Improved Tumor Targeting Research Articles

Standard requirements for clinical very high energy electron and ultra high dose rate medical devices

Very High-Energy Electrons (VHEE) present a promising innovation in radiation therapy (RT), particularly for the treatment of deep-seated tumors using Ultra High Dose Rate (UHDR) within the framework of FLASH-RT. VHEE offers significant advantages, such as improved tumor targeting, reduced treatment times, and potential utilization of the FLASH effect, which may minimize normal tissue toxicity. However, the lack of an international technical standard for VHEE systems, especially for UHDR applications, remains a critical challenge. Current standards for radiation therapy equipment, such as IEC 60601-2-1 and IEC 60601-2-64, do not encompass VHEE technology. This regulatory gap underscores the need for developing a structured international standard to ensure the basic safety and essential performance of VHEE medical devices. Addressing this challenge requires overcoming complex dose delivery issues, such as the interaction of multiple fields and beam conformality and incorporating novel techniques like broad beam or pencil beam scanning. Establishing comprehensive regulatory standards is essential to ensure patient safety, consistent treatment practices, and the successful clinical integration of VHEE systems. These standards must encompass design guidelines, radiation protection protocols, and integration with existing oncology practices. Collaborative research and development efforts are crucial to formulating evidence-based guidelines, fostering the safe and effective use of VHEE in clinical settings. By addressing these challenges, VHEE technology has the potential to revolutionize cancer therapy, particularly for deep-seated tumors, while enhancing therapeutic outcomes for patients.

Targeted Drug Delivery in Cancer Therapy

Targeted medication delivery in cancer therapy is a promising method for increasing efficacy while minimizing side effects. This technique uses NANO materials, antibodies, or LIGAND-conjugated medicines to deliver medications directly to cancer cells while limiting damage to healthy organs. Advances in nanotechnology, such as liposomes, DENDRIMERS, and NANO particles, have enabled precise tumor targeting based on specific molecular markers expressed on cancer cells. Furthermore, the emergence of stimuli-responsive drug delivery systems, which release their payload in reaction to environmental changes like pH, temperature, or certain enzymes, provides new opportunities for site-specific treatment. Clinical trials have shown improved therapeutic outcomes, such as increased medication stability, decreased systemic toxicity, and improved tumor targeting. However, issues like immune system evasion, scalability, and tumor heterogeneity remain to be solved. Further research and innovation in tailored drug delivery platforms show significant promise for transforming cancer treatment, enhancing patient quality of life, and potentially overcoming resistance to standard medicines[1].

Zinc ferrite nanoparticle with enhanced magnetic attraction for controlled drug delivery and in vivo tumor therapy

Iron oxide nanoparticles (IONPs) have been widely applied in drug delivery systems for tumor-targeting over the past decade. However, their efficacy in remote control and targeting by magnetic attraction is still limited by insufficient magnetic force. Herein, we introduce non-toxic zinc ferrite NPs (ZFNPs) with strong magnetism as enhancers for tumor-targeting. They were encapsulated in larger poly lactic-co-glycolic acid (PLGA) NPs together with the anticancer drug, SN38 resulting in ZFNP-containing magnetic NPs (ZMNPs). Upon magnetic attraction, the cellular uptake of ZMNPs increased by 15.43 times compared to treatment without a magnet. This was remarkable because the NP-encapsulating traditional IONPs (MNPs) showed only 2.47 times increase. In vivo biodistribution analysis in SCC7 tumor-bearing mice revealed that magnetic attraction enhanced the tumor accumulation of ZMNPs by 3.9 times. Furthermore, ZMNPs exhibited antitumor effects by reducing the tumor volume to 214 mm3 with magnetic attraction, whereas it was 1016.7 mm3 without it. These results demonstrate that the enhanced magnetism of ZMNPs led to improved tumor targeting, resulting in superior therapeutic outcomes compared to traditional MNPs. We expect that these small ZFNPs could be encapsulated in other types of NPs with various structures, suggesting their universal potential for enhanced tumor-targeting.

Magnetic resonance imaging-guided single-fraction preoperative radiotherapy for early-stage breast cancer (the RICE trial): feasibility study

BackgroundOver the past decade, the adoption of screening programs, digital mammography, and magnetic resonance imaging (MRI) has increased early-stage breast cancer diagnosis rates. Mortality rates have decreased due to early detection and improved treatments, including personalized therapies. Accelerated partial-breast irradiation (APBI) is emerging as a convenient and effective treatment for some patients, with studies exploring its preoperative use. Preoperative APBI, especially with MRI guidance, offers improved tumor targeting and potentially reduced side effects. Magnetic Resonance Imaging-Guided Single-Fraction Pre-Operative Radiotherapy for Early-Stage Breast Cancer (RICE trial) aims to assess the feasibility and efficacy of MRI-guided single-dose radiotherapy (RT) for early-stage breast cancer.MethodsThe RICE study is a prospective, single-arm study evaluating single-fraction preoperative, APBI treatment for patients with early-stage breast cancer using a magnetic resonance imaging linear accelerator (MRI linac). Eligible patients enrolled in this study will have a core biopsy to confirm estrogen receptor-positive and HER2-negative sub-type. RT planning will use a planning computed tomography (CT) co-registered with a MRI with the patient in either the supine or prone position. For the diagnostic workup, [18F] fluorodeoxyglucose positron emission tomography/CT ([18F] FDG PET/CT) and [18F] fluoroestradiol positron emission tomography/CT ([18F] FES PET/CT) will be performed prior to treatment. Thirty patients will receive a single ablative RT dose of 21 Gray to the tumor. Pre-treatment and post-treatment MRI scans will be acquired at baseline and 5 weeks post-RT respectively. Breast-conserving surgery will be scheduled for 6 weeks after APBI treatment using the MRI linac.The primary study endpoint is the successful administration of a single fraction of preoperative breast RT under the guidance of an MRI linac. Secondary endpoints include evaluating the utility of MRI, [18F] FDG PET/CT, and [18F] FES PET/CT as a non-invasive method for assessing treatment response in patients undergoing single-fraction preoperative APBI.ConclusionThe RICE trial represents a significant step in breast cancer treatment, offering insights that could lead to treatment protocols with minimized RT appointments and enhanced patient outcomes.Trial registrationThis trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). Registered 31st of May 2021. Registration number: ACTRN12621000659808.

An oncolytic HAdV-5 with reduced surface charge combines diminished toxicity and improved tumor targeting

Human adenovirus type 5 (HAdV-5)-based oncolytic viruses hold significant promise for anti-cancer therapy. However, poor tumor-targeting and off-target organ transduction after systemic administration limit their therapeutic efficacy. Additionally, the strong liver tropism of HAdV-5-based vectors poses the risk of hepatotoxicity. By genetic modification of the major capsid protein Hexon we generated a HAdV-5-based oncolytic vector (HAdV-5-HexPos3) with reduced negative surface charge. Coxsackie- and adenovirus receptor (CAR) binding-ablated (ΔCAR) HAdV-5-HexPos3_ΔCAR exhibited superior and CAR-independent transduction of various cancer cell lines in vitro, further enhanced in the presence of HAdV-5 naïve murine plasma. Upon intravenous administration into tumor-bearing immunodeficient NSG mice, replication-deficient HAdV-5-HexPos3_ΔCAR vector particles showed significantly reduced off-target organ tropism in all tissues analyzed, including the liver. Moreover, we detected a significantly increased intratumoral vector load for HAdV-5-HexPos3_ΔCAR, leading to a 29-fold elevated tumor-to-liver ratio compared to a control vector with unmodified Hexon. Intravenous injection of a conditionally replicating Hexon-unmodified control vector induced severe hepatotoxicity in tumor-bearing NSG mice, while a conditionally replicating HAdV-5-HexPos3_ΔCAR vector was well tolerated and resulted in intratumoral vector presence for up to 56 days. HAdV-5-HexPos3_ΔCAR represents a promising vector platform for the generation of HAdV-5-based oncolytic viruses with reduced systemic toxicity and improved therapeutic efficacy.

Enhancing chemoimmunotherapy for colorectal cancer with paclitaxel and alantolactone via CD44-Targeted nanoparticles: A STAT3 signaling pathway modulation approach

Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found to augment the anticancer efficacy of paclitaxel (P) at a molar ratio of 1:0.5 (P:A) through induction of more potent ICD via modulation of STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve tumor targeting ability and bioavailability of hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) was chemically modified with paclitaxel (PTX) and hyaluronic acid (HA) as a backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed for co-delivery of A and P in colorectal cancer treatment, aiming to achieve synergistic toxicity-based chemo-immunotherapy. The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting, providing a solid foundation for subsequent synergistic therapy and immunoregulation. In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation, thus offering a novel approach for colorectal cancer chemoimmunotherapy.

Biomimetic etoposide-loaded PLGA nanoparticles induce immunogenic cell death against colorectal cancer

Colorectal cancer (CRC) is a prevalent malignancy, ranking third in incidence among all cancers. The inherent heterogeneity and the immunosuppressive tumor microenvironment (ITME) of CRC poses significant challenges in developing effective treatment strategies. In this study, we found that etoposide (ETO) could induce immunogenic cell death (ICD) in CRC cells, highlighting its potential to activate anti-tumor immunity. To overcome the limitations of ETO's poor solubility and low bioavailability, we developed ETO-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Additionally, we employed biomimetic modification using CT26 cell-derived membranes to enhance tumor accumulation through homologous targeting and to evade macrophage phagocytosis. In vitro experiments confirmed the enhanced cytotoxicity and ICD characteristics in CT26 cells. In vivo studies further validated the improved tumor targeting, resulting in significant tumor inhibition. Notably, there was a marked increase in the proportion of CD8+T cells in tumors and lymph nodes (LNs), indicating an improved immunosuppressive microenvironment. The construction of ETO-PLGA@CM presents a promising approach for CRC treatment by synergistically activating specific anti-tumor immune responses.

Glycopolymeric Nanoparticles Enrich Less Immunogenic Protein Coronas, Reduce Mononuclear Phagocyte Clearance, and Improve Tumor Delivery Compared to PEGylated Nanoparticles.

Nanoparticles (NPs) offer significant promise as drug delivery vehicles; however, their in vivo efficacy is often hindered by the formation of a protein corona (PC), which influences key physiological responses such as blood circulation time, biodistribution, cellular uptake, and intracellular localization. Understanding NP-PC interactions is crucial for optimizing NP design for biomedical applications. Traditional approaches have utilized hydrophilic polymer coatings like polyethylene glycol (PEG) to resist protein adsorption, but glycopolymer-coated nanoparticles have emerged as potential alternatives due to their biocompatibility and ability to reduce the adsorption of highly immunogenic proteins. In this study, we synthesized and characterized glycopolymer-based poly[2-(diisopropylamino)ethyl methacrylate-b-poly(methacrylamidoglucopyranose) (PDPA-b-PMAG) NPs as an alternative to PEGylated NPs. We characterized the polymers using a range of techniques to establish their molecular weight and chemical composition. PMAG and PEG-based NPs showed equivalent physicochemical properties with sizes of ∼100 nm, spherical morphology, and neutral surface charges. We next assessed the magnitude of protein adsorption on both NPs and catalogued the identity of the adsorbed proteins using mass spectrometry-based techniques. The PMAG NPs were found to adsorb fewer proteins in vitro as well as fewer immunogenic proteins such as Immunoglobulins and Complement proteins. Flow cytometry and confocal microscopy were employed to examine cellular uptake in RAW 264.7 macrophages and MDA-MB-231 tumor cells, where PMAG NPs showed higher uptake into tumor cells over macrophages. In vivo studies in BALB/c mice with orthotopic 4T1 breast cancer xenografts showed that PMAG NPs exhibited prolonged circulation times and enhanced tumor accumulation compared to PEGylated NPs. The biodistribution analysis also revealed greater selectivity for tumor tissue over the liver for PMAG NPs. These findings highlight the potential of glycopolymeric NPs to improve tumor targeting and reduce macrophage uptake compared to PEGylated NPs, offering significant advancements in cancer nanomedicine and immunotherapy.

Strategies for Non-Covalent Attachment of Antibodies to PEGylated Nanoparticles for Targeted Drug Delivery.

Polyethylene glycol (PEG)-modified nanoparticles (NPs) often struggle with reduced effectiveness against metastasis and liquid tumors due to limited tumor cell uptake and therapeutic efficacy. To address this, actively targeted liposomes with enhanced tumor selectivity and internalization are being developed to improve uptake and treatment outcomes. Using bi-functional proteins to functionalize PEGylated NPs and enhance targeted drug delivery through non-covalent attachment methods has emerged as a promising approach. Among these, the one-step and two-step targeting strategies stand out for their simplicity, efficiency, and versatility. The one-step strategy integrates streptavidin-tagged antibodies or bispecific antibodies (bsAbs: PEG/DIG × marker) directly into PEGylated NPs. This method uses the natural interactions between antibodies and PEG for stable, specific binding, allowing the modification of biotin/Fc-binding molecules like protein A, G, or anti-Fc peptide. Simply mixing bsAbs with PEGylated NPs improves tumor targeting and internalization. The two-step strategy involves first accumulating bsAbs (PEG/biotin × tumor marker) on the tumor cell surface, triggering an initial attack via antibody-dependent and complement-dependent cytotoxicity. These bsAbs then capture PEGylated NPs, initiating a second wave of internalization and cytotoxicity. Both strategies aim to enhance the targeting capabilities of PEGylated NPs by enabling specific recognition and binding to disease-specific markers or receptors. This review provides potential pathways for accelerating clinical translation in the development of targeted nanomedicine.

