Tumor Targeting Efficiency Research Articles

FeS2@COF based nanocarrier for photothermal-enhanced chemodynamic/thermodynamic tumor therapy and immunotherapy via reprograming tumor-associated macrophages.

Developing high-performance nanomedicines to enhance antitumor efficacy remains a hot point in the field of biomedicine. In this study, we designed a versatile nanocomposite (FeS₂@COF-HA/AIPH) integrating covalent organic frameworks (COF) functionalized with pyrite (FeS₂) for synergistic photothermal (PTT), chemodynamic (CDT), thermodynamic (TDT) therapies, and immunotherapy. The superior photothermal effects and catalytic capabilities of FeS₂@COF enabled a minimally invasive PTT/CDT combination. The nanoplatform, with its mesoporous structure, also served as a drug delivery system, encapsulating the thermos-decomposable initiator AIPH. The hyaluronic acid (HA) coating not only improved tumor-targeting efficiency but also prevented nonspecific AIPH release. Under near-infrared (NIR) irradiation, the localized hyperthermia triggered AIPH decomposition, generating toxic alkyl radicals (•R) for TDT, further enhancing CDT efficiency. The combination of PTT, CDT, TDT, and immunotherapy led to potent antitumor effects with minimal systemic toxicity, both in vitro and in vivo. Notably, the nanoplatform effectively reprogrammed tumor-associated macrophages (TAMs) from an M2 to M1 phenotype, boosting antitumor immunity. This multifunctional platform thus offers a promising strategy for integrated PTT, CDT, TDT, and immune activation in tumor therapy.

Simple theranostics nanoagent for precision suppression of tumor growth and metastasis: A traditional fermented product having a novel functional breakthrough

Biomass-based nanoagents constitute a focal point in the clinical development of tumor nanotheranostics, characterized by their high biocompatibility, biodegradability, controllability, and sustainability. However, achieving satisfactory nanoagents with biological safety and high theranostic efficacy for clinical translation remains a significant challenge. Herein, based on the design concept of medicine food homology, we developed a simple, mass-produced theranostics nanoagent (HSAVMn@CM NA) using Shanxi aged vinegar (SAV) as the raw material, enabling second near-infrared fluorescence/photoacoustic (NIR-II FL/PA) imaging-guided photo/catalytic/chemodynamic synergistic tumor therapy. A novel strategy involving the hydrolysis of SAV (HSAV) via the hydrolysis-acidification method has been developed to enhance NIR-II FL imaging performance. The HSAVMn@CM NAs have improved tumor-targeted efficiency through biomimetic modification of tumor membranes. Guided by NIR-II FL/PA dual-modal imaging, the HSAVMn@CM NAs achieve targeted photothermal/photodynamic synergistic phototherapy. Notably, the employment of a single laser source for simultaneous photothermal/photodynamic therapy has led to an enhancement in the efficacy of phototherapy. Moreover, the HSAVMn@CM NAs effectively chelated Zn2+ ions within the tumor microenvironment, to inhibit matrix metalloproteinase 2/9 (MMP 2/9) activity, thereby synergistically suppressing primary tumor growth and metastasis. Taken together, this research provides a novel design strategy for biomass-based nanoagents with potential clinical translation in precise tumor theranostics.

Dual-drug loaded manganese dioxide nanoparticles coated with bacterial outer-membrane vesicles for chemo-immunotherapy in lung cancer

Lung cancer is the most leading cause of cancer death. Traditional chemotherapy has unavoidable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. Nanocarriers can achieve accurate delivery and reduce adverse reactions of drugs, which have received extensive attention. In this work, hollow manganese dioxide (HMnO2) nanoparticle (NP) that is highly responsive to tumor microenvironment, was simultaneously loaded with paclitaxel (PTX), a chemotherapy drug, and imiquimod (R837), a toll-like receptor 7 agonist. Those NPs were then coated with bacterial outer-membrane vesicles (OMVs-HMnO2@PTX + R837 NPs), whose surface proteins could act as tumor-specific antigens. The obtained nanovaccine inherited superior tumor-targeting capacity of OMVs and promoted retention in tumors. As a result, intravenous injection of the nanovaccine led to remarkable tumor growth inhibition. Furthermore, we found that the nanovaccine effectively boosted dendritic cells maturation and increased cytotoxic T lymphocytes infiltration. Taken together, these results demonstrated the great potential in applying OMVs-enveloped nano-activator in cancer chemo-immunotherapy.

