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Distinct Chemical Cues Reprogram Cellular and Multicellular Phenotypes in Ovarian Cancer Spheroids

Abstract The self‐organization of cellular collectives is crucial in development and cancer. Multicellular aggregation in cancer is associated with a higher efficiency of metastasis. However, it is not fully understood how mechanochemical microenvironmental cues affect the organization and stability of such ensembles. Here, using a model system of ovarian cancer spheroids, which temporally transit from solid, dysmorphic moruloids to structurally plastic, lumen‐containing blastuloids, it is shown that the periodic volume fluctuations observed in blastuloids are driven by lumenal fluid influx and cell‐cell junctional states. Furthermore, blastuloid cell states are reprogrammed, which enables them to rapidly recover from even complete structural disintegration and self‐organize into fully lumenized ensembles. Using targeted chemical perturbations, two distinct cues are identified that regulate separate transition traits: calcium levels establish cell states cognate to, and pH regulates the fluctuation dynamics of blastuloid phenotypes. The work holds significant implications toward understanding mechanisms governing structural resilience and plasticity in complex cellular assemblies.

Personalized Versus Precision Nanomedicine for Treatment of Ovarian Cancer

AbstractThe response to treatment is substantially varied between individual patients with ovarian cancer. However, chemotherapy treatment plans rarely pay sufficient attention to the mentioned factors. Instead, standardized treatment protocols are usually employed for most ovarian cancer patients. Variations in an individual's sensitivity to drugs significantly limit the effectiveness of treatment in some patients and lead to severe toxicities in others. In the present investigation, a nanotechnology‐based approach for personalized treatment of ovarian carcinoma (the most lethal type of gynecological cancer) constructed on the individual genetic profile of the patient's tumor is developed and validated. The expression of predefined genes and proteins is analyzed for each patient sample. Finally, a mixture of the complex nanocarrier‐based targeted delivery system containing drug(s)/siRNA(s)/targeted peptide is selected from the pre‐synthesized bank and tested in vivo on murine cancer model using cancer cells isolated from tumors of each patient. Based on the results of the present study, an innovative approach and protocol for personalized treatment of ovarian cancer are suggested and evaluated. The results of the present study clearly show the advantages and perspectives of the proposed individual treatment approach.

Ciprofloxacin Derivative‐Loaded Nanoparticles Synergize with Paclitaxel Against Type II Human Endometrial Cancer

AbstractCombinations of chemotherapeutic agents comprise a clinically feasible approach to combat cancers that possess resistance to treatment. Type II endometrial cancer is typically associated with poor outcomes and the emergence of chemoresistance. To overcome this challenge, a combination therapy is developed comprising a novel ciprofloxacin derivative‐loaded PEGylated polymeric nanoparticles (CIP2b‐NPs) and paclitaxel (PTX) against human type‐II endometrial cancer (Hec50co with loss of function p53). Cytotoxicity studies reveal strong synergy between CIP2b and PTX against Hec50co, and this is associated with a significant reduction in the IC50 of PTX and increased G2/M arrest. Upon formulation of CIP2b into PEGylated polymeric nanoparticles, tumor accumulation of CIP2b is significantly improved compared to its soluble counterpart; thus, enhancing the overall antitumor activity of CIP2b when co‐administered with PTX. In addition, the co‐delivery of CIP2b‐NPs with paclitaxel results in a significant reduction in tumor progression. Histological examination of vital organs and blood chemistry was normal, confirming the absence of any apparent off‐target toxicity. Thus, in a mouse model of human endometrial cancer, the combination of CIP2b‐NPs and PTX exhibits superior therapeutic activity in targeting human type‐II endometrial cancer.

Enhanced Chemodynamic Therapy Mediated by a Tumor‐Specific Catalyst in Synergy with Mitophagy Inhibition Improves the Efficacy for Endometrial Cancer

AbstractChemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2O2 level) responsive Fenton‐like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1)high catalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β‐lapachone (β‐Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β‐Lap to produce excess H2O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double‐strand breaks, and promote apoptosis. Moreover, shRNA‐mediated NQO1 knockdown or dicoumarol rescues NQO1high EC cells from β‐Lap‐induced cytotoxicity. Arginine‐glycine‐aspartic acid (RGD)‐functionalized iron‐based metal‐organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H2O2 into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD‐positive target cells. Furthermore, mitophagy inhibition by Mdivi‐1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti‐tumor efficacy of stepwise‐amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)‐based synergistic antitumor therapy decreases to only 50.46% in NQO1‐deficient KLE tumors. Tumor‐specific chemotherapy and CDT‐triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1high EC.

