Co-administration Of iRGD Research Articles

Targeting vascular disrupting agent-treated tumor microenvironment with tissue-penetrating nanotherapy

Cancer treatment with vascular disrupting agents (VDAs) causes rapid and extensive necrosis in solid tumors. However, these agents fall short in eliminating all malignant cells, ultimately leading to tumor regrowth. Here, we investigated whether the molecular changes in the tumor microenvironment induced by VDA treatment sensitize the tumors for secondary nanotherapy enhanced by clinical-stage tumor penetrating peptide iRGD. Treatment of peritoneal carcinomatosis (PC) and breast cancer mice with VDA combretastatin A-4 phosphate (CA4P) resulted in upregulation of the iRGD receptors αv-integrins and NRP-1, particularly in the peripheral tumor tissue. In PC mice treated with CA4P, coadministration of iRGD resulted in an approximately threefold increase in tumor accumulation and a more homogenous distribution of intraperitoneally administered nanoparticles. Notably, treatment with a combination of CA4P, iRGD, and polymersomes loaded with a novel anthracycline Utorubicin (UTO-PS) resulted in a significant decrease in the overall tumor burden in PC-bearing mice, while avoiding overt toxicities. Our results indicate that VDA-treated tumors can be targeted therapeutically using iRGD-potentiated nanotherapy and warrant further studies on the sequential targeting of VDA-induced molecular signatures.

Co-Administration of iRGD with Sorafenib-Loaded Iron-Based Metal-Organic Framework as a Targeted Ferroptosis Agent for Liver Cancer Therapy.

PurposeHepatocellular carcinoma (HCC) is one of the most common fatal cancers, with no curative therapy available. The concept of ferroptosis is attracting increasing attention in cancer research. Herein, we describe the use of a nanodevice as an effective strategy for inducing ferroptosis to manage HCC.MethodsTo improve ferroptosis-induced treatment of HCC, we constructed sorafenib (sor)-loaded MIL-101(Fe) nanoparticles (NPs) [MIL-101(Fe)@sor] and evaluated the efficacy of ferroptosis-based HCC therapy after co-administration with the iRGD peptide both in vitro and in vivo.ResultsThe prepared MIL-101(Fe) NPs have several promising characteristics including drug-loading, controllable release, peroxidase activity, biocompatibility, and T2 magnetic resonance imaging ability. MIL-101(Fe)@sor NPs significantly induced ferroptosis in HepG2 cells, increased the levels of lipid peroxidation and malondialdehyde, and reduced those of glutathione and glutathione peroxidase 4 (GPX-4). The in vivo results showed that the MIL-101(Fe)@sor NPs significantly inhibited tumor progression and decreased GPX-4 expression levels, with negligible long-term toxicity. Meanwhile, co-administration of MIL-101(Fe)@sor NPs with iRGD significantly accelerated ferroptosis.ConclusionOur findings suggest that MIL-101(Fe)@sor NPs co-administered with iRGD are a promising strategy for inducing HCC ferroptosis.

IRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery.

The unique structure and physiology of a tumor microenvironment impede intra-tumoral penetration of chemotherapeutic agents. A novel iRGD peptide that exploits the tumor microenvironment can activate integrin-dependent binding to tumor vasculatures and neuropilin-1 (NRP-1)-dependent transport to tumor tissues. Recent studies have focused on its dual-targeting ability to achieve enhanced penetration of chemotherapeutics for the efficient eradication of cancer cells. Both the covalent conjugation and the co-administration of iRGD with chemotherapeutic agents and engineered delivery vehicles have been explored. Interestingly, the iRGD-mediated drug delivery also enhances penetration through the blood–brain barrier (BBB). Recent studies have shown its synergistic effect with BBB disruptive techniques. The efficacy of immunotherapy involving immune checkpoint blockades has also been amplified by using iRGD as a targeting moiety. In this review, we presented the recent advances in iRGD technology, focusing on cancer treatment modalities, including the current clinical trials using iRGD. The iRGD-mediated nano-carrier system could serve as a promising strategy in drug delivery to the deeper tumor regions, and be combined with various therapeutic interventions due to its novel targeting ability.

