Targeting Ligands Research Articles

Gold nanocomposites in colorectal cancer therapy: characterization, selective cytotoxicity, and migration inhibition.

The third most prevalent type of cancer in the world, colorectal cancer, poses a significant treatment challenge due to the nonspecific distribution, low efficacy, and high systemic toxicity associated with chemotherapy. To overcome these limitations, a targeted drug delivery system with a high cytotoxicity against cancer cells while maintaining a minimal systemic side effects represents a promising therapeutic approach. Therefore, the aim of this study was to develop an efficient gold nanocarrier for the targeted delivery of the anticancer agent everolimus to Caco-2 cells. A novel gold nanocomposite (EV-β-CD-HA-Chi-AuNCs) functionalized with a targeting ligand (hyaluronic acid), a permeation enhancement excipient (chitosan), and an anticancer inclusive compound consisting of beta-cyclodextrin and everolimus was proposed and prepared via Turkevich method. Characterization was performed with a UV spectrometer, FTIR, Zetasizer, and HRTEM. Its drug release profile was also evaluated in media with three different pH values. Cytotoxicity and biocompatibility studies were performed on a colorectal cancer cell line (Caco-2) and a normal fibroblast line (MRC-5), respectively, via xCELLigence real-time cellular analysis (RTCA) technology. The inhibitory effect on migration was also further tested via the xCELLigence RTCA technique and a scratch assay. Characterization studies revealed the successful formation of EV-β-CD-HA-Chi-AuNCs with a size and charge which are suitable for the use as targeted drug delivery carrier. In the cytotoxic study, the EV-β-CD-HA-Chi-AuNCs showed a lower IC50 (16 ± 1 µg/ml) than the pure drug (25 ± 3 µg/ml) toward a colorectal cell line (Caco-2). In the biocompatibility study, the EV-β-CD-HA-Chi-AuNCs have minimal toxicity, while the pure drug has severe toxicity toward healthy fibroblasts (MRC-5) despite its low concentration. In the cell migration study, the EV-β-CD-HA-Chi-AuNCs also showed a greater inhibitory effect than the pure drug. Compared with the pure drug, the EV-β-CD-HA-Chi-AuNCs exhibit an excellent selective cytotoxicity between cancerous colorectal Caco-2 cells and healthy MRC-5 cells, making it a potential carrier to carry the drug to the cancerous site while maintaining its low toxicity to the surrounding environment. In addition, an increase in the cytotoxic activity of the EV-β-CD-HA-Chi-AuNCs toward cancerous colorectal Caco-2 cells was also observed, which can potentially improve the treatment of colorectal cancer.

Aptamer-conjugated liposome system for targeting MUC1-positive cancer: an in silico screening approach

This study aims to overcome the adverse effects of conventional cytotoxic chemotherapy on healthy organs by developing a target-specific approach utilizing Doxorubicin (DOX)-encapsulated liposome conjugated with aptamer which has high binding affinity to the overexpressed Mucin-1 (MUC1) protein in various cancer types. To ensure optimal aptamer selection, we conducted a comprehensive in silico comparison of several MUC1-targeting aptamers, including 5TR1, MA3, S1.6, S2.2, and STRG2. As a results, the S1.6 aptamer was selected as a targeting ligand by comparing the thermodynamic stability, docking score, confidence score, and binding affinity. Also, spectrophotometer, gel electrophoresis, and Dynamic light scattering (DLS) confirm the size, zeta potential, DOX encapsulation rate, stability, and aptamer conjugation of liposomes. In addition, flow cytometry results validate MUC1 expression in MCF7 cells while not in MDA-MB-231 cells, while confocal microscopy confirmed the specific cellular uptake of the lipo-aptamer complex. Consequently, this aptamer-mediated liposomal drug delivery approach shows potential for enhancing the specificity and reducing the side effects of conventional chemotherapy, while the use of in silico methods provides an efficient and cost-effective strategy for screening and optimizing aptamer candidates, simplifying the overall development process. Further in vivo evaluation for therapeutic efficacy and clinical applications is warranted.Graphical

Surface Functionalization of Nanocarriers with Anti-EGFR Ligands for Cancer Active Targeting

Surface Functionalization of Nanocarriers with Anti-EGFR Ligands for Cancer Active Targeting

Niosomal Encapsulation of Anti-Cancer Peptides: A Revolutionary Strategy in Cancer Therapy.

Cancer treatment has evolved significantly over the years, incorporating a range of modalities including surgery, radiation, chemotherapy, and immunotherapy. However, challenges such as drug resistance, systemic toxicity, and poor targeting necessitate innovative approaches. Peptides have gained attention in cancer therapy due to their specificity, potency, and ability to modulate various biological pathways. Peptide-based drugs can act as hormones, enzyme inhibitors, or targeting ligands, contributing to their versatile role in cancer treatment. However, peptides face several challenges, including instability, rapid degradation, and poor bioavailability. One promising strategy is the use of niosomal delivery systems for peptidebased therapies. Niosomes, which resemble liposomes in structure, are vesicles based on nonionic surfactants. They are composed of a bilayer created through the self-assembly of non-ionic surfactants in water, enabling them to encapsulate hydrophilic, lipophilic, and amphiphilic drugs. Their unique properties, such as biocompatibility, biodegradability, and ability to encapsulate diverse therapeutic agents, make them suitable for drug delivery applications. This review aims to explore how the niosomal preparation of peptides can revolutionize oncology drugs by overcoming critical challenges like drug resistance, systemic toxicity, poor targeting, instability, rapid degradation, and low bioavailability. This review aims to explore how niosomes can specifically address key limitations in cancer therapy, including targeting, bioavailability, and stability of peptide-based drugs. By consolidating recent advancements, the review sheds light on how niosomal encapsulation can overcome barriers in cancer treatment and improve therapeutic outcomes for patients.

Control of biomedical nanoparticle distribution and drug release in vivo by complex particle design strategies.

The utilization of targeted nanoparticles as a selective drug delivery system is a powerful tool to increase the amount of active substance reaching the target site. This can increase therapeutic efficacy while reducing adverse drug effects. However, nanoparticles face several challenges: upon injection, the immediate adhesion of plasma proteins may mask targeting ligands, thereby diminishing the target cell selectivity. In addition, opsonization can lead to premature clearance and the widespread presence of receptors or enzymes limits the accuracy of target cell recognition. Nanoparticles may also suffer from endosomal entrapment, and controlled drug release can be hindered by premature burst release or insufficient particle retention at the target site. Various strategies have been developed to address these adverse events, such as the implementation of switchable particle properties, regulating the composition of the formed protein corona, or using click-chemistry based targeting approaches. This has resulted in increasingly complex particle designs, raising the question of whether this development actually improves the therapeutic efficacy in vivo. This review provides an overview of the challenges in targeted drug delivery and explores potential solutions described in the literature. Subsequently, appropriate strategies for the development of nanoparticular drug delivery concepts are discussed.

Artificial Intelligence in Computer-Aided Drug Design (CADD) Tools for the Finding of Potent Biologically Active Small Molecules: Traditional to Modern Approach.

Computer-Aided Drug Design (CADD) entails designing molecules that could potentially interact with a specific biomolecular target and promising their potential binding. The stereo- arrangement and stereo-selectivity of small molecules (SMs)--based chemotherapeutic agents significantly influence their therapeutic potential and enhance their therapeutic advantages. CADD has been a well-established field for decades, but recent years have observed a significant shift toward acceptance of computational approaches in both academia and the pharmaceutical industry. Recently, artificial intelligence (AI), bioinformatics, and data science have played a significant role in drug discovery to accelerate the development of effective treatments, reduce expenses, and eliminate the need for animal testing. This shift can be attributed to the availability of extensive data on molecular properties, binding to therapeutic targets, and their 3D structures. Increasing interest from legislators, pharmaceutical companies, and academic and industrial scientists is evidence that AI is reshaping the drug discovery industry. To achieve success in drug discovery, it is necessary to optimize pharmacodynamic, pharmacokinetic, and clinical outcome-related properties. Moreover, the advent of on-demand virtual libraries containing billions of drug-like SMs, coupled with abundant computing capacities, has further facilitated this transition. To fully capitalize on these resources, rapid computational methods are needed for effective ligand screening. This includes structure-based virtual screening (SBVS) of vast chemical spaces, aided by fast iterative screening approaches. At the same time, advances in deep learning (DL) predictions of ligand properties and target activities have become very helpful, as they no longer need information about the structure of the receptor. This study examines recent progress in the drug discovery and development (DDD) approach, their potential to reshape the entire DDD process, and the challenges they face. This review examines the role of artificial intelligence as a fundamental component in drug discovery, particularly focusing on small molecules. It also discusses how AI-driven approaches can expedite the identification of diverse, potent, target-specific, and drug-like ligands for protein targets. This advancement has the potential to make drug discovery more efficient and cost-effective, ultimately facilitating the development of safer and more effective therapeutics.

Organelle-Targeting Nanoparticles.

Organelles are specialized subunits within cells which carry out vital functions crucial to cellular survival and form a tightly regulated network. Dysfunctions in any of these organelles are linked to numerous diseases impacting virtually every organ system in the human body. Targeted delivery of therapeutics to specific organelles within the cell holds great promise for overcoming challenging diseases and improving treatment outcomes through the minimization of therapeutic dosage and off-target effects. Nanoparticles are versatile and effective tools for therapeutic delivery to specific organelles. Nanoparticles offer several advantageous characteristics, including a high surface area-to-volume ratio for efficient therapeutic loading and the ability to attach targeting moieties (tethers) that enhance delivery. The choice of nanoparticle shape, size, composition, surface properties, and targeting ligands depends on the desired target organelle and therapeutic effect. Various nanoparticle platforms have been explored for organelle targeting, such as liposomes, polymeric nanoparticles, dendrimers, and inorganic nanoparticles. In this review, current and emerging approaches to nanoparticle design are examined in the context of various diseases linked to organelle dysfunction. Specifically, advances in nanoparticle therapies targeting organelles such as the nucleus, mitochondria, lysosomes/endosomes, Golgi apparatus, and endoplasmic reticulum are comprehensively and critically discussed.

Discovering Cell-Targeting Ligands and Cell-Surface Receptors by Selection of DNA-Encoded Chemical Libraries against Cancer Cells without Predefined Targets.

Small molecules that can bind to specific cells have broad applications in cancer diagnosis and treatment. Screening large chemical libraries against live cells is an effective strategy for discovering cell-targeting ligands. The DNA-encoded chemical library (DEL or DECL) technology has emerged as a robust tool in drug discovery and has been successfully utilized in identifying ligands for biological targets. However, nearly all DEL selections have predefined targets, while target-agnostic DEL selections interrogating the entire cell surface remain underexplored. Herein, we systematically optimized a cell-based DEL selection method against cancer cells without predefined targets. A 104.96-million-member DEL was selected against MDA-MB-231 and MCF-7 breast cancer cells, representing high and low metastatic properties, respectively, which led to the identification of cell-specific small molecules. We further demonstrated cell-targeting applications of these ligands in cancer photodynamic therapy and targeted drug delivery. Finally, leveraging the DNA tag of DEL compounds, we identified α-enolase (ENO1) as the cell surface receptor of one of the ligands targeting the more aggressive MDA-MB-231 cells. Overall, this work offers an efficient approach for discovering cell-targeting small molecule ligands by using DELs and demonstrates that DELs can be a useful tool to identify specific surface receptors on cancer cells.

A Conjugate of an EGFR-Binding Peptide and Doxorubicin Shows Selective Toxicity to Triple-Negative Breast Cancer Cells.

Selective targeting of cancer cells via overexpressed cell-surface receptors is a promising strategy to enhance chemotherapy efficacy and minimize off-target side effects. In this study, we designed peptide 31 (YHWYGYTPERVI) to target the overexpressed epidermal growth factor receptor (EGFR) in triple-negative breast cancer (TNBC) cells. Peptide 31 is internalized by TNBC cells through EGFR-mediated endocytosis and shares sequence and structural similarities with human EGF (hEGF), a natural EGFR ligand. Unlike hEGF, peptide 31 does not induce cell migration in TNBC cells. A novel conjugate of peptide 31 with doxorubicin (Dox) retains selectivity for TNBC cells and exhibits significant toxicity comparable to that of unconjugated Dox. Importantly, this conjugate shows no toxicity toward normal breast epithelial cells up to a high concentration (25 μM). Thus, peptide 31 serves as a versatile targeting ligand for developing novel conjugates with high selectivity for EGFR-positive cancers.

Carbon-based nanozymes for cancer therapy and diagnosis: A review.

Carbon-based nanozymes (CNs) have emerged as a significant innovation in targeted cancer therapy, demonstrating great potential for advancing cancer diagnosis and treatment. With exceptional catalytic properties, remarkable biocompatibility, and the ability to precisely target cancer cells, CNs provide a promising avenue for the development of novel oncological therapies. By functionalizing their surfaces with targeting ligands, such as antibodies or peptides, CNs can specifically recognize and bind to cancer cells. This targeted approach ensures that therapeutic agents are delivered directly to the tumor site, minimizing off-target effects, and reducing systemic toxicity. Additionally, the enzyme-like activities of CNs, when combined with conventional therapies such as chemotherapeutics, photothermal therapy, and photodynamic therapy, or other modalities can enhance therapeutic outcomes. Integrating CNs into clinical practice could significantly improve therapeutic efficacy, reduce probable side effects, enhance patient outcomes, and drive a shift towards more personalized cancer care. Besides, CNs can also be employed in biosensors and diagnostic nanomaterials, enabling rapid, selective, and highly accurate detection of specific biomarkers. Their versatile functionalities open new avenues for refining imaging techniques, ultimately contributing to early diagnosis and better clinical decision-making. This review consolidates recent studies exploring CNs in cancer targeting, highlighting both their diagnostic and therapeutic potential in oncology.

Localized InVivo Prodrug Activation Using Radionuclides.

Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof of principle, we tested whether this strategy of radionuclide-induced drug engagement for release (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy. Methods: We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule-destabilizing monomethyl auristatin E (MMAE) caged by a radiation-responsive phenyl azide, and we interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using the fibroblast activation protein inhibitor (FAPI) agents [99mTc]Tc-FAPI-34 and [177Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [177Lu]Lu-PSMA-617, combined with caged MMAE or caged exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. Results: RAiDER efficiency varied by 70-fold across radionuclides (99mTc > 111In > 177Lu > 64Cu > 32P > 68Ga > 223Ra > 18F), yielding up to 320 nM prodrug activation/Gy of exposure from 99mTc. Computational simulations implicated low-energy electron-mediated free radical formation as driving prodrug activation. Radionuclide-activated caged MMAE restored the prodrug's ability to destabilize microtubules and increased its cytotoxicity by up to 2,600-fold that of the nonactivated prodrug. Mice treated with [99mTc]Tc-FAPI-34 and caged MMAE accumulated concentrations of activated MMAE that were up to 3,000 times greater in tumors than in other tissues. RAiDER with [99mTc]Tc-FAPI-34 or [177Lu]Lu-FAPI-04 delayed tumor growth, whereas monotherapies did not (P < 0.003). Clinically guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. Conclusion: This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and can potentially improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biologic and therapeutic responses.

Co-Delivery of Dacarbazine and miRNA 34a Combinations to Synergistically Improve Malignant Melanoma Treatments.

The incidence of malignant melanoma (MM) has risen over the past three decades, and despite advancements in treatment, there is still a need to improve treatment modalities. This study developed a promising strategy for tumor-targeted co-delivery of Dacarbazine (DTIC) and miRNA 34a-loaded PHRD micelles (Co-PHRD) for combination treatment of MM. To construct the dual drug-loaded delivery system Co-PHRD, poly (L-arginine)-poly (L-histidine)-polylactic acid (PLA) was employed as a building block. In this system, poly (L-arginine) and PLA function as hydrophilic and hydrophobic blocks, respectively, which self-assemble into micelles in aqueous solution. Poly(L-arginine) and poly(L-histidine) are efficiently taken up by cells and perform efficient gene condensation, which facilitate the release of encapsulated miRNA 34a into the cytoplasm. Due to its lipophilic properties, PLA can effectively encapsulate DTIC. The polypeptide aptamer DR5-TAT (D21) was used as a targeting ligand. The properties of Co-PHRD and its in vitro release behaviour were characterized. Additionally, the synergetic effects of DTIC and miRNA 34a in melanoma therapy were investigated in vitro and in vivo. Compared to DTIC treatment alone, Co-PHRD treatment exhibited 1.84-fold greater cytotoxicity in A375 cells, demonstrating that miRNA 34a enhanced the efficacy of DTIC. The particle size of Co-PHRD at an N/P ratio of 10 was 164.1 ± 4.5 nm, and the zeta potential of Co-PHRD was 27.3 ± 1.38 mV. The flow cytometry and CLSM results revealed both DTIC and miRNA 34a were avidly taken up by A375 cells at 1h and 4h in PHRD. In addition, in vivo results indicated that Co-PHRD micelles can significantly inhibit tumor growth without causing significant damage to major organs. Co-delivery of DTIC and miRNA 34a via polypeptide micelles showed synergistic effects against MM, offering a new strategy for gene and chemotherapy.