Cancer cell membrane-camouflaged curcumin nanoparticles trigger ferroptosis for accurate gastric cancer therapy

Curcumin (CUR) is a hydrophobic polyphenol with considerable antitumor efficiency, but its clinical application is limited because of its poor solubility and low stability in aqueous solution and lack of targeting in vivo. Herein, we fabricated a tumor-targeting drug delivery system by loading CUR and cloaking homologous cancer cell membrane (CM) onto mesoporous silica NPs (MSN-CUR@CM). Characterization analysis showed that MSN-CUR@CM with a size of approximately 70 nm showed high water solubility and biocompatibility. Besides, MSN-CUR@CM exhibited tumor-targeting and excellent anti-gastric cancer efficiency both in vitro and in vivo owing to the cellular self-recognition of CM. In the established xenograft tumor nude mouse model, it was still significantly drug accumulated at the tumor site 72 h post administration. In addition, the mean tumor volume and weight of the MSN-CUR@CM group were was 3.97 and 7.47 times smaller than those of the CUR group. Ferroptosis, a type of non-apoptotic regulated cell death accompanied by iron-dependent lipid peroxidation, was triggered by MSN-CUR@CM. Further analysis demonstrated that MSN-CUR@CUR upregulated heme oxygenase (HO)-1 levels whereas it downregulated the expression of glutathione peroxidase 4 (GPX4) in SGC7901 cells in vitro, indicating that the canonical and noncanonical ferroptosis pathways were regulated by MSN-CUR@CM. In conclusion, our study demonstrated that MSN-CUR@CM with high water solubility, biocompatibility, and tumor-targeting properties inhibited gastric cancer both in vitro and in vivo by triggering ferroptosis and provided an admirable cancer therapy efficacy.

Technetium-99m radiolabeling of graphene quantum dots (GQDs) as a new probe for glioblastoma tumor imaging

Purpose Cancer diagnosis involves a multi-step process. Accurate identification of the tumor, staging and development of cancer cells is crucial for selecting optimal treatments to minimize disease recurrence. Quantum dots (QDs) represent an exciting class of fluorescent nanoprobes in molecular detection and targeted tumor imaging. Materials and methods In this study, graphene quantum dots (GQDs) were synthesized by pyrolysis of citric acid (CA) as a carbon precursor under high temperatures. The morphology of the obtained GQDs was first characterized using physical (TEM and DLS) and spectroscopic (fluorescence, FTIR and UV–Vis) methods. In the following,99mTc-labeled GQDs were prepared in the presence of SnCl2.2H2O as a reducing agent between 95 and 100 °C. The biodistribution and tumor targeting efficiency of radiolabeled GQDs as a novel agent for C6 glioma tumor scintigraphy in an animal model were evaluated. Furthermore, organ uptake, human serum albumin binding and tumor accumulation were measured. Results The TEM image of the prepared GQDs showed a relatively uniform size distribution in the range of diameter 6-9 nm and spherical shape. Radiolabeled GQDs showed a radiochemical yield of >97% (n = 3). Through incubation in human serum, almost 15% of 99mTc-labeled GQDs degraded after 6 h. The amount of uptake in xenograft models of glioma C6 rats was 1.10 ± 0.36% of injection dose per gram after 1 h. The kidneys, intestinal and glioma tumor sites were observed via scintigraphy imaging. Conclusion Our data suggest that 99mTc-labeled GQDs, as a new radiotracer, efficiently accumulate in the tumor site and could be included as a radiotracer for detecting glioma tumors.

Platinum Group Metals Nanoparticles in Breast Cancer Therapy.

Despite various methods currently used in cancer therapy, breast cancer remains the leading cause of morbidity and mortality worldwide. Current therapeutics face limitations such as multidrug resistance, drug toxicity and off-target effects, poor drug bioavailability and biocompatibility, and inefficient drug delivery. Nanotechnology has emerged as a promising approach to cancer diagnosis, imaging, and therapy. Several preclinical studies have demonstrated that compounds and nanoparticles formulated from platinum group metals (PGMs) effectively treat breast cancer. PGMs are chemically stable, easy to functionalise, versatile, and tunable. They can target hypoxic microenvironments, catalyse the production of reactive oxygen species, and offer the potential for combination therapy. PGM nanoparticles can be incorporated with anticancer drugs to improve efficacy and can be attached to targeting moieties to enhance tumour-targeting efficiency. This review focuses on the therapeutic outcomes of platinum group metal nanoparticles (PGMNs) against various breast cancer cells and briefly discusses clinical trials of these nanoparticles in breast cancer treatment. It further illustrates the potential applications of PGMNs in breast cancer and presents opportunities for future PGM-based nanomaterial applications in combatting breast cancer.

A novel tetrahedral framework nucleic acid-derived chemodynamic therapy agent for effective glioblastoma treatment.

Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood-brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H2O2 within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs-ANG-3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs-ANG-3AT was constructed by anchoring iron ions (Fe3+) onto the dual appendages-modified tFNAs. Specifically, one appendage, Angiopep-2 (ANG, a penetrating peptide), facilitates Fe@tFNAs-ANG-3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3-Amino-1,2,4-triazole (3AT, a H2O2 enzyme inhibitor), augments the H2O2 levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe3+ in Fe@tFNAs-ANG-3AT is reduced to Fe2+ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (·OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs-ANG-3AT holds promise as a transformative treatment strategy for GBM.

EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment

BackgroundBetulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME.MethodsAfter the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models.ResultsWe found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model.ConclusionsEnhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.Graphical abstract

Enhancing photodynamic and radionuclide therapy by small interfering RNA (siRNA)-RAD51 transfection via self-emulsifying delivery systems (SNEDDS)

Background aimsGene-silencing by small interfering RNA (siRNA) is an attractive therapy to regulate cancer death, tumor recurrence or metastasis. Because siRNAs are easily degraded, it is necessary to develop transport and delivery systems to achieve efficient tumor targeting. Self-nanoemulsifying systems (SNEDDS) have been successfully used for pDNA transport and delivery, so they may be useful for siRNA. The aim of this work is to introduce siRNA-RAD51 into a SNEDDS prepared with Phospholipon-90G, Labrafil-M1944-CS and Cremophor-RH40 and evaluate its efficacy in preventing homologous recombination of DNA double-strand breaks caused by photodynamic therapy (PDT) and ionizing radiation (IR). MethodsThe siRNA-RAD51 was loaded into SNEDDS using chitosan. Transfection capacity was estimated by comparison with Lipofectamine-2000. ResultsSNEDDS(siRNA-RAD51) induced gene silencing effect on the therapies evaluated by cell viability and clonogenic assays using T47D breast cancer cells. ConclusionsSNEDDS(siRNA-RAD51) shown to be an effective siRNA-delivery system to decrease cellular resistance in PDT or IR.

IRGD-Guided Silica/Gold Nanoparticles for Efficient Tumor-Targeting and Enhancing Antitumor Efficacy Against Breast Cancer.