Plasmonic Mesoporous Gold‐Based SERS Biosensor for Ovarian Cancer‐Derived Extracellular Vesicles

AbstractExtracellular vesicles (EVs) are lipids bilayer‐delimited particles carrying bioactive molecules such as proteins, lipids, and nucleic acids, reflecting the physiological state of their origin. Found in biofluids like saliva, urine, blood, and peritoneal fluid, EVs serve as promising minimally invasive biomarkers for several conditions including cancer. However, achieving high sensitivity and specificity in EV detection remains technically challenging. Placental Alkaline Phosphatase (PLAP), an enzyme primarily expressed in the placenta during pregnancy, has emerged as a clinically relevant biomarker in gynecological malignancies, including ovarian cancer (OC). In this study, a nanoengineered mesoporous gold (mAu)‐based Surface‐Enhanced Raman Spectroscopy (SERS) platform is reported for the rapid and ultrasensitive detection of PLAP‐positive EVs in OC patients. The mAu offers high surface roughness, enabling numerous localized plasmonic hotspots that amplify Raman signals and improve probe and antibody loading. This allowed the detection of as few as 100 EVs mL−1 with excellent reproducibility (RSD < 5%,n = 3). In clinical validation (n = 30), the assay achieved 90% sensitivity (95% CI: 60%–100%) and 85% specificity (95% CI: 15%–100%) in distinguishing OC patients from those with benign and healthy controls, demonstrating superior performance compared to CA‐125. The mAu‐SERS platform shows considerable promise as a minimally invasive and clinically applicable diagnostic strategy for OC, especially for differential diagnosis for their ability to distingluis between benign and OC conditions.

Targeting Mucin Protein Enables Rapid and Efficient Ovarian Cancer Cell Capture: Role of Nanoparticle Properties in Efficient Capture and Culture

AbstractThe development of specific and sensitive immunomagnetic cell separation nanotechnologies is central to enhancing the diagnostic relevance of circulating tumor cells (CTCs) and improving cancer patient outcomes. The limited number of specific biomarkers used to enrich a phenotypically diverse set of CTCs from liquid biopsies has limited CTC yields and purity. The ultra‐high molecular weight mucin, mucin16 (MUC16) is shown to physically shield key membrane proteins responsible for activating immune responses against ovarian cancer cells and may interfere with the binding of magnetic nanoparticles to popular immunomagnetic cell capture antigens. MUC16 is expressed in ≈90% of ovarian cancers and is almost universal in High Grade Serous Epithelial Ovarian Cancer. This work demonstrates that cell bound MUC16 is an effective target for rapid immunomagnetic extraction of expressor cells with near quantitative yield, high purity and viability from serum. The results provide a mechanistic insight into the effects of nanoparticle physical properties and immunomagnetic labeling on the efficiency of immunomagnetic cell isolation. The growth of these cells has also been studied after separation, demonstrating that nanoparticle size impacts cell‐particle behavior and growth rate. These results present the successful isolation of “masked” CTCs enabling new strategies for the detection of cancer recurrence and select and monitor chemotherapy.

Antibody Generation Using Cancer‐Derived Small Extracellular Vesicles (sEVs): A Platform for Targeted Cancer Therapy and Potential Personalized Applications

Abstract Despite advances in tumor‐targeting therapies, drug delivery efficiency to solid tumors remains low in most preclinical studies, highlighting the need for more effective targeting ligands. A novel method is developed to generate tumor‐targeting monoclonal antibodies (mAbs) using cancer‐derived small extracellular vesicles (sEVs), which inherit the structural and functional features of their parent cells. sEVs isolated from human ovarian carcinoma cell lines (OVCAR‐8) are injected into mice to elicit an immune response. Hybridoma technology is used to generate mAbs, which are screened for either high specificity or cytotoxicity toward OVCAR‐8 cells. Two lead mAbs are individually decorated onto paclitaxel‐loaded CD8⁺ T cell‐derived sEVs (antibody‐functionalized TSEV/P; AB‐TSEV/P), and the resulting formulations are evaluated in OVCAR‐8 tumor‐bearing mice. Both AB‐TSEV/P formulations significantly reduce tumor growth without affecting body weight. Biodistribution studies using IR780‐loaded AB‐TSEV reveal enhanced tumor accumulation compared to non‐targeted controls. RNA sequencing and spatial transcriptomics show that antibody‐decorated sEVs induce transcriptional changes associated with immune activation and tumor suppression. This antibody generation strategy enables cancer cell‐specific targeting and supports its application in targeted cancer therapy and personalized oncology.

A Biomimetic Hierarchical Porous Microneedle for Transdermal Ovarian Cancer Detection

Abstract Precision in early‐stage ovarian cancer detection is crucial for improving survival rates, yet often involves invasive or resource‐intensive procedures. It is here engineered a portable transdermal biosensor comprising antibody‐functionalized hierarchical porous microneedles (hp‐MNs) that enables on ‐needle quantitatively detect human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) via fluorescence immunoassay. Fabricated through a novel phase separation micro‐molding technique, the biomimetic microneedles feature a coral‐like hierarchