%) in HepG2-bearing nude mice without inducing toxicity. These data suggested further research of cRGD-PSH-NP/S in hepatocarcinoma therapy.

A versatile nanoagent for multimodal imaging-guided photothermal and anti-inflammatory combination cancer therapy.

Photothermal therapy (PTT) has drawn great attention in cancer treatment because of its minimal invasiveness and high spatiotemporal selectivity, but it still encounters severe obstacles like heat-resistance, metastasis and recurrence. A key reason for the treatment failure is the highly inflammatory tumor microenvironment caused by hyperthermia. A simultaneous anti-inflammatory therapy alongside the PTT has great potential for overcoming the drawbacks of PTT; however, it has been less reported and further study is urgently needed. In addition, as many inorganic photothermal agents have no inherent imaging capability, diagnostic strategies should be introduced to help identify cancerous lesions and find the best treatment time period for PTT. Herein, we developed a versatile theranostic nanoagent (named T-lipos-CPAuNCs) for synergistic multimodal imaging-guided photothermal/anti-inflammatory cancer therapy. Perfluorohexane (PFH) loaded AuNCs and the anti-inflammatory drug celecoxib were encapsulated into the tumor-targeting cyclic Arg-Gly-Asp (cRGD) peptide modified liposomes to form T-lipos-CPAuNCs. The T-lipos-CPAuNCs accumulated in the tumor tissue and selectively targeted the cancer cells, and converted photo to thermal energy under near-infrared (NIR) laser irradiation to kill the cancer cells by PTT. The high temperature further accelerated the release of celecoxib to exert an anti-inflammatory effect, while on the other hand led to liquid to gas phase transition of PFH to facilitate ultrasound (US) imaging. The T-lipos-CPAuNCs also exhibited photoacoustic (PA) imaging capability. In vitro and in vivo experiments established that under the guidance of multimodal imaging, T-lipos-CPAuNCs significantly suppressed the tumor growth by PTT and prevented tumor metastasis with non-apparent tumor inflammation. The developed theranostic nanosystem (T-lipos-CPAuNCs) shows great potential for PA/US multimodal imaging guided photothermal/anti-inflammatory combination cancer therapy.

PH-Activatable Cyanine Dyes for Selective Tumor Imaging Using Near-Infrared Fluorescence and Photoacoustic Modalities.

Photoacoustic (PA) imaging is an emerging molecular imaging modality that complements fluorescence imaging and enables high resolution within deep tissue. Fluorescence/PA multimodality imaging would be a powerful technique to extract more comprehensive information from targets than traditional single-modality imaging. In this paper, we developed a new pH-activatable sensor, CypHRGD, which is applicable to both fluorescence and PA detection. CypHRGD was derived from our previous near-infrared pH-sensing platform, in which substitution with a bulky phenyl group and functionalization with a cRGD peptide remarkably improved the sensor's biocompatibility with attenuated dye aggregation. The multimodality imaging applications of CypHRGD were demonstrated in cultured cells and cancer-xenografted mice with rapid kinetics and high sensitivity and specificity, which relies on cRGD-facilitated tumor targeting, probe accumulation and subsequent activation in the acidic organelles after endocytosis.

Red Light-Initiated Cross-Linking of NIR Probes to Cytoplasmic RNA: An Innovative Strategy for Prolonged Imaging and Unexpected Tumor Suppression.

Improving the enrichment of drugs or theranostic agents within tumors is very vital to achieve effective cancer diagnosis and therapy while greatly reducing the dosage and damage to normal tissues. Herein, as a proof of concept, we for the first time report a red light-initiated probe-RNA cross-linking (RLIPRC) strategy that can not only robustly promote the accumulation and retention of the probe in the tumor for prolonged imaging but also significantly inhibits the tumor growth. A near-infrared (NIR) fluorescent probe f-CR consisting of a NIR dye (Cyanine 7) as a signal reporter, a cyclic-(arginine-glycine-aspartic acid) (cRGD) peptide for tumor targeting, and a singlet oxygen (1O2)-sensitive furan moiety for RNA cross-linking was rationally designed and synthesized. This probe possessed both passive and active tumor targeting abilities and emitted intense NIR/photoacoustic (PA) signals, allowing for specific and sensitive dual-modality imaging of tumors in vivo. Notably, probe f-CR could be specifically and covalently cross-linked to cytoplasmic RNAs via the cycloaddition reaction between furan and adenine, cytosine, or guanine under the oxidation of 1O2 generated in situ by irradiation of methylene blue (MB) with 660 nm laser light, which effectively blocks the exocytosis of the probes resulting in enhanced tumor accumulation and retention. More excitingly, for the first time, we revealed that the covalent cross-linking of probe f-CR to cytoplasmic RNAs could induce severe apoptosis of cancer cells leading to remarkable tumor suppression. This study thus represents the first red light-initiated RNA cross-linking system with high potential to improve the diagnostic and therapeutic outcomes of tumors in vivo.

AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

AZD9291 can effectively prolong survival of non‐small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH‐sensitive shell–core nanoparticles CP@NP‐cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP‐cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP‐cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH‐sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP‐cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p‐ERK1/2 in vitro. CQ in CP@NP‐cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP‐cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications.

Cyclic RGD Peptide Targeting Coated Nano Drug Co-Delivery System for Therapeutic Use in Age-Related Macular Degeneration Disease.

Vascular endothelial growth factor (VEGF) expression increased significantly in the pathogenesis of age-related macular degeneration, which induced the formation of pathological blood vessels. Dexamethasone is an exogenous anti-angiogenic drug while bevacizumab is an endogenous anti-angiogenic drug. They both have been widely used in ophthalmology. However, independent administration is not enough to completely block the development of choroidal neovascularization (CNV), and the number of eyes vitreous injections is limited. Reasonable combination of drugs may produce significantly better therapeutic effect than single drug treatment. The cyclic RGD (cRGD) peptide has a particularly high affinity with retinal pigment epithelial cells, where VEGF secretes from. In this study, we prepared nanoparticles of bevacizumab and dexamethasone with cRGD peptide as the target (aBev/cRGD-DPPNs). The particle size of the aBev/cRGD-DPPNs was 213.8 ± 1.5 nm, SEM results showed that the nano-carriers were well dispersed and spherical. The cell uptake study demonstrated the selectivity of the aBev/cRGD-DPPN to ARPE-19 with αVβ3 over expressed. The aBev/cRGD-DPPNs had a better apoptosis induction effect and an obvious inhibitory effect on migration, invasion, and capillary-like structures formation of human umbilical vein epithelial cells. The fluorescein fundus angiography study, immunohistochemistry and histopathological evaluation showed the aBev/cRGD-DPPNs greatly reduced the development of CNV on a rabbit model.

Selenium Tethered Mesoporous Silica Nanocomposite Enhances Drug Delivering Efficiency to Target Breast Cancer

The development of multifunctional nanocomposite can greatly improve therapeutic effects to impair tumor proliferation. In the present study, we developed a new class of dual-drug delivering system, the Selenium Mesoporous Silica (SMS) nanocomposites to achieve molecular based tumor-targeting. A series of experiments have been performed to tether Mesoporous Silica nanoparticle (MSN) with chitosan-selenium complex using cysteine amino acid. The Chemical and biological assays authenticated that a perfect “chemistry works” between the formulated SMS nanocomposites and selected drugs, namely, Metformin (MT) and Cisplatinn (Cis). As a sequential reaction, the MT-MSN-CS-Se-Cis nanocomposites allowed the cRGD peptide to attach with MSN. Furthermore, the sulfur groups of MT-MSN-Cys make a conjugation with Se-Cis-CS material, on which cRGD peptide was grafted as a target moiety. This multifunctional SMS nanocomposite enhances specific cellular uptake of drugs, controlled release and higher inhibitory effects against MDA-MB-231 cells. Further studies demonstrated that the formulated nanocomposites significantly induce apoptosis through DNA damage and ROS overproduction that accounts for critical antitumor activity. Additionally, animal studies provide significantly enhanced the anti-tumor efficacy of formulated nanocomposites on tumor-bearing mice. Hence, the formulated nanocomposite is an effective multifunctional drug delivery podium which might have elicited the molecular targeted chemotherapeutic efficacy against cancer.

Cyclic RGD-Functionalized closo-Dodecaborate Albumin Conjugates as Integrin Targeting Boron Carriers for Neutron Capture Therapy.

Cyclic RGD (cRGD) peptide-conjugated boronated albumin was developed to direct toward integrin αvβ3, which overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)] and maleimide-conjugated closo-dodecaborate (MID) to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic toward both U87MG and A549 cells. As compared with l-BPA, selective antitumor activity of cRGD-MID-BSA toward U87MG cells overexpressing integrin αvβ3 was identified after thermal neutron irradiation. In vivo fluorescence live imaging of Cy5-conjugated cRGD-MID-BSA and MID-BSA revealed that both cRGD-MID-BSA and MID-BSA similarly reached the maximum accumulation during 8-12 h after injection. The selective accumulation and retention of Cy5-cRGD-MID-BSA was more pronounced than Cy5-MID-BSA after 24 h. An in vivo boron neutron capture therapy (BNCT) study revealed that the cRGD peptide ligand combination enhanced accumulation of MID-BSA into tumor cells in U87MG xenograft models. The significant tumor growth suppression was observed in U87MG xenograft models at a dose of 7.5 mg [10B]/kg after neutron irradiation.

Biomimetic Nanocomposites Cloaked with Bioorthogonally Labeled Glioblastoma Cell Membrane for Targeted Multimodal Imaging of Brain Tumors

AbstractBrain tumor targeted delivery of diagnostic contrast agents has been an elusive goal due to the presence of the blood brain barrier (BBB) and the complex brain tumor microenvironment. Herein, an ingenious design of nanoscale contrast agents coated by bioorthogonally labeled brain tumor cell membrane for targeted diagnosis of glioblastoma through multiple complementary imaging modalities is presented. Taking advantage of bioorthogonal click reactions, an endothelial integrin receptor‐targeting peptide cRGD is decorated onto the nanocomposite surface to act in synergy with brain tumor cell membrane to offer BBB‐penetrating and homotypic targeting effect in the brain tumor microenvironment. Cellular and animal experimental results validate the superior targeting outcomes achieved by cRGD‐labeled brain tumor cell membrane coating. This study offers an example of a surface modified cell membrane as a potential theranostic strategy to overcome the delivery barriers in brain tumors.

Heparan sulfate co-immobilized with cRGD ligands and BMP2 on biomimetic platforms promotes BMP2-mediated osteogenic differentiation

The chemical and physical properties of the extracellular matrix (ECM) are known to be fundamental for regulating growth factor bioactivity. The role of heparan sulfate (HS), a glycosaminoglycan, and of cell adhesion proteins (containing the cyclic RGD (cRGD) ligands) on bone morphogenetic protein 2 (BMP2)-mediated osteogenic differentiation has not been fully explored. In particular, it is not known whether and how their effects can be potentiated when they are presented in controlled close proximity, as in the ECM. Here, we developed streptavidin platforms to mimic selective aspects of the in vivo presentation of cRGD, HS and BMP2, with a nanoscale-control of their surface density and orientation to study cell adhesion and osteogenic differentiation. We showed that whereas a controlled increase in cRGD surface concentration upregulated BMP2 signaling due to β3 integrin recruitment, silencing either β1 or β3 integrins negatively affected BMP2-mediated phosphorylation of SMAD1/5/9 and alkaline phosphatase expression. Furthermore, the presence of adsorbed BMP2 promoted cellular adhesion at very low cRGD concentrations. Finally, we proved that HS co-immobilized with cRGD both sustained BMP2 signaling and enhanced osteogenic differentiation compared to BMP2 directly immobilized on streptavidin, even with a low cRGD surface concentration. Altogether, our results show that HS facilitated and sustained the synergy between BMP2 and integrin pathways and that the co-immobilization of HS and cRGD peptides optimised BMP2-mediated osteogenic differentiation. Statement of significance The growth factor BMP2 is used to treat large bone defects. Previous studies have shown that the presentation of BMP2 via extracellular matrix molecules, such as heparan sulfate (HS), can upregulate BMP2 signaling. The potential advantages of dose reduction and local specificity have stimulated interest in further investigations into biomimetic approaches. We designed a streptavidin model surface eligible for immobilizing tunable amounts of molecules from the extracellular space, such as HS, adhesion motifs (cyclic RGD) and BMP2. By studying cellular adhesion, BMP2 bioactivity and its osteogenic potential we reveal the combined effect of integrins, HS and BMP2, which contribute in answering fundamental questions regarding cell-matrix interaction.

CRGD mediated redox and pH dual responsive poly(amidoamine) dendrimer-poly(ethylene glycol) conjugates for efficiently intracellular antitumor drug delivery

To improve antitumor efficiency of chemotherapy and reduce side effect, according to the physiological characteristics of tumor tissues and tumor intracellular microenvironment, a multifunctional drug delivery system with properties of long circulation, active targeting, redox and pH triggered drug release was established based on the Generation 4 polyamidoamine dendrimer (PAMAM). First, the redox cleavable disulfide bonds (SS) were introduced for linking polyethylene glycol (PEG) with PAMAM to form PAMAM-S-S-PEG (PSSP). Then cRGD peptide was applied to the PEG end of PSSP to construct RGD-PSSP conjugates. Finally, encapsulating the antitumor chemotherapy drug doxorubicin (DOX) into the hydrophobic cavity of RGD-PSSP conjugates constructed the RGD-PSSP/DOX drug delivery system. The in vitro experiments displayed that RGD-PSSP/DOX NPs showed obviously redox and pH dual sensitive drug release profile. MTT and cell uptake observation elucidated cRGD modification could increase the cytotoxicity, and promote the uptake of B16 cells and HUVEC cells both overexpressing integrin ανβ3on cell membrane. Cell uptake mechanism investigation further revealed that RGD-PSSP/DOX interacted with plasma membrane via specific recognition of cRGD peptide with integrin ανβ3, and was subsequently internalized mainly through clathrin- and caveolin-mediated endocytosis. Remarkably, RGD-PSSP/DOX presented superior anticancer activity and lower heart and kidney toxicity in vivo, which could be regarded as a potential candidate for efficient antitumor chemotherapy drug delivery.

Focal adhesion kinase is activated by microtubule-depolymerizing agents and regulates membrane blebbing in human endothelial cells.

Microtubule‐depolymerizing agents can selectively disrupt tumor vessels via inducing endothelial membrane blebbing. However, the mechanism regulating blebbing is largely unknown. IMB5046 is a newly discovered microtubule‐depolymerizing agent. Here, the functions of focal adhesion kinase (FAK) during IMB5046‐induced blebbing and the relevant mechanism are studied. We found that IMB5046 induced membrane blebbing and reassembly of focal adhesions in human vascular endothelial cells. Both FAK inhibitor and knock‐down expression of FAK inhibited IMB5046‐induced blebbing. Mechanism study revealed that IMB5046 induced the activation of FAK via GEF‐H1/ Rho/ ROCK/ MLC2 pathway. cRGD peptide, a ligand of integrin, also blocked IMB5046‐induced blebbing. After activation, FAK further promoted the phosphorylation of MLC2. This positive feedback loop caused more intensive actomyosin contraction and continuous membrane blebbing. FAK inhibitor blocked membrane blebbing via inhibiting actomyosin contraction, and stimulated stress fibre formation via promoting the phosphorylation of HSP27. Conclusively, these results demonstrate that FAK is a molecular switch controlling endothelial blebbing and stress fibre formation. Our study provides a new molecular mechanism for microtubule‐depolymerizing agents to be used as vascular disrupting agents.

Carry-On Nitric-Oxide Luggage for Enhanced Chemotherapeutic Efficacy.

In this work, we proposed a carry-on nitric-oxide (NO) luggage strategy for enhanced chemotherapeutic efficacy. A stimuli-responsive NO-releasing polypeptide was prepared as the building block to assemble into a micelle as a chemodrug-carrier. The micelle was anchored with cRGD peptide with the aim of targeting to tumors' neoangiogenesis. In situ generation of NO at the tumor site can promote the neovascularization to recruit more chemotherapeutics. Besides, the introduced exogenous NO can directly induce apoptosis, synergistically with the chemotherapeutics. A specific near-infrared-region (NIR) NO-probe was also developed to be coloaded to the micelle to report the in situ NO-release. In vitro and in vivo experiments were performed to demonstrate the targeting capability, increased accumulation, real-time NO-release reporting phenomenon, improved antitumor efficacy, and favorable biosafety. Embedding NO into drug cargo as carry-on luggage for enhanced chemotherapeutic efficacy, hopefully, can cast new lights and build a basic principle in the future clinical translation of nanomedicines.

PEGylated Dimeric BODIPY Photosensitizers as Nanocarriers for Combined Chemotherapy and Cathepsin B-Activated Photodynamic Therapy in 3D Tumor Spheroids.