Cascade catalyzed dual-responsive Gold-Ferri “bomb-like” nanoreactors for positive feedback penetrating in sequential targeted triple glioblastoma therapy

Glioblastoma (GBM) is the most common malignant primary brain tumor, with an overall median survival of less than two years after resection. The urgent goal in pre-clinical investigations is to develop effective therapeutic strategies to prolong the GBM patients’ survival and improve the poor prognosis. Although various inorganic nanoplatforms have been applied in GBM treatment, they still face obstacles such as poor brain targeting, low tumor effective penetration, and serious monotherapy resistance. Here, we designed an environmental-dependent tumor-killing nanoreactor (RFcAD) with a gold-ferri nanoagglomerates form structure that effectively inhibits GBM proliferation via catalyzing reactive oxygen species (ROS) generation, exhausting glucose, and NIR-based photothermal therapy. With iRGD decoration, RFcAD can effectively penetrate the blood–brain barrier and target GBM. The “bomb-like” structured RFcAD exhibited a glutathione (GSH)-responsive release of toxicity agent DM1 and pH-dependent nanoagglomerates degradation with gold particles and superparamagnetic iron oxide nanoparticles (SPIONS) release. Gold particles and SPIONS destroy GBM cells as chemodynamic therapy agents via exhibiting a glucose oxidase (GOx)-like and peroxide (POx)-like catalytic ability to generate cytotoxic ROS and exhaust intracellular glucose, respectively. Synergistic with DM1-based chemotherapy and NIR-induced photothermal therapy, RFcAD can significantly reduce GBM proliferation both in vitro and in vivo. This work highlights that the RFcAD nanoreactor can benefit GBM inhibition by improving tumor targeting, tissue penetration, and cytotoxicity.

Lipid Drug Conjugates in Pharmaceutical Formulations and Drug Delivery Systems

Abstract: Drugs that have been covalently altered with lipids are known as lipid-drug conjugates. Drug characteristics are altered and their lipophilicity is increased when lipids are conjugated to drug molecules. The conjugates exhibit a number of benefits, including increased oral bioavailability, improved lymphatic targeting, improved tumor targeting, and reduced cytotoxicity. Different conjugation techniques and chemical bridges can be utilized to create lipid-drug conjugates depending on the chemical makeup of medicines and lipids. For lipid-drug conjugates to function at their best, linkers and/or conjugation techniques are essential. They control how medications are released from lipid-drug conjugates. The numerous lipids utilized to make lipid-drug conjugates and the various conjugation techniques are outlined in this article. Although these conjugates can be delivered without a delivery vehicle, many of them are put into suitable delivery techniques. Drug loading into lipophilic parts of vehicles can be considerably improved by the lipid component in the conjugates, leading to combinations with significant drug content and superior stability.

Revitalizing Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer: Nanotechnology and Bioengineering Approaches.

Bacillus Calmette-Guérin (BCG) immunotherapy has been a cornerstone treatment for non-muscle-invasive bladder cancer for decades and still faces challenges, such as severe immune adverse reactions, which reduce its use as a first-line treatment. This review examines BCG therapy's history, mechanisms, and current status, highlighting how nanotechnology and bioengineering are revitalizing its application. We discuss novel nanocarrier systems aimed at enhancing BCG's efficacy while mitigating specific side effects. These approaches promise improved tumor targeting, better drug loading, and an enhanced stimulation of anti-tumor immune responses. Key strategies involve using materials such as liposomes, polymers, and magnetic particles to encapsulate BCG or functional BCG cell wall components. Additionally, co-delivering BCG with chemotherapeutics enhances drug targeting and tumor-killing effects while reducing drug toxicity, with some studies even achieving synergistic effects. While most studies remain experimental, this research direction offers hope for overcoming BCG's limitations and advancing bladder cancer immunotherapy. Further elucidation of BCG's mechanisms and rigorous safety evaluations of new delivery systems will be crucial for translating these innovations into clinical practice.

Pretheranostic agents with extraordinaryNIRF/photoacoustic imaging performanceand photothermal oncotherapy efficacy

Cervical cancer, the most common gynecological malignancy, significantly and adversely affects women's physical health and well-being. Traditional surgical interventions and chemotherapy, while potentially effective, often entail serious side effects that have led to an urgent need for novel therapeutic methods. Photothermal therapy (PTT) has emerged as a promising approach due to its ability to minimize damage to healthy tissue. Connecting a biothiol detection group to PTT-sensitive molecules can improve tumor targeting and further minimize potential side effects. In this study, we developed a near-infrared fluorescence (NIRF)/photoacoustic (PA) dual-mode probe, S-NBD, which demonstrated robust PTT performance. This innovative probe is capable of activating NIRF/PA signals to enable the detection of biothiols with high emission wavelength (838 nm) and large Stokes shift (178 nm), allowing for in vivo monitoring of cancer cells. Additionally, the probe achieved an outstanding photothermal conversion efficiency of 67.1%. The application of laser irradiation (660 nm, 1.0 W/cm2, 5 min) was able to achieve complete tumor ablation without recurrence. In summary, this seminal study presents a pioneering NIRF/PA dual-mode dicyanoisophorone-based probe for biothiol imaging, incorporating features from PTT for the first time. This pioneering approach achieves the dual objectives of improving tumor diagnosis and treatment.

Development of receptor-targeted and pH-responsive zeolitic imidazole framework-90 nanoplatform for anti-ovarian cancer

The covalent functionalization of the zeolitic imidazolate framework (ZIF) is rapidly progressing and is being exploited as a nanoplatform for antitumor drug delivery to improve tumor targeting and drug release. Here, a novel nanoplatform strategy was developed by encapsulating Carboplatin (CBP) in ZIF-90 nanospheres (NPs) to obtain CBP@ZIF-90 NPs and then, modifying folate-terminated methoxypoly(ethylene glycol) (FA-PEG-NH2) on the aldehyde group of ZIF-90 to form CBP@ZIF-90-NPF NPs with acid-sensitive Schiff base bond. The research results indicate that the yield of ZIF-90 was 72.77 ± 0.27 %, and the encapsulation efficiency and the loading content of CBP@ZIF-90 were 45.22 ± 0.49 % and 24.65 ± 0.34 %, respectively. The size of CBP@ZIF-90-NPF was 107.7 ± 1.7 nm in monodispersity with a single crystalline dodecahedral structure. Furthermore, the in vitro release behavior study revealed the sustained-release and the pH-responsive dissociation properties of the NPs. Only 6.84 % of CBP was released from the nanocarrier under physiological pH conditions for 48 h, while the release from the tumor microenvironment was 92.89 %. In addition, the cellular uptake result clearly showed that most of the FA-PEG-NH2 modified NPs exhibited specific selectivity in tumor cell nuclei. Finally, the cell counting kit-8 (CCK8) assay based on human ovarian cancer cell line (OVCAR-3) and human normal ovarian epithelial (IOSE-80) cell line obviously indicated that the ZIF-90 NPs had good biocompatibility and minimal cytotoxicity, as well as the high inhibition efficiency of the CBP@ZIF-90-NPF NPs meant that a much higher amount of CBP was transferred into the folate receptor (FR)-overexpressed ovarian cancer cells via FR mediated endocytosis. These results suggest that ZIF-90-NPF NPs could be an ideal targeted drug delivery vehicle for CBP, serving as a promising strategy for ovarian cancer treatment.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

A gene delivery system with autophagy blockade for enhanced anti-angiogenic therapy against Fusobacterium nucleatum-associated colorectal cancer

Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum (F. nucleatum) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum-associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3′-diaminodipropylamine-pendant poly(β-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum-colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum-resident CRC. Statement of significanceUp-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum. To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum-associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum-resident CRC.

Folate-PEG-PROTAC Micelles for Enhancing Tumor-Specific Targeting Proteolysis In Vivo.

Proteolysis targeting chimeras (PROTACs) technology is rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting, and low efficacy in vivo. Herein, self-assembling micelles of FA-PEG-PROTAC are designed for cancer cell selective targeting and reductive-response proteolysis in tumor-bearing mice. FA-PEG-PROTAC is prepared by conjugating folic acid (FA)-PEG with EGFR-targeting PROTAC via a disulfide bond. The FA-PEG-PROTAC micelles, formed by self-assembling, are demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti-tumor efficacy in the mouse xenograft model compared to the traditional PROTACs. The strategy of applying self-assembled FA-PEG-PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but also broaden applications in the development of PROTAC-based drugs.

Targeted Nanoparticle-Based Diagnostic and Treatment Options for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics.

Enhanced anti-glioma activity of annonaceous acetogenins based on a novel liposomal co-delivery system with ginsenoside Rh2

Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p < .05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck.

Abstract 3615: Targeting high-risk neuroblastoma by TGFβ imprinted natural killer cells

Abstract Background: Neuroblastoma (NB) is a common malignant extracranial solid tumor in children, responsible for 11% of cancer deaths in pediatric patients under 15 (Smith et al, Cancer, 2014). High-risk neuroblastoma is a metastatic disease in children aged 18 months or older with L2, M, or MS disease with amplification of the MYCN oncogene (Chuang Pediatr Blood Cancer 2021). Recent analyses by COG show that HR Neuroblastoma still has a 5-year event free survival of 51% despite an extensive treatment regimen (Steven et al, ASCO, 2022). To address improved tumor targeting and overcome antigen escape, chimeric antigen receptor (CAR) technology to Natural Killer (NK) cell therapy has been adapted (Chu/Cairo, et al, Frontiers in Oncology, 2019). TGFβ is a potent mechanism of the NK cell anti-tumor resistance and is present at elevated levels in the NB tumor microenvironment (TME) (Foltz, Cancers, 2018). Studies demonstrated that blockade of TGF-β signaling in NK cells caused the accumulation of NK cells that produce IFN-γ and neutralization of TGF-β prevented NKG2D downregulation and also restored NK cell anti-tumor reactivity (Nayyar/Chu/Cairo, et al Frontierls in Oncology, 2018). ROR1, a transmembrane protein is highly expressed on the majority of NB (Rebagay/Yan Front Oncol, 2012). Our group has successfully expanded functional and active peripheral blood NK cells (exPBNK) with irradiated feeder cells and electroporated CAR mRNA to exPBNK (Chu/Cairo, et al Cancer Immunol Res, 2015). Objective: To determine in vitro cytotoxicity against neuroblastoma cells by ex vivo expanded TGFβ imprinting (TGFβi) NK cells. Methods: TGFβi NK cells are generated by culturing expanded NK cells with irradiated K562-41BBL-mbIL21 in 50 IU/mL IL-2 plus 10 ng/mL TGFβ every 2-3 days for two weeks. NK and TGFβi NK cells specific in-vitro cytotoxicity were compared via luciferase reporter assay against ROR1+ NB cell lines as we previously described (Chu/Cairo, et al, JITC, 2022). Cytokine/chemokine levels secreted by NK and TGFβi NK cells were compared using ELISA assays (Chu/Cairo, et al, JITC, 2022). Results: We have successfully expanded TGFβi NK cells. These TGFβi NK cells showed significantly enhanced in vitro cytotoxicity against NB cells compared to NK cells under TGFβ environment (20+2.4% vs 0%; p&amp;lt;0.001) at E:T=3:1 and consistently, TGFβ-imprinting NK secreted significantly high level of TNF-alpha (393.7pg/ml+16.77pg/ml) against NB cells (p&amp;lt;0.001) compared to NK cells (79.7pg/ml+14.7pg/ml) under TGFβ environment. Conclusion: Our data indicate TGFβi NK cells may be a promising novel therapy to overcome the immunosuppression of TGFβ in the tumor microenvironment for pediatric NB tumors. We will further engineer these TGFβi NK cells to express anti-ROR1 CAR to enhance the targeting specificity against NB tumors and investigate the anti-tumor effects of anti-ROR1 CAR TGFβi NK cells against NB tumors in-vitro and in-vivo (Funded by U54 CA232561). Citation Format: Jessica A. Ayala-Cuesta, Yaya Chu, Keira Foley, Meijuan Tian, Kayleigh Klose, Alyssa S. Mendelowitz, Timothy P. Cripe, Dean A. Lee, Mitchell S. Cairo. Targeting high-risk neuroblastoma by TGFβ imprinted natural killer cells [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 3615.