A subtype specific probe for targeted magnetic resonance imaging of M2 tumor-associated macrophages in brain tumors.

Pro-tumoral M2 tumor-associated macrophages (TAMs) play a critical role in the tumor immune microenvironment (TIME), making them an important therapeutic target for cancer treatment. Approaches for imaging and monitoring M2 TAMs, as well as tracking their changes in response to tumor progression or treatment are highly sought-after but remain underdeveloped. Here, we report an M2-targeted magnetic resonance imaging (MRI) probe based on sub-5 nm ultrafine iron oxide nanoparticles (uIONP), featuring an anti-biofouling coating to prevent non-specific macrophage uptake and an M2-specific peptide ligand (M2pep) for active targeting of M2 TAMs. The targeting specificity of M2pep-uIONP was validated in vitro, using M0, M1, and M2 macrophages, and in vivo, using an orthotopic patient-tissue-derived xenograft (PDX) mouse model of glioblastoma (GBM). MRI of the mice revealed hypointense contrast in T2-weighted images of intracranial tumors 24 h after receiving intravenous (i.v.) injection of M2pep-uIONP. In contrast, no noticeable contrast change was observed in mice receiving scrambled-sequence M2pep-conjugated uIONP (scM2pep-uIONP) or the commercially available iron oxide nanoparticle formulation, Ferumoxytol. Measurement of nanoparticle-induced T2 value changes in tumors showed 38 %, 9 %, and 2 % decrease for M2pep-uIONP, scM2pep-uIONP, and Ferumoxytol, respectively. Moreover, M2pep-uIONP exhibited 88.7-fold higher intra-tumoral accumulation compared to co-injected Ferumoxytol at 24 h post-injection. Immunofluorescence-stained tumor sections showed that CD68+/CD163+ M2 TAMs were highly co-localized with Cy7-M2pep-uIONP, but not with Cy7-scM2pep-uIONP and Cy7-Ferumoxytol. Flow cytometry analysis revealed 26 ± 10 % of M2 TAMs were targeted by M2pep-uIONP, which was significantly higher than Ferumoxytol (16 ± 1 %) and scM2pep-uIONP (13 ± 4 %) with the same dosage (20 mg Fe/kg). These findings demonstrate that M2pep-uIONP functions as a ligand-mediated MRI probe for targeted imaging of M2 TAMs in GBM, with potential applications for imaging of M2 TAM in other cancer types. STATEMENT OF SIGNIFICANCE: Targeting the pro-tumoral M2 subtype of tumor-associated macrophages (TAMs) to modulate the tumor immune microenvironment (TIME) is an emerging strategy for developing novel cancer therapies and enhancing the efficacy of existing treatments. In this study, we have developed a magnetic resonance imaging (MRI) probe using sub-5 nm ultrafine iron oxide nanoparticles (uIONP), which are coated with an anti-biofouling polymer and conjugated to an M2-specific peptide ligand (M2pep). Our results demonstrate that M2pep-uIONP exhibits an 88.7-fold higher accumulation in intracranial tumors in an orthotopic patient-derived xenograft (PDX) model of glioblastoma compared to the commercial iron oxide nanoparticle, Ferumoxytol. This enhanced accumulation enables M2pep-uIONP to induce significant MRI contrast, providing a non-invasive imaging tool to visualize M2 TAMs and monitor changes in the TIME of brain tumors and potentially other cancers.