The development of enzyme-activatable photosensitizers and their combination with conventional chemodrugs for antitumor therapy are of great interest. In this work, we reported a strategy of constructing activatable photosensitizers by interfering with the intramolecular charge transfer (ICT) state of an orthogonal boron dipyrromethene (BODIPY) chromophore. By conjugating a cathepsin B substrate peptide with a photosensitizer, BDP-BDP-NH2, the reactive oxygen species (ROS) generation of the product (ABP) was significantly suppressed due to the blockage of the electron-donating amino group. In vitro experiments proved the recovery of ROS generation under laser irradiation after the peptide linker was cleaved by cathepsin B. The ABP was then PEGylated and modified with a cRGD peptide (RNC) to encapsulate a hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT). The formed RNC/HCPT nanoparticles had good stability in serum-containing solutions with a hydrodynamic size of around 200 nm. The combination of cathepsin B-activated PDT and chemotherapy exhibited a strong ability to inhibit the growth of 4T1 breast cancer cells while promoting the induction of cell apoptosis. The RNC/HCPT nanoparticles also showed the ability to penetrate the 4T1 three-dimensional (3D) tumor spheroids and effectively shrunk the size of the spheroids. Taken together, our strategy offers a platform for antitumor drug delivery with an activatable PDT effect and combined therapy.

Functional supramolecular bioactivated electrospun mesh improves tissue ingrowth in experimental abdominal wall reconstruction in rats

Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Therefore, we aimed to develop a functionalized electrospun mesh that promotes tissue ingrowth and provides adequate mechanical strength and compliance during degradation. We describe the in vivo function of a new supramolecular bioactivated polycarbonate (PC) material based on fourfold hydrogen bonding ureidopyrimidinone (UPy) units (UPy-PC). The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Morphometric analysis of the musculofascial content during wound healing showed that cRGD functionalization promotes myogenesis with inhibition of collagen deposition at 14 days. It also prevents muscle atrophy at 90 days and exerts an immunomodulatory effect on infiltrating macrophages at 14 days and foreign body giant cell formation at 14 and 90 days. Additionally, the bioactivated material promotes neovascularization and connective tissue ingrowth. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in the rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. Our results provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP. Statement of SignificanceDevelopment of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Ureidopyrimidinone-polycarbonate is a elastomeric and biodegradable electrospun mesh, which could mimic physiological compliance. The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. These data provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP.

CRGD-modified and disulfide bond-crosslinked polymer nanoparticles based on iopamidol as a tumor-targeted CT contrast agent

The disulfide bond-crosslinked polymer nanoparticles based on iopamidol were prepared and then surface-modified with cRGD peptide through the linkages of PEG to acquire a CT contrast agent for breast cancer-targeted imaging.

A novel αvβ3 integrin-targeted NIR-II nanoprobe for multimodal imaging-guided photothermal therapy of tumors in vivo.

Developing novel small-molecule-based probes with both deep tissue imaging and therapeutic functions is highly significant in cancer diagnosis and treatment. Herein, we report a novel second near-infrared (NIR-II) fluorescent probe QT-RGD constructed with a NIR-II emissive organic fluorophore and two cyclic-(arginine-glycine-aspartic acid) (cRGD) peptides that can specifically bind to the tumor-associated αvβ3 integrin for accurate tumor diagnosis and targeting therapy. The isotopic 125I-labeled probe exhibited great tumor targeting ability and emitted intensive NIR-II/photoacoustic (PA)/single-photon emission computed tomography (SPECT) signals, which allows specific and sensitive multimodal visualization of tumors in vivo. More notably, this probe could also be applied for effective imaging-guided photothermal therapy (PTT) of tumors in mouse models owing to its prominent photothermal conversion efficiency and excellent photothermal stability. We thus envision that our work which unveils a combination of NIR-II/PA/SPECT imaging and PTT would offer a valuable means of improving tumor diagnostic accuracy as well as therapeutic efficacy.

Synthesis and Evaluation of Caged siRNAs with Single cRGD Modification for Photoregulating RNA Interference.

We designed and synthesized caged siRNAs with photolabile linker and single cRGD peptide modifications for the photoregulation of gene expression. Photolabile linker and cRGD were inserted at 5' terminus of siRNAs to obtain cRGD-modified caged siRNAs. All these caged siRNAs could be activated through light activation to release the native siRNAs and further achieve the photoregulation of gene silencing of two exogenous reporter genes (firefly luciferase and green fluorescent protein, GFP) and one endogenous gene (the mitosis motor protein, Eg5). The intracellular distribution and cellular uptake pathways of these caged siRNAs were also investigated. Tumor-bearing mice were further used to demonstrate the photoregulation of gene silencing with cRGD-modified caged siRNAs in vivo. Overall, the data support the use of this new generation of caged siRNAs in cancer therapy.