Abstract 3041: Co-administration of iRGD and therapeutic EGFR-antibodies Cetuximab and Panitumumab enhances drug penetration in NSCLC PDX based 3D multicellular spheroids

Abstract Three-dimensional (3D) cell culture platforms are increasingly being used in cancer research and drug development. Using patient derived xenograft (PDX) as tumor cell source the clinical relevance of those platforms increases significantly. In combination with live cell imaging capabilities a powerful tool for dynamic studies of drug-cell interactions arises. In the current study we determined the penetration of anti-EGFR antibodies cetuximab and panitumumab in NSCLC spheroids in different culture conditions (w/wo human dermal fibroblasts, HDF) and in combination with the permeabilization-enhancing peptide iRGD. Six different NSCLC PDX models were selected based on their EGFR protein expression level (ranging from high to low determined by immunohistochemistry on PDX tissue). Cetuximab and panitumumab, were labelled with an Alexa-Fluor488 dye and their real-time uptake kinetics were quantified in an IncuCyte S3 device (1 image/well/h, Sartorius). Apart from the absolute fluorescence within the spheroid, we developed a mathematical description, fitting intensity levels in separate regions of the spheroids to estimate spatial dependent penetration of the compound in a time-resolved manner. The accumulation of EGFR antibodies over time was positively correlated with the target expression on the corresponding PDX. In addition, the invasion of the antibodies was significantly influenced by the compactness of the spheroids. The compactness of the tumor spheroid was model immanent and dependent on the molecular make-up of the respective tumor line. Enhancing the compactness by adding HDF to the tumor spheroid reduced the infiltration of both tested antibodies markedly. The simultaneous treatment of anti-EGFR antibodies with iRGD enhanced the penetration capacity in a dose dependent manner. The data of the current study highlight the importance of the tumor microenvironment (TME) for the sensitivity of tumor cells towards anticancer treatment. The modulation of the TME will be an important approach to increase antitumoral activity by enhancing the compound concentration in the tumor tissue. In general, this screening approach can be applied to fluorescence-labelled large molecules as well as compounds with intrinsic fluorescence characteristics. The combination of life cell imaging and image analysis is a promising tool in preclinical drug development to optimize compounds with regard to tissue penetration and binding efficiency. Citation Format: Kanstantsin Lashuk, Hagen Klett, Agon Kolica, Claudia Göttlich, Julia Schüler. Co-administration of iRGD and therapeutic EGFR-antibodies Cetuximab and Panitumumab enhances drug penetration in NSCLC PDX based 3D multicellular spheroids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3041.

IRGD Co-Administration with Paclitaxel-Loaded PLGA Nanoparticles Enhance Targeting and Antitumor Effect in Colorectal Cancer Treatment.

To explore the targeting effect of PLGA-NP and iRGD co-administration with PTXPLGA NP (PTX-PLGA + iRGD) on colorectal cancer. Whether PLGA-NP co-administration with iRGD peptide could show effective tumor-targeting ability in contrast to with PLGA-NP in colorectal cancer mice models was evaluated. Moreover, the chemotherapeutics Paclitaxel (PTX) was loaded into the PLGA-NP to impart anti-tumor efficiency to the PTX-PLGA. Whether iRGD co-administration with PTX-PLGA NP (PTX-PLGA + iRGD) in colorectal cancer models enabled PTX to achieve better anti-tumor efficiency and biocompatibility was further assessed. The targeting ability of PLGA-NP was enhanced in cell experiment and colorectal cancer mice models by co-administration of iRGD. As a result, PTX-PLGA + iRGD achieved better anti-tumor efficacy than PTX and PTX-PLGA. Conlusion: The nanocarrier based on PLGA with specific targeting ability could promote the clinical application of various chemotherapeutics similar to PTX. The combination of drug-loaded nanoparticles and iRGD could develop into a promising drug delivery system.

IRGD-reinforced, photo-transformable nanoclusters toward cooperative enhancement of intratumoral penetration and antitumor efficacy

Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2), the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (∼5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.

The construction of in vitro nasal cavity-mimic M-cell model, design of M cell-targeting nanoparticles and evaluation of mucosal vaccination by nasal administration

In order to better evaluate the transport effect of nanoparticles through the nasal mucosa, an in vitro nasal cavity-mimic model was designed based on M cells. The differentiation of M cells was induced by co-culture of Calu-3 and Raji cells in invert model. The ZO-1 protein staining and the transport of fluorescein sodium and dexamethasone showed that the inverted co-culture model formed a dense monolayer and possessed the transport ability. The differentiation of M cells was observed by up-regulated expression of Sialyl Lewis A antigen (SLAA) and integrin β1, and down-regulated activity of alkaline phosphatase. After targeting M cells with iRGD peptide (cRGDKGPDC), the transport of nanoparticles increased. In vivo, the co-administration of iRGD could result in the increase of nanoparticles transported to the brain through the nasal cavity after intranasal administration. In the evaluation of immune effect in vivo, the nasal administration of OVA-PLGA/iRGD led to more release of IgG, IFN-γ, IL-2 and secretory IgA (sIgA) compared with OVA@PLGA group. Collectively, the study constructed in vitro M cell model, and proved the enhanced effect of targeting towards M cell with iRGD on improving nasal immunity.

Abstract 1106: Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2

Abstract Background: Recombinant IL-2 at high doses is an effective immunotherapy treatment for various types of solid tumors. However, its clinical utility has been limited by serious mechanism-based side-effects. The clinical-stage iRGD peptide specifically targets tumors and, via activation of the ‘CendR’ trans-tissue transport pathway, increases tumor penetration and accumulation of various types of co-administered drugs. By selectively increasing the drug delivery into tumors, but not to normal tissues, iRGD potentiates the pharmacological activity of various anti-cancer agents within tumor tissue, while reducing their toxicities. In this study we investigate whether co-administration of iRGD with low-dose IL-2 can improve the tumor immune microenvironment by increasing in the ratios of tumor-killing effector CD8 cells vs. the immunosuppressive T-regulatory cells. Methods: Subcutaneous breast tumors (4T1) were generated in immunocompetent mice. Mice were treated with either vehicle control, iRGD, IL-2, or IL-2 + iRGD for 5 days. Tumors were preserved for immunohistochemistry (IHC) or enzymatically digested for fluorescence activated cell sorting (FACS) 16 hours after the last dosing. The FACS and IHC panels were designed to detect the percentage of total T cells, CD4 and CD8 T cells, and Treg cells. Results: Low doses of IL-2 alone were found to increase Tregs within the tumor but had no effect in CD4 or CD8 effector T cells, compared to vehicle treatment. However, when Low dose IL-2 was co-administered with iRGD, we observed a significantly lower percentage of T regs and an increase in CD4 effector T cells. More importantly the ratio of CD8 / Treg cells was increased by at least 10-fold, compared to low dose IL-2 alone. Conclusions: The combination treatment with iRGD and low doses of IL-2 is capable of favorably altering the tumor immune microenvironment such that immunosuppressive T reg cells were reduced, while there was an increase in the effector CD4 and CD8 T-cell populations. The tumor-selective IL-2 pharmacology benefit obtained with iRGD co-administration may provide new options for the use of the well-validated IL-2 in solid tumor patients, including a strategy to overcome the primary resistance to PD-1 blockade. Citation Format: Harri Jarvelainen, Gregory P. Botta, Tatiana Hurtado De Mendoza, Erkki Ruoslahti. Co-administration of the iRGD tumor-penetrating peptide improves the tumor immunostimulatory effects of low-dose IL-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1106.

Engineering of Bone- and CD44-Dual-Targeting Redox-Sensitive Liposomes for the Treatment of Orthotopic Osteosarcoma.

This study aimed to develop an efficient step-by-step osteosarcoma (OS)-targeting liposome system functionalized with a redox-cleavable, bone- and cluster of differentiation 44 (CD44)-dual-targeting polymer. Furthermore, the effect of coadministration of a tumor-penetrating peptide, internalizing RGD (iRGD), was investigated. First, a bone-targeting moiety, alendronate (ALN), was conjugated with hyaluronic acid (HA), a ligand for CD44. This ALN-HA conjugate was coupled with DSPE-PEG2000-COOH through a bioreducible disulfide linker (-SS-) to obtain a functionalized lipid, ALN-HA-SS-L, to be postinserted into preformed liposomes loaded with doxorubicin (DOX). The roles of ALN, HA, and the redox sensitivity of the ALN-HA-SS-L liposomes (ALN-HA-SS-L-L) in the anti-OS effect were critically evaluated against various reference liposomal formulations (with only ALN, HA, or redox sensitivity). ALN-HA-SS-L-L displayed a zeta potential of -26.07 ± 0.32 mV and selectively disassembled in the presence of a reducing agent, 10 mM glutathione, which can be found in cancer cells. Compared to various reference liposomes, ALN-HA-SS-L-L/DOX had significantly higher cytotoxicity to human OS MG-63 cells alongside high and rapid cellular uptake. In the orthotopic OS nude mouse models, ALN-HA-SS-L-L/DOX showed remarkable tumor growth suppression and prolonged survival time. This result was further improved by the coadministration of iRGD. The antitumor effects of various liposomes were ranked in the same order as the degree of tumor biodistribution shown by in vivo/ex vivo imaging: ALN-HA-SS-L-L coadministered with iRGD > ALN-HA-SS-L-L > HA-SS-L-L > HA-L-L > PEG-L> free drug. ALN-HA-SS-L-L/DOX also reduced the cardiotoxicity of DOX and lung metastases. Overall, this study demonstrated that ALN-HA-SS-L-L/DOX, equipped with bone- and CD44-dual-targeting abilities and redox sensitivity, could be a promising OS-targeted therapy. The efficacy could also be augmented by coadministration of iRGD.

Comment on "Coadministration of iRGD with Multistage Responsive Nanoparticles Enhanced Tumor Targeting and Penetration Abilities for Breast Cancer Therapy".

Nanomedicine is at the forefront of targeted drug delivery for cancer therapy. An improved combinatorial approach is highlighted for breast cancer treatment by Hu et al. in this issue of ACS Applied Materials and Interfaces. The authors demonstrated that, by combining multistage-responsive nanoparticles carrying a therapeutic drug, doxorubicin, a photothermal agent, indocyanine green, and a nitric oxide donor with photothermal therapy and intravenous injection of a tumor-homing iRGD peptide, one could achieve efficient therapeutics distribution deep inside the tumor and nearly eradicate primary tumor growth. An in-depth understanding of this approach in combination with other strategies such as the use of immunomodulators would facilitate treatingmetastasis in distant organs, and clinical translation of this platform, benefiting cancer patients by providing long-lasting efficacy.

Abstract 4662: Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide

Abstract Clinical efficacy of paclitaxel, a potent chemotherapeutic agent, is limited by its nonspecificity that leads to toxic side effects. Polymeric micellar formulations of paclitaxel were designed with the long term goals of decreasing toxicity by tumor targeting, increasing circulation time, and enhancing permeability and retention in solid tumors. Biodegradable amphiphilic block copolymers that self assemble into micelles were used to entrap hydrophobic paclitaxel in the core. Traditional 2D cell culture models are standard for cytotoxicity assays. However, they lack the diffusion gradient and cell to cell interactions present in solid tumors which 3D multicellular tumor spheroids are capable of providing. We evaluated the in vitro cytotoxicity of polymeric micelles entrapping paclitaxel in 3D multicellular tumor spheroids of triple negative breast cancer cells and compared it with the standard 2D model. We added the cell penetrating iRGD peptide with the expectation that the iRGD peptide will increase the cellular uptake of the paclitaxel micelles. Particle uptake is enhanced due to the interaction of the iRGD peptide with the highly expressed integrin receptor on the cell surface, followed by neuropilin receptor binding which mediates an active transport system for deep tumor permeation. Paclitaxel loaded micelles were prepared and the drug content was analyzed. The cytotoxicity of the micellar paclitaxel nanocarrier system was studied in both the 2D and 3D cell culture models. Micellar paclitaxel induced cytotoxicity was significantly higher than free paclitaxel for the same concentrations of paclitaxel. Furthermore, a synergistic growth inhibitory response was observed upon coadministration of iRGD compared to treatment with the paclitaxel loaded nanocarriers on their own. Significantly higher concentration of the drug was needed in the 3D cultures to achieve comparable levels of cytotoxicity to the 2D cell culture models. This suggested that multicellular tumor spheroids exhibit higher resistance to anticancer drugs, supporting the fact that 3D culture is the better model to study in vitro cytotoxicity and likely to produce biorelevant data. Citation Format: Nayela N. Chowdhury, Nandita G. Das, Sudip K. Das. Comparing 2D and 3D culture models for in vitro therapeutic screening of paclitaxel loaded micelles co-administered with iRGD peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4662.

Coadministration of iRGD with Multistage Responsive Nanoparticles Enhanced Tumor Targeting and Penetration Abilities for Breast Cancer Therapy.

