Tumor-homing Peptide Research Articles

Targeting BRIX1 via Engineered Exosomes Induces Nucleolar Stress to Suppress Cancer Progression.

Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre-rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface-decorated with iRGD, a tumor-homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD-Exo-siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5-FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy.

A Tumor Homing Peptide-Linked Arsenic Compound Inhibits Pancreatic Cancer Growth and Enhances the Inhibitory Effect of Gemcitabine.

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth in vitro and to promote the inhibitory effects of gemcitabine (Gem) on PC in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested in vitro and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth in vitro more potently, with IC50 values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer.

LLM4THP: a computing tool to identify tumor homing peptides by molecular and sequence representation of large language model based on two-layer ensemble model strategy

Tumor homing peptides (THPs) have a distinctive capacity to specifically attach to tumor cells, providing a promising approach for targeted cancer treatment and detection. Although THPs have the potential for significant impact, their detection by conventional methods is both time-consuming and expensive. To tackle this issue, we provide LLM4THP, an innovative computational approach that utilizes large language models (LLMs) to quickly and effectively detect THPs. LLM4THP utilizes two protein LLMs, ESM2 and Prot_T5_XL_UniRef50, to encode peptide sequences. This allows for the capture of complex patterns and relationships within the peptide data. In addition, we utilize inherent sequence characteristics such as Amino Acid Composition (AAC), Pseudo Amino Acid Composition (PAAC), Amphiphilic Pseudo Amino Acid Composition (APAAC), and Composition, Transition, and Distribution (CTD) to improve the representation of peptides. The RDKitDescriptors feature representation approach transforms peptide sequences into molecular objects and computes chemical characteristics, resulting in enhanced THP identification. The LLM4THP ensemble strategy incorporates various features into a two-layer learning architecture. The first layer consists of LightGBM, XGBoost, Random Forest, and Extremely Randomized Trees, which generate a set of meta results. The second layer utilizes Logistic Regression to further refine the identification of sequences as either THP or non-THP. LLM4THP exhibits exceptional performance compared to the most advanced methods, showcasing enhancements in accuracy, Matthew’s correlation coefficient, F1 score, area under the curve, and average precision. The source code and dataset can be accessed at the following URL: https://github.com/abcair/LLM4THP.

Delivery of BikDD proapoptotic gene in Peptide-18-targeted Poly(2-oxazoline)-DOPE nanoliposomes for breast cancer models.

Breast cancer is one of the most common cancers and a significant cause of death in females worldwide. For effective breast cancer treatment, using systems with a promising delivery of anticancer agents is an important strategy. Peptide 18 (P18), a tumor-homing peptide, shows a high binding affinity toward breast cancer cells. Nanoliposomes are known to have enhanced accumulation ability in tumors with longer systemic circulation. In this study, Poly (2-ethyl-2-oxazoline) (PEtOx) polymers conjugated with DOPE are used to prepare PEtOx-DOPE nanoliposomes. BikDD, a mutant form of the Bik gene and a member of the BH3-only proapoptotic genes, mimics the constitutively phosphorylated form of the gene. To the best of our knowledge, this study presents a novel approach by investigating P18-conjugated PEtOx-DOPE nanoliposomes (P18-PEtOx-DOPE) for the targeted delivery of BikDD to the AU565 breast cancer model. A site-directed mutated BikDD was loaded into P18-PEtOx-DOPE nanoliposomes, and the targeted drug delivery system was assessed in in vitro and in vivo breast cancer models for efficiency, safety, and efficacy. The increased Bik mRNA expression levels in AU565 cells suggest a high effectiveness of the targeting PEtOx-DOPE nanoliposomes. Following the in vitro studies, the delivery of BikDD by P18-PEtOx-DOPE nanoliposomes was analyzed in CD-1 nude mice models. The animal study showed no significant difference in the tumor volume of the CD-1 nude mice treated with P18-PEtOx-DOPE-BikDD nanoliposomes compared to the free delivery of BikDD. Our preclinical studies suggest that P18-PEtOx-DOPE-BikDD nanoliposomes may be promising gene carriers for targeted breast cancer therapy. Thus, further studies should be carried out to determine the prolonged use of this drug delivery system in breast cancer therapy.

Enhancing the potency of anti-P32-active targeted PEGylated liposomal doxorubicin using various spacers: In silico, in vitro and in vivo studies

Even though nanoliposomal drug delivery systems are superior to conventional drug delivery methods, studies indicate that they may deliver small quantities of drugs through passive targeting. Specific peptides are used to decorate the surface of the liposomes for active targeting of tumors. Among these, CGKRK is the tumor homing peptide to target p32 protein on the surface of endothelial and tumor cells. In the present study, serine-glycine (SG) and glycine-glycine-glycine (GGG) spacer were added to CGKRK, an anti-P32 peptide and in silico molecular docking studies were conducted. PEGylated liposomal doxorubicin (PLD) was then surface modified with these peptides. All liposomal formulations had the sizes between 96 and 110 nm, negative zeta potentials and there were spherical in shape. The release of the doxorubicin (Dox) followed the same pattern for all formulations during 24 h. The cytotoxic effects of the formulations during 1, 3 and 6 h of the incubation, indicated the time-dependent cytotoxicity of formulations, while the PLD-CGGGKRK was the most potent. Apoptosis and antiangiogenic assays were also demonstrated the ability of PLD-CGGGKRK in inducing apoptosis and decreasing vessels densities. The in vivo anti-tumor study demonstrated the efficacy of CGGGKRK surface-modified PLDs in delaying tumor growth and increasing the median survival. Our findings indicated that the GGG spacer could improve the efficacy of anti-P32 peptide, CGKRK, in targeting breast cancer tumor models in mice and merit further investigation.

HER-2 Receptor and αvβ3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.

Tumor targeting peptide TMTP1 modified Antigen capture Nano-vaccine combined with chemotherapy and PD-L1 blockade effectively inhibits growth of ovarian cancer

The mortality of ovarian cancer (OC) has long been the highest among gynecological malignancies. Although OC is considered to be an immunogenic tumor, the effect of immunotherapy is not satisfactory. The immunosuppressive microenvironment is one reason for this, and the absence of recognized effective antigens for vaccines is another. Chemotherapy, as one of the most commonly used treatment for OC, can produce chemotherapy-associated antigens (CAAs) during treatment and show the effect of in situ vaccine. Herein, we designed an antigen capture nano-vaccine NP-TP1@M-M with tumor targeting peptide TMTP1 and dendritic cell (DC) receptor mannose assembled on the surface and adjuvant monophosphoryl lipid A (MPLA) encapsulated in the core of poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles. PLGA itself possessed the ability of antigen capture. TMTP1 was a tumor-homing peptide screened by our research team, which held extensive and excellent tumor targeting ability. After these modifications, NP-TP1@M-M could capture and enrich more tumor-specific antigens after chemotherapy, stimulate DC maturation, activate the adaptive immunity and combined with immune checkpoint blockade to maximize the release of the body’s immune potential, providing an eutherapeutic strategy for the treatment of OC.

Computational modeling study of IL-15-NGR peptide fusion protein: a targeted therapeutics for hepatocellular carcinoma

The primary challenge to improving existing cancer treatment is to develop drugs that specifically target tumor cell. NGR peptide is tumor homing peptide that selectively target cancer cells while interleukin 15 is a pleiotropic cytokine with anticancer properties. This study computationally engineered a IL15-NGR fusion peptide by linking the homing peptide NGR with the targeting peptide IL-15. After evaluating and validating the chimeric peptide, we docked it to the IL-15Rα/IL-15Rβ/γc heterodimer receptor, examining the interactions and binding energy and lastly, molecular dynamics simulations were performed. The secondary and tertiary structures, along with physicochemical properties of the designed IL-15-NGR chimeric protein, were predicted using GOR IV, trRosetta and ProtParam online servers respectively. The quality and 3D structure validation were confirmed via ProSA-web and SAVES 6.0 analysis which predicted an ERRAT score of 96.72%, with 97.6% of residues in the Ramachandran plot, validating its structure. Finally, Docking, MD simulations and interaction analysis were performed using ClusPro 2.0 and GROMACS and PDBsum, which exhibited significant hydrogen bonding and salt bridges, confirming the formation of a stable docked complex. These results were further corroborated by simulation analysis, which demonstrated a stable and dynamic behavior of the docked complex in a biological environment. The predicted high expression value of fusion protein was 0.844 in E.coli using SOLUPROT tool. These findings suggest efficient expression of the IL15-NGR fusion protein if its gene is inserted into E. coli and indicates its potential as a safe and effective anticancer treatment, paving the way for targeted therapeutic interventions.Graphical abstract

Boosting ferroptosis by intervention of redox balance and synergetic with photothermal/photodynamic therapy for suppression of pancreatic cancer

Metal-doped iron oxide nanoparticles have attracted increasing attention for their Fenton reaction ability, which converts H2O2 to cytotoxic reactive oxygen species (ROS) and is recently utilized as ferroptosis activator in pancreatic cancer therapy. However, low intracellular H2O2 level hinders ferroptosis effect and leads to unsatisfactory efficacy. Herein, a transferrin coated and tumor homing peptide decorated bimetallic magnetic nanoparticles copper-doped iron oxide nanosystems embedded with photothermal agent IR820 and iron ions (denoted as PCTIFL) is constructed for synergistic treatment for pancreatic cancer by combining ferroptosis and photothermal/photodynamic therapy (PTT/PDT) under 808 nm laser irradiation. Benefiting from the homologous targeting property of LyP-1, the nanosystems can be precisely delivered and gradually accumulate at tumor site. For the synergistic therapy, IR820 generates ROS via photodynamic effect and enables cancer cell temperature elevation via PTT effect upon 808 nm laser irradiation on the one hand and metal ions such as Fe2+, Fe3+ and Cu2+ catalyze H2O2 into ROS and finally triggered ferroptosis on the other hand. Moreover, PCTIFL nanosystems can be applied in pancreatic cancer diagnosis for their MRI/NIR dual imaging function. Overall, this work not only presents a promising strategy for augmenting the ferroptosis induced by iron oxide, but also a fantastic paradigm for pancreatic cancer diagnosis and synergistic therapy.

Tumour-specific activation of a tumour-blood transport improves the diagnostic accuracy of blood tumour markers in mice

The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport. To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of α-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer. Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer. We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer. Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.

Tumor-Homing Peptides as Crucial Component of Magnetic-Based Delivery Systems: Recent Developments and Pharmacoeconomical Perspective.

According to data from the World Health Organization (WHO), cancer is considered to be one of the leading causes of death worldwide, and new therapeutic approaches, especially improved novel cancer treatment regimens, are in high demand. Considering that many chemotherapeutic drugs tend to have poor pharmacokinetic profiles, including rapid clearance and limited on-site accumulation, a combined approach with tumor-homing peptide (THP)-functionalized magnetic nanoparticles could lead to remarkable improvements. This is confirmed by an increasing number of papers in this field, showing that the on-target peptide functionalization of magnetic nanoparticles improves their penetration properties and ensures tumor-specific binding, which results in an increased clinical response. This review aims to highlight the potential applications of THPs in combination with magnetic carriers across various fields, including a pharmacoeconomic perspective.

In Vitro Study of Tumor-Homing Peptide-Modified Magnetic Nanoparticles for Magnetic Hyperthermia.

Cancer cells have higher heat sensitivity compared to normal cells; therefore, hyperthermia is a promising approach for cancer therapy because of its ability to selectively kill cancer cells by heating them. However, the specific and rapid heating of tumor tissues remains challenging. This study investigated the potential of magnetic nanoparticles (MNPs) modified with tumor-homing peptides (THPs), specifically PL1 and PL3, for tumor-specific magnetic hyperthermia therapy. The synthesis of THP-modified MNPs involved the attachment of PL1 and PL3 peptides to the surface of the MNPs, which facilitated enhanced tumor cell binding and internalization. Cell specificity studies revealed an increased uptake of PL1- and PL3-MNPs by tumor cells compared to unmodified MNPs, indicating their potential for targeted delivery. In vitro hyperthermia experiments demonstrated the efficacy of PL3-MNPs in inducing tumor cell death when exposed to an alternating magnetic field (AMF). Even without exposure to an AMF, an additional ferroptotic pathway was suggested to be mediated by the nanoparticles. Thus, this study suggests that THP-modified MNPs, particularly PL3-MNPs, hold promise as a targeted approach for tumor-specific magnetic hyperthermia therapy.

A Computational Predictor for Accurate Identification of Tumor Homing Peptides by Integrating Sequential and Deep BiLSTM Features.

Cancer remains a severe illness, and current research indicates that tumor homing peptides (THPs) play an important part in cancer therapy. The identification of THPs can provide crucial insights for drug-discovery and pharmaceutical industries as they allow for tailored medication delivery towards cancer cells. These peptides have a high affinity enabling particular receptors present upon tumor surfaces, allowing for the creation of precision medications that reduce off-target consequences and enhance cancer patient treatment results. Wet-lab techniques are considered essential tools for studying THPs; however, they're labor-extensive and time-consuming, therefore making prediction of THPs a challenging task for the researchers. Computational-techniques, on the other hand, are considered significant tools in identifying THPs according to the sequence data. Despite many strategies have been presented to predict new THP, there is still a need to develop a robust method with higher rates of success. In this paper, we developed a novel framework, THP-DF, for accurately identifying THPs on a large-scale. Firstly, the peptide sequences are encoded through various sequential features. Secondly, each feature is passed to BiLSTM and attention layers to extract simplified deep features. Finally, an ensemble-framework is formed via integrating sequential- and deep features which are fed to a support vector machine which with 10-fold cross-validation to carry to validate the efficiency. The experimental results showed that THP-DF worked better on both [Formula: see text] and [Formula: see text] datasets by achieving accuracy of > 95% which are higher than existing predictors both datasets. This indicates that the proposed predictor could be a beneficial tool to precisely and rapidly identify THPs and will contribute to the cutting-edge cancer treatment strategies and pharmaceuticals.

A dual drug-loaded tumor vasculature-targeting liposome for tumor vasculature disruption and hypoxia-enhanced chemotherapy

Vascular disrupting agents (VDAs) can destroy tumor vasculature and lead to tumor ischemia and hypoxia, resulting in tumor necrosis. However, VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells. Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome. Here, we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA, which can specifically target tumor vessels and stroma) and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride (AQ4N) and a VDA combretastatin A4 (CA4), respectively. CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels, which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region. As a consequence, AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment. The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro. In addition, in vivo experiments confirm the excellent tumor-targeting/accumulation, tumor vasculature-damaging, and tumor inhibition effects of the liposome. This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection, and is expected to benefit the future development of effective antitumor liposomal drugs.

Development of a Novel Peptide with RGD Tumor Homing Motif: Evaluation of its Anticancer Potential in Hepatocellular Carcinoma and Colon Cancer Cells

Background: Peptide-based therapy has emerged as a promising avenue for treating various disorders, and recent research has highlighted the potential of anti-cancer peptides (ACPs) in cancer treatment. In this context, this study aimed to design a novel peptide incorporating a tumor-homing peptide (RGD) and C-amidation to enhance its anticancer activity, particularly against liver (HepG2) and colon (HCT-116) cancer cell lines. Objectives: The primary objective was to design a peptide with improved anticancer properties by leveraging the tumor-homing capabilities of RGD and enhancing its activity through C-amidation. The study sought to evaluate the cytotoxicity of the designed peptide against red blood cells (RBCs) and normal Vero cells. Furthermore, the anticancer efficacy of the peptide was assessed in hepatocellular carcinoma (HepG2) and colon cancer (HCT-116) cell lines. The specific objectives included examining the apoptotic induction and morphological changes in treated cells compared to untreated cells. Methods: The peptide was designed using the ACPred-FL bioinformatics tool, and its cytotoxicity was assessed through hemolysis assays against RBCs and normal Vero cells. Anticancer activity was evaluated against HepG2 and HCT-116 cell lines. The analysis of apoptotic induction involved measuring the relative gene expression of oncogenic marker BCL2 and apoptotic markers (BAX, BID, CAS-8). Additionally, Cytopathological examination and Western Blot analysis were employed to study morphological changes and confirm the quantification of relevant markers. Results: The designed peptide, consisting of twelve amino acids with a molecular mass of 1230.6233 Da and an isoelectric point of 9.81, exhibited low erythrocyte lysis and minimal toxicity to normal cells. The IC50 values demonstrated significant anticancer activity against both HepG2 (36.49±2.6 μg/mL) and HCT-116 (11.03±2.5 μg/mL) cell lines. Treated cells exhibited a significant decrease in the oncogenic marker BCL2 and an upregulation of apoptotic markers (BAX, BID, CAS-8). Western Blot analysis confirmed these findings, and Cytopathological examination revealed scattered apoptotic and degenerative changes. Conclusion: The designed peptide displayed remarkable anticancer activity against hepatocellular carcinoma and colon cancer cell lines, effectively modulating apoptotic and oncogenic markers. These findings highlight the potential of the peptide as a therapeutic agent for cancer treatment, emphasizing its clinical significance in combating liver and colon cancers. Nonetheless, further research and development are warranted to explore the translational potential of this peptide in clinical settings.

Translational use of homing peptides: Tumor and placental targeting

HypothesisTissue-specific homing peptides have been shown to improve chemotherapeutic efficacy due to their trophism for tumor cells. Other sequences that selectively home to the placenta are providing new and safer therapeutics to treat complications in pregnancy. Our hypothesis is that the placental homing peptide RSGVAKS (RSG) may have binding affinity to cancer cells, and that insight can be gained into the binding mechanisms of RSG and the tumor homing peptide CGKRK to model membranes that mimic the primary lipid compositions of the respective cells. ExperimentsFollowing cell culture studies on the binding efficacy of the peptides on a breast cancer cell line, a systematic translational characterization is delivered using ellipsometry, Brewster angle microscopy and neutron reflectometry of the extents, structures, and dynamics of the interactions of the peptides with the model membranes on a Langmuir trough. FindingsWe start by revealing that RSG does indeed have binding affinity to breast cancer cells. The peptide is then shown to exhibit stronger interactions and greater penetration than CGKRK into both model membranes, combined with greater disruption to the lipid component. RSG also forms aggregates bound to the model membranes, yet both peptides bind to a greater extent to the placental than cancer model membranes. The results demonstrate the potential for varying local reservoirs of peptide within cell membranes that may influence receptor binding. The innovative nature of our findings motivates the urgent need for more studies involving multifaceted experimental platforms to explore the use of specific peptide sequences to home to different cellular targets.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Targeted delivery of the metastasis-specific tumour homing TMTP1 peptide to non-small-cell lung cancer (NSCLC) using inhalable hybrid nano-assemblies.