Breast cancer presents significant challenges due to the limited effectiveness of available treatments and the high likelihood of recurrence. iRGD possesses both RGD sequence and C-terminal sequence and has dual functions of targeting and membrane penetration. iRGD-modified nanocarriers can enhance drug targeting of tumor vascular endothelial cells and penetration of new microvessels, increasing drug concentration in tumor tissues. The amidation reaction was carried out between SiO2/AuNCs and iRGD/PTX, yielding a conjugated drug delivery system (SiO2/AuNCs-iRGD/PTX, SAIP@NPs). The assessment encompassed the characterization of the morphology, particle size distribution, physicochemical properties, in vitro release profile, cytotoxicity, and cellular uptake of SAIP@NPs. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed using a small animal in vivo imaging system and a tumor-bearing nude mice model, respectively. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed utilizing a small animal in vivo imaging system and an in situ nude mice breast cancer xenograft model, respectively. The prepared SAIP@NPs exhibited decent stability and a certain slow-release effect in phosphate buffer (PBS, pH 7.4). In vitro studies had shown that, due to the dual functions of transmembrane and targeting of iRGD peptide, SAIP@NPs exhibited strong binding to integrin αvβ3, which was highly expressed on the membrane of MDA-MB-231 cells, improving the uptake capacity of tumor cells, inhibiting the rapid growth of tumor cells, and promoting tumor cell apoptosis. The results of animal experiments further proved that SAIP@NPs had longer residence time in tumor sites, stronger anti-tumor effect, and no obvious toxicity to major organs of experimental animals. The engineered SAIP@NPs exhibited superior functionalities including efficient membrane permeability, precise tumor targeting, and imaging, thereby significantly augmenting the therapeutic efficacy against breast cancer with a favorable safety profile.

DNA nanomachine‐driven chemodynamic therapy against glioblastoma

AbstractChemodynamic therapy (CDT) has shown promising antitumor effects in various malignant tumors. However, its application for glioblastoma (GBM) is significantly hindered by the challenge of delivering CDT agents across the blood‐brain barrier (BBB) and achieving efficient tumor targeting. To overcome these obstacles, this study presents a novel DNA nanomachine (Cu@tFNAs‐G‐A NM) by loading copper ions (Cu2+) onto tetrahedral framework nucleic acids (tFNAs) functionalized with dual DNA aptamers. The dual DNA aptamers (GS24 for BBB penetration and AS1411 for tumor targeting) empowered Cu@tFNAs‐G‐A NM with the ability to effectively penetrate the BBB and selectively accumulate in tumor cells. Upon internalization, the loaded Cu2+ reacted with tumor‐overexpressed reductive glutathione (GSH) and hydrogen peroxide (H2O2), generating hydroxyl radicals (·OH) and inducing tumor cell death. Additionally, Cu@tFNAs‐G‐A NM was found to be rapidly cleared from the brain and normal tissues within 24 h, minimizing potential systemic toxic side effects. These findings demonstrate the promising potential of Cu@tFNAs‐G‐A NM for effective CDT against GBM and open up new avenues for the development of targeted therapies for GBM.

Red blood cell derived nanocarrier drug delivery system: A promising strategy for tumor therapy

AbstractNano drug delivery systems have been widely used in tumor therapy. Researchers have been devoted to exploring novel nano‐carriers to prolong circulation time biocompatibility and tumor targeting efficiency in vivo. Erythrocyte membranes as bionic nano‐drug delivery systems have attracted more attention recently. There are abundant red blood cells (RBCs) in circulation, which are natural carriers for nanomaterial delivery. There are mainly two strategies to use RBCs as nanomaterial carriers: RBC‐hitchhiking and bionic nanomaterial coated with erythrocyte membrane loading with drugs. Although nano‐carrier based on RBCs have yielded some progress, the mechanism of mutual effect between nanoparticles and RBCs is still unclear. Here, we review the effects of nanoparticles on RBCs (morphology and function, etc) and application of RBCs membrane as nano‐drug delivery carriers in tumor therapy.

Hybrid nanopotentiators with dual cascade amplification for glioma combined interventional therapy

Glioma is an aggressive malignant brain tumor with a very poor prognosis for survival. The poor tumor targeting efficiency and tumor microenvironment penetration barrier also as troubles inhibited the effective glioma chemotherapy. Here, we design a core-shell structure cascade amplified hybrid catalytic nanopotentiators CFpAD with DM1 encapsulated to overcome the glioma therapeutic obstacles. NIR laser-based BBB penetrating enhances the tumor accumulation of CFpAD. When CFpAD, as the cascade amplified drug, is treated on the cancer cells, the bomb-like CFpAD releases gold nanoparticles as glucose oxidase (GOx) and ferric oxide nanoparticles (FNPs) as peroxides (POx) after blasting, producing ROS via a cascade amplification for tumor cell apoptosis. Gold nanoparticles can rest CAFs and reduce ECM secretion, achieving deep penetration of CFpAD. Moreover, CFpAD also cuts off the nutritional supply of the tumor, reduces the pH value, and releases free radicals to destroy the cancer. The glioma cell viability was significantly decreased through DNA damage and ROS aggregation due to the DM1-based chemotherapy synergistically combined with interventional photothermal therapy (IPTT) and radiotherapy (RT). This domino cascade amplified loop, combined with starvation therapy with IPTT and RT, has good tumor penetration and outstanding antitumor efficacy, and is a promising glioma treatment system.

Black Phosphorus Quantum Dot Loaded Bioinspired Nanoplatform Synergized with aPD-L1 for Multimode Cancer Immunotherapy.

Efforts to prolong the blood circulation time and bypass immune clearance play vital roles in improving the therapeutic efficacy of nanoparticles (NPs). Herein, a multifunctional nanoplatform (BPP@RTL) that precisely targets tumor cells is fabricated by encapsulating ultrasmall phototherapeutic agent black phosphorus quantum dot (BPQD), chemotherapeutic drug paclitaxel (PTX), and immunomodulator PolyMetformin (PM) in hybrid membrane-camouflaged liposomes. Specifically, the hybrid cell membrane coating derived from the fusion of cancer cell membrane and red blood cell membrane displays excellent tumor targeting efficiency and long blood circulation property due to the innate features of both membranes. After collaboration with aPD-L1-based immune checkpoint blockade therapy, a boosted immunotherapeutic effect is obtained due to elevated dendritic cell maturation and T cell activation. Significantly, laser-irradiated BPP@RTL combined with aPD-L1 effectively eliminates primary tumors and inhibits lung metastasis in 4T1 breast tumor model, offering a promising treatment plan to develop personalized antitumor strategy.

As1411-modified liposomes to enhance drug utilization and augment the anti-tumor efficacy

BackgroundThe utilization of liposomes in drug delivery has garnered significant attention due to their efficient drug loading capacity and excellent biocompatibility, rendering them a promising platform for tumor therapy. However, the average size of liposomes ~ 100 nm leads to liposomes being susceptible to hepatic and renal metabolism to excretion outside the body leading to poor drug delivery efficiency with a total utilization rate of less than 0.7%, resulting in unfavorable treatment outcomes.ResultsWe have developed a novel liposome platform equipped with tumor surface nucleolin-targeting capacity to enhance drug accumulation at the tumor in vivo. The encapsulation of doxorubicin through thin film hydration has resulted in the formation of D@L-AS1411. Through in vivo experiments, we have demonstrated the effective accumulation of D@L-AS1411 at the tumor site and its ability to improve doxorubicin utilization rates by 40%. Additionally, D@L-AS1411 induces immunogenic death of tumor cells, release of tumor-associated antigens, upregulation of calreticulin expression, and recruitment of active T cell infiltration, and ultimately improves the therapeutic efficacy against tumors (70%).ConclusionsBased on the nucleic acid aptamer AS1411, D@L-1411 is developed to specifically enhance the accumulation of Dox at tumor sites, thereby inhibiting and enhancing the anti-tumor effect. In summary, this study not only provides an efficient tumor-targeting delivery platform but also contributes to the improvement of chemotherapy–immunotherapy combination for tumor treatment strategy in the clinic.

Shorter Peptide Nucleic Acid Probes Improve Affibody-Mediated Peptide Nucleic Acid-Based Pretargeting.

Affibody-mediated PNA-based pretargeting shows promise for HER2-expressing tumor radiotherapy. In our recent study, a 15-mer ZHER2:342-HP15 affibody-PNA conjugate, in combination with a shorter 9-mer [177Lu]Lu-HP16 effector probe, emerged as the most effective pretargeting strategy. It offered a superior tumor-to-kidney uptake ratio and more efficient tumor targeting compared to longer radiolabeled effector probes containing 12 or 15 complementary PNA bases. To enhance the production efficiency of our pretargeting system, we here introduce even shorter 6-, 7-, and 8-mer secondary probes, designated as HP19, HP21, and HP20, respectively. We also explore the replacement of the original 15-mer Z-HP15 primary probe with shorter 12-mer Z-HP12 and 9-mer Z-HP9 alternatives. This extended panel of shorter PNA-based probes was synthesized using automated microwave-assisted methods and biophysically screened in vitro to identify shorter probe combinations with the most effective binding properties. In a mouse xenograft model, we evaluated the biodistribution of these probes, comparing them to the Z-HP15:[177Lu]Lu-HP16 combination. Tumor-to-kidney ratios at 4 and 144 h postinjection of the secondary probe showed no significant differences among the Z-HP9:[177Lu]Lu-HP16, Z-HP9:[177Lu]Lu-HP20, and the Z-HP15:[177Lu]Lu-HP16 pairs. Importantly, tumor uptake significantly exceeded, by several hundred-fold, that of most normal tissues, with kidney uptake being the critical organ for radiation therapy. This suggests that using a shorter 9-mer primary probe, Z-HP9, in combination with 9-mer HP16 or 8-mer HP20 secondary probes effectively targets tumors while minimizing the dose-limiting kidney uptake of radionuclide. In conclusion, the Z-HP9:HP16 and Z-HP9:HP20 probe combinations offer good prospects for both cost-effective production and efficient in vivo pretargeting of HER2-expressing tumors.

Theranostic Bottle-Brush Polymers Tailored for Universal Solid-Tumor Targeting.

Designing an efficient nanocarrier to target multiple types of cancer remains a major challenge in the development of cancer nanomedicines. The majority of systemically administered nanoparticles (NPs) are rapidly cleared by the liver, resulting in poor tumor-targeting efficiency and severe side effects. Here, we present a delicately tailored design and synthesis of fluorescent bottle-brush polymers and screen nine derived NPs, each varying in size and surface coatings, for tumor imaging and targeted delivery. Our optimized polymer bearing (oligo(ethylene glycol) methyl ether methacrylate) in the side chains shows reduced macrophage uptake, prolonged blood-circulation time (up to 27 h), and exceptionally high accumulation in the tumor compared to the liver, elucidating an immune-evasion-induced tumor-targeting mechanism. High tumor accumulation significantly improved the antitumor efficacy. The outstanding tumor-targeting ability has been further validated across five distinct tumor models, including orthotopic glioblastoma and pancreatic cancer, which demonstrate the universality of our polymeric nanocarrier for tumor-targeting delivery.

Influence of Molecular Design on the Tumor Targeting and Biodistribution of PSMA-Binding Tracers Labeled with Technetium-99m.

Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE3 chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand's total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [99mTc]Tc-BQ0411 and [99mTc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [99mTc]Tc-BQ0411 was 1.6-fold higher compared to [99mTc]Tc-BQ0412 and [99mTc]Tc-BQ0413. [99mTc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [99mTc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed.

Abstract 4491: Development of IRE-1 inhibitors for B cell cancer therapy

Abstract In response to the endoplasmic reticulum (ER) stress, the IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor. XBP-1s is critically important for the growth and survival of B cell leukemia, lymphoma, and multiple myeloma. When compared with other inhibitors targeting IRE-1, the tricyclic chromenone-based inhibitors B-I09 and D-F07, prodrugs harboring an aldehyde-masking group, emerged as the very reliable inhibitors for potent suppression of the XBP-1s protein. Protection of the aldehyde as a 1,3-dioxane acetal led to strong fluorescence emitted by the coumarin chromophore, enabling both B-I09 and D-F07 to be tracked inside the cell. We installed a photolabile structural cage on the hydroxy group of D-F07 to generate PC-D-F07. Such a modification significantly stabilized the 1,3-dioxane acetal protecting group, allowing for specific stimulus-mediated control of the inhibitory activity. Upon photoactivation, the re-exposed hydroxy group triggered the aldehyde-protecting 1,3-dioxane acetal to slowly decompose, leading to the inhibition of the RNase activity of IRE-1. Since chemical modifications of the hydroxy group could be used to tune 1,3-dioxane prodrug stability, we installed reactive oxygen species (ROS)-sensitive boronate cage groups onto B-I09 (BC-B-I09) and D-F07 (BC-D-F07) to achieve stimuli-responsive activities and improve tumor-targeting efficiency based on that cancerous B cells indeed produced higher levels of ROS than normal B cells. These boronate caged compounds could be further combined with the FDA-approved Auranofin, a thioredoxin reductase inhibitor, to achieve synergistic cancer-killing effects. These results led us to further develop a novel prodrug, TC-D-F07, in which a thiol-reactive dinitrobenzenesulfonyl (Dns) cage was installed onto the hydroxy group of D-F07. The electron-withdrawing Dns group in TC-D-F07 similarly stabilized the neighboring 1,3-dioxane acetal, allowing for stimulus-mediated control of its inhibitory activity. TC-D-F07 exhibited high sensitivity to intracellular thiols produced by cancerous B cells. In addition, when TC-D-F07 was decomposed into D-F07, we observed that a dinitrophenyl cysteine adduct resulting from cleavage of the Dns group could induce the ER stress, causing cancerous B cells to increase the expression of XBP-1s. However, the accumulated levels of D-F07 from TC-D-F07 and its gradual decomposition into the active IRE-1 inhibitor could eventually deprive cancer cells of all XBP-1s, leading to more severe apoptosis in TC-D-F07-treated than in D-F07-treated cells. Thus, TC-D-F07 with both ER stress-inducing and XBP-1s-inhibiting activities represents an IRE-1-targeting caged prodrug that can be used to treat B cell cancer effectively. Citation Format: Andong Shao, Chih-Hang Anthony Tang, Juan R. Del Valle, Chih-Chi Andrew Hu. Development of IRE-1 inhibitors for B cell cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4491.

Molecular Imaging for Lung Cancer: Exploring Small Molecules, Peptides, and Beyond in Radiolabeled Diagnostics.

It is evident that radiolabeled drug delivery systems hold great promise in the field of lung cancer management. The combination of therapeutic agents with radiotracers not only allows for precise localization within lung tumors but also enables real-time monitoring of drug distribution. This approach has the potential to enhance targeted therapy and improve patient outcomes. The integration of advanced imaging modalities, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), has played a crucial role in the non-invasive tracking of radiolabeled drugs. These techniques provide valuable insights into drug pharmacokinetics, biodistribution, and tumor-targeting efficiency, offering clinicians the ability to personalize treatment regimens. The comprehensive analysis of preclinical and clinical studies presented in this review underscores the progress made in the field. The evidence suggests that radiolabeled drug delivery systems have the potential to revolutionize oncology by offering precise, targeted, and image-guided therapeutic interventions for lung cancer. This innovative approach not only enhances the effectiveness of treatment but also contributes to the development of personalized medicine strategies, tailoring interventions to the specific characteristics of each patient's cancer. The ongoing research in this area holds promise for further advancements in lung cancer management, potentially leading to improved outcomes and quality of life for patients.