Limited tumor targeting and poor penetration of nanoparticles are two major obstacles to improving the outcome of tumor therapy. Herein, coadministration of tumor-homing peptide iRGD and multistage-responsive penetrating nanoparticles for the treatment of breast cancer are reported. This multistage-responsive nanoparticle, IDDHN, was comprised of an NO donor-modified hyaluronic acid (HN) shell and a small-sized dendrimer, namely, dendri-graft-l-lysine conjugated with doxorubicin and indocyanine (IDD). The results showed that IDDHN could be degraded rapidly from about 330 nm to a smaller size that was in a size range of 35 to 150 nm (most at 35-60 nm) after hyaluronidase (HAase) incubation for 4 h; in vitro cellular uptake demonstrated that iRGD could mediate more endocytosis of IDDHN into 4T1 cells, which was attributed to the overexpression of αvβ3 integrin receptor. Multicellular spheroids penetration results showed synergistically enhanced deeper distribution of IDDHN into tumors, with the presence of iRGD, HAase incubation, and NO release upon laser irradiation. In vivo imaging indicated that coadministration with iRGD markedly enhanced the tumor targeting and penetration abilities of IDDHN. Surprisingly, coadministration of IDDHN with iRGD plus 808 nm laser irradiation nearly suppressed all tumor growth. These results systematically revealed the excellent potential of coadministration of iRGD with multistage-responsive nanoparticles for enhancing drug delivery efficiency and overcoming the 4T1 breast cancer.

Co-administration of kla-TAT peptide and iRGD to enhance the permeability on A549 3D multiple sphere cells and accumulation on xenograft mice.

To enhance the anticancer activity, tumor penetration ability of the hybrid anticancer peptide, in this study, a TAT (RKKRRQRRR) peptide modified kla peptide (KLAKLAKKLAKLAK, with all D-amino acids), named kla-TAT, was co-administrated with the homing/penetrating peptide iRGD which could enhance the permeability of chemical drug in solid tumor and tumor vessel by co-administration. In this study, the nonsmall cell lung cancer A549 cell line with the iRGD targeting receptor neuropilin-1 high expression was selected to establish the 2D monolayer cell, 3D multiple cell spheroids, and xenograft mice model. The co-administration of iRGD strengthened the permeability of kla-TAT peptide against A549 2D and 3D sphere model with the penetration improvement property of iRGD; more importantly, co-administration with iRGD dramatically enhanced the accumulation of kla-TAT peptide in tumor tissue on the xenograft mice model with the homing property of iRGD. The co-administration of iRGD strategy confers targeting ability to the hybrid peptide kla-TAT. We believe the chemical conjugation plus co-administration approach may provide a promising way for cancer treatment in clinical practices.

Co-administration of iRGD with peptide HPRP-A1 to improve anticancer activity and membrane penetrability

To improve the specificity and penetration of anticancer peptides against tumors, in this study, we examined the effects of co-administration of the membrane-active peptide HPRP-A1 and the tumor homing/penetrating peptide iRGD. iRGD peptide is widely recognized as an efficient cell membrane penetration peptide targeting to αvβ3 integrins and neuropilin-1 (NRP-1) receptors, which show high expression in many tumor cells. The anticancer activity, cancer specificity and penetration activity in vitro and in vivo of the co-administered peptides were examined on 2D monolayer cells, 3D multi-cellular spheroids (MCS) and xenograft nude mice. Co-administration of iRGD and HPRP-A1 exhibited stronger anticancer activity and tumor specificity against A549 non-small cell lung cancer cells with NRP-1 receptor overexpression compared with HPRP-A1 alone. A549 cells showed uptake of the peptide combination and destruction of the integrity of the cell membrane, as well as adherence to the mitochondrial net, resulting in induction of apoptosis by a caspase-dependent pathway. The iRGD peptide dramatically increased the penetration depth of HPRP-A1 on A549 MCS and anticancer efficacy in an A549 xenograft mouse model. Our results suggest that the co-administration strategy of anticancer and penetrating peptides could be a potential therapeutic approach for cancer treatment in clinical practice.

Coadministration of a tumor-penetrating peptide improves the therapeutic efficacy of paclitaxel in a novel air-grown lung cancer 3D spheroid model.

Three-dimensional (3 D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In this study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3 D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology and 3 D structure of air-grown MCS were characterized by brightfield, fluorescent and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were coadministered as compared with PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that coadministration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3 D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated.

Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1-mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer-coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome-based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.

Highly Stable Fluorinated Nanocarriers with iRGD for Overcoming the Stability Dilemma and Enhancing Tumor Penetration in an Orthotopic Breast Cancer.

The stability dilemma and limited tumor penetration of nanocarriers in cancer chemotherapy remain two predominant challenges for their successful clinical translation. Herein, the pH-sensitive fluorocarbon-functionalized nanocarriers (SFNs) with a tumor-homing and penetrating peptide iRGD are reported to overcome the stability dilemma and enhance tumor accumulation and penetration in an orthotopic breast cancer. The highly stable SFNs with a low critical association concentration provide a safe and spacious harbor for hydrophobic drugs. Furthermore, the stimulus-responsive evaluation and in vitro drug release study show that the SFNs can balance intracellular dissociation for drug release and extracellular stability in the blood circulation. Additionally, the tumor penetration capacity has been dramatically enhanced in 3D multicellular spheroids, effectively affecting cells far from the periphery. This can be ascribed to the coadministration of iRGD having tumor-penetrating ability and fluorocarbon chains having good cell membrane permeability. The combination of SFNs and iRGD is a viable approach to assist drugs' effective accumulation in primary and metastasized tumor sites, significantly inhibiting the breast tumor growth and curbing lung and liver metastases in an orthotopic-tumor-bearing mouse model. Taken together, this pH-sensitive fluorinated nanosystem having excellent stability and tumor accumulation and penetration properties paves the way to combat cancer.

IRGD-mediated core-shell nanoparticles loading carmustine and O6-benzylguanine for glioma therapy

iRGD (internalizing RGD) with high affinity to αν integrins was reported to enhance tumor penetrability by binding to neuropilin-1 (NRP-1). Based on our previous study, chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs), loaded with carmustine (BCNU) and its sensitizer (O6-benzylguanine, BG) showed stronger anti-tumor effect than free drugs. In present study, PLGA/CS NPs (NPs) with core-shell structure were prepared and modified with iRGD or mPEG. F98, C6 or U87 cell lines with different receptors levels were selected for in vitro and in vivo studies. After administration of iRGD-mediated NPs, including iRGD-modified NPs (iRGD-NPs) and co-administration of iRGD and NPs (iRGD + NPs), their effects on glioma were compared with NPs. iRGD-NPs showed stronger cytotoxicity and cellular uptake than other groups. iRGD-NPs and iRGD + NPs displayed deeper tumor penetration and stronger anti-invasion effect on three dimensional (3D) glioma spheroids than NPs. On F98 glioma-bearing mice model, iRGD-mediated NPs showed enhanced crossing BBB ability and brain tumor accumulation levels. Correspondingly, the median survival time of iRGD + NPs, iRGD-NPs and NPs groups were 58, 49 and 34.5 days, respectively. Present studies supported the iRGD-mediated strategy to improve the efficacy of antitumor drug delivery system. Importantly, co-administration of iRGD may be a greater way over the conjugation of iRGD.

Co-administration of iRGD enhancing the anticancer efficacy of cisplatin-loaded polypeptide nanoparticles

Co-administration of iRGD enhancing the anticancer efficacy of cisplatin-loaded polypeptide nanoparticles

Cisplatin-loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) nanoparticles as a potential chemotherapeutic agent against osteosarcoma

Herein, cisplatin-loaded poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) nanoparticles were evaluated as a potential chemotherapeutic agent against osteosarcoma by using alone or with an iRGD (internalizing RGD, CRGDKDPDC). The release rate of platinum from the cisplatin-loaded nanoparticles CDDP/PLG160-g-mPEG2K (CDDP-NPs) accelerated with the increase of the acidity of the environment. In vitro test demonstrated that CDDP-NPs could inhibit the proliferation of MNNG/Hos osteosarcoma cells with IC50 (72 h) of 12.2 μg·mL−1. In vivo test for MNNG/Hos osteosarcoma tumor bearing mice exhibited that CDDP-NPs had comparable or slightly higher efficacy but significantly lower side effects in comparison with free CDDP. The coadministration of iRGD could further enhance the anticancer efficacy of CDDP-NPs against MNNG/Hos osteosarcoma without bringing obvious side effects. Therefore, CDDP-NPs using alone or with iRGD have great potential for the treatment of osteosarcoma.