Multiarm-Assisted Design of Dendron-like Degradable Ionizable Lipids Facilitates Systemic mRNA Delivery to the Spleen.

Lipid nanoparticles (LNPs) have emerged as pivotal vehicles for messenger RNA (mRNA) delivery to hepatocytes upon systemic administration and to antigen-presenting cells following intramuscular injection. However, achieving systemic mRNA delivery to non-hepatocytes remains challenging without the incorporation of targeting ligands such as antibodies, peptides, or small molecules. Inspired by comb-like polymeric architecture, here we utilized a multiarm-assisted design to construct a library of 270 dendron-like degradable ionizable lipids by altering the structures of amine heads and multiarmed tails for optimal mRNA delivery. Following in vitro high-throughput screening, a series of top-dendron-like LNPs with high transfection efficacy were identified. These dendron-like ionizable lipids facilitated greater mRNA delivery to the spleen in vivo compared to ionizable lipid analogs lacking dendron-like structure. Proteomic analysis of corona-LNP pellets showed enhancement of key protein clusters, suggesting potential endogenous targeting to the spleen. A lead dendron-like LNP formulation, 18-2-9b2, was further used to encapsulate Cre mRNA and demonstrated excellent genome modification in splenic macrophages, outperforming a spleen-tropic MC3/18PA LNP in the Ai14 mice model. Moreover, 18-2-9b2 LNP encapsulating therapeutic BTB domain and CNC homologue 1 (BACH1) mRNA exhibited proficient BACH1 expression and subsequent Spic downregulation in splenic red pulp macrophages (RPM) in a Spic-GFP transgene model upon intravenous administration. These results underscore the potential of dendron-like LNPs to facilitatem RNA delivery to splenic macrophages, potentially opening avenues for a range of mRNA-LNP therapeutic applications, including regenerative medicine, protein replacement, and gene editing therapies.

Tumor Microenvironment Responsive Key Nanomicelles for Effective Against Invasion and Metastasis in Ovarian Cancer Using Mice Model.

Ovarian cancer is difficult to detect in its early stages, and it has a high potential for invasion and metastasis, along with a high rate of recurrence. These factors contribute to the poor prognosis and reduced survival times for patients with this disease. The effectiveness of conventional chemoradiotherapy remains limited. Nano-particles, as a novel drug delivery system, have significant potential for improving therapeutic efficacy and overcoming these challenges. According to the high expression level of matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, MMP-2 responsive nano-particles (PVGLIG-MTX-D/T-NMs) containing docetaxel and triptolide were prepared by the thin-film dispersion method. The synergistic effect between docetaxel and triptolide was systematically investigated, the ratio of the two drugs was optimized, and the physicochemical properties of the nano-particles and their ability to inhibit ovarian cancer cell growth and metastasis were evaluated in vitro and in vivo. PVGLIG-MTX-D/T-NMs enhanced the targeting, stability, and bioavailability of the drug, while reducing the dose and toxicity. In addition, by regulating the expression levels of E-Cadherin, N-Cadherin, matrix metalloproteinases (MMPs), hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF), it exhibited an inhibitory effect on epithelial-mesenchymal transformation (EMT) and tumor cell angiogenesis, and effectively inhibited the invasion and metastasis of ovarian cancer cells. PVGLIG-MTX-D/T-NMs achieved passive targeting of tumor sites by enhancing permeability and retention (EPR) effects. Subsequently, the uptake of the drug by tumor cells was enhanced by MMP-2 responsiveness and the modification of methotrexate targeting ligands. By regulating the expression levels of invasion- and metastasis-related proteins in tumor tissues, the nano-particles affected the EMT process, inhibited tumor angiogenesis, and suppressed the malignant potential of invasion and metastasis in ovarian cancer. These findings provided a new direction for further exploration of tumor-targeted therapy.

Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (&gt;90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment.

Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

A Three-In-One Heptamethine Cyanine Dye Induces Endoplasmic Reticulum Stress and Apoptosis in Colorectal Cancer.

One of the most significant challenges for image-guided cancer-targeted therapy is to develop multifunctional optical contrast agents enabling simultaneous targeting and therapy. Herein, a feasible strategy is based on the incorporation of therapeutic moieties into the non-delocalized structure of polymethine indocyanines, known as the "structure-inherent targeting" concept. By possessing a rigid chloro-cyclohexenyl ring in the heptamethine cyanine backbone, a new type of multifunctional near-infrared fluorescent dye, Ph790H, that targets tumor without the need for additional targeting ligands is synthesized. Armed with a phthalimide pharmacophore holding a prominent position in medicinal chemistry, Ph790H simultaneously induces endoplasmic reticulum (ER) stress to exert targeted therapeutic effects on HT-29 colorectal cancer xenografts. In terms of molecular mechanism, the lipophilic cationic Ph790H can be actively internalized into HT-29 cells through clathrin-mediated endocytosis. Consequently, mitochondrial reactive oxygen species (ROS) overproduction further induces activation of ER stress, demonstrated by increased ROS concentration and decreased mitochondrial membrane potential, which contributes to cell apoptosis and inhibition of tumor growth. Overall, Ph790H represents an effective "three-in-one" agent for the integration of cancer targeting, imaging, and therapy, which may provide a practical strategy to develop multifunctional small molecule theranostic agents for simultaneous cancer diagnosis and therapy.

Polymer-Based Nanoparticles as Efficient Non-Viral Vectors for Gene Delivery in CAR-T Cell Therapy

Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a revolutionary method in cancer immunotherapy, achieving notable success in treating hematological malignancies. However, its effectiveness in solid tumors is limited, and the therapy faces challenges such as severe toxicities and high production costs. Polymer-based nanoparticles (PNPs) are gaining attention as a non-viral gene delivery system that can help address these issues, providing greater safety, scalability, and cost-effectiveness compared to viral vectors. This mini-review delves into various types of PNPs, including cationic, biodegradable, and stimuli-responsive polymers, showcasing their mechanisms for cellular uptake and sustained gene expression in CAR-T cells. Innovations like lipid-polymer hybrid nanoparticles and combination therapies improve gene delivery efficiency and therapeutic outcomes. Despite progress, challenges, including toxicity and immunogenicity, remain, prompting strategies such as surface modifications and targeting ligands. Recent advancements illustrate the potential of hybrid nanoparticles in enhancing CAR-T therapies, particularly for solid tumors, highlighting their critical role in cancer immunotherapy advancements.

Conversion of Chemical Drugs into Targeting Ligands on RNA Nanoparticles and Assessing Payload Stoichiometry for Optimal Biodistribution in Cancer Treatment

Active targeting-mediated nanodelivery takes advantages of ligand-receptor specificity to avoid non-specific distribution, holding great promise for the treatment of a spectrum of diseases. RNA nanoparticles have demonstrated rapid spontaneous tumor targeting and very little organ accumulation due to rapid renal clearance of non-tumor accumulated RNA nanoparticles. However available ligands for specific cells are limited, yet many chemical entities possess receptor targeting capability and remains unexplored. To provide specific tumor accumulation, a multivalent targeting strategy on RNA nanoparticles to control their in vivo fate is implemented. Methotrexate (MTX), a clinically approved chemotherapy was used as a tumor-targeting ligand through conjugation to our RNA nanoparticle with controlled conjugation of various copy numbers. As copies of conjugated MTX increased on the nanoparticle, the specific binding to overexpressed folate receptor was enhanced as demonstrated by flow cytometry analysis and confocal microscopy imaging. Increasing the amounts of conjugated MTX did not significantly change the nanoparticle size, Zeta potential, or cytokine induction. Increased amounts of conjugated MTX resulted in improved cell inhibition due to MTX release following cell internalization. However, increasing conjugated MTX to the RNA nanoparticles reduced the melting temperature of RNA nanoparticles and increased in vitro serum protein binding to the nanoparticles. Thus, in vivo biodistribution profiles of RNA nanoparticles revealed different behaviors based on MTX conjugation in cancer targeting and clearance. Increased copies of MTX changed the ability of nanoparticles to target tumors, accumulate in healthy organs, and rapidly clear through the urine. Nanoparticle design must be closely considered for optimized cancer targeting and therapy, providing the rationale for a proper design of RNA nanodelivery in cancer treatment.