Lung cancer is one of the most fatal malignancies, with the highest death rate (∼19%), and the NSCLC type accounts for ∼85% of lung cancers. In the search for new treatments, antimicrobial peptides have received much attention due to their propensity for selective destruction of cancer cells. In the current study, we evaluated the efficacy of the metastasis-specific tumour-homing-TMTP1 peptide against lung cancer using inhalable hybrid nano-assemblies of the PEG-PLGA copolymer as a carrier for pulmonary delivery which was assessed for aerodynamic and physicochemical properties, along with the peptide-release profile, physical stability, cellular uptake and biocompatibility, generation of reactive oxygen species, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Optimization of inhaled dose, lung retention, and efficacy studies was conducted to evaluate the formulation in an NNK (nicotine-derived nitrosamine ketone) induced tumour-bearing lung cancer murine model. After inhalation, the formulation with nano-scale physiognomies showed good lung deposition, retention, and metabolic stability. The inhalable nano-assemblies have shown enhanced generation of reactive oxygen species with increased autophagy flux and apoptotic cell death. Pre-clinical animal trials show substantial tumour regression by inhalable TMTP1-based nano-formulation with limited side effects. Our results on metastasis targeting and tumour-homing peptide TMTP1 demonstrate its effective tumour targeting and tumour-killing efficacy and provide a reference for the development of new therapeutics for NSCLC.

The investigation of the death-inducing potency of a recombinant Adenovector expressing Mda-7-tlyp-1 on different cancer cell lines.

The potency of Adenovector expressing Mda7-tLyp1 (Ad-Mda7-tLyp1) for death induction was evaluated on the breast (MCF7), liver (HepG2), and gastric (MKN45) cancer cell lines. Mda-7 could be a possible complementary to traditional cancer therapy, and tethering to tumor-homing peptides (THPs) might improve its therapeutic efficacy. After the preparation of recombinant Ad-Mda7-tLyp1 and Ad-Mda7, the expression of recombinant proteins was analyzed by ELISA. Adenovectors were transduced (MOI=2-5) into Hep-G2, MCF7, MKN45, and normal skin fibroblast, then tumor-killing effect was measured by cytopathic effect (CPE) monitoring, MTT viability test, BAX gene expression analysis, and Caspase3/7 assay. ELISA assay revealed a sustained level of recombinant protein secretion following Adenovector transduction. In CPE microscopy, all cancer cell lines showed a significant reduction (≥50%) in their normal phenotype after receiving Ad-Mda7-tLyp1 and Ad-Mda7. The viability was significantly lower compared to the control, indicating an anti-proliferating effect. In parallel, the viability test showed that Ad-Mda7 and Ad-Mda7-tLyp1 have a significant killing effect (≥50%) on MCF-7, Hep-G2, and MKN45 compared to normal fibroblast (P≤0.05). BAX gene expression analysis showed that both Ad-Mda7-tLyp1 and Ad-Mda7 vectors induced >2-fold increase of apoptosis (P<0.05), particularly in MCF7. Similarly, caspase3/7 activity showed a significant increase (P<0.05) following Ad-Mda7, and Ad-Mda7-tLyp1 transduction into cancer cell lines, but not in normal fibroblasts. The newly constructed Ad-Mda-tlyp1 showed a suitable tumor cell killing activity and enough specificity on studied cell lines.

Tumor–homing peptide iRGD-conjugate enhances tumor accumulation of camptothecin for colon cancer therapy

Poor intracellular uptake of therapeutics in the tumor parenchyma is a key issue in cancer therapy. We describe a novel approach to enhance tumor targeting and achieve targeted delivery of camptothecin (CPT) based on a tumor–homing internalizing RGD peptide (iRGD). We synthesized an iRGD–camptothecin conjugate (iRGD–CPT) covalently coupled by a heterobifunctional linker and evaluated its in vitro and in vivo activity in human colon cancer cells. In vitro studies revealed that iRGD–CPT penetrated cells efficiently and reduced colon cancer cell viability to a significantly greater extent at micromolar concentrations than did the parent drug. Furthermore, iRGD–CPT showed high distribution toward tumor tissue, effectively suppressed tumor progression, and showed enhanced antitumor effects relative to the parent drug in a mouse model, demonstrating that iRGD–CPT is effective in vivo cancer treatment. These results suggest that intracellular delivery of CPT via the iRGD peptide is a promising drug delivery strategy that will facilitate the development of CPT derivatives and prodrugs with improved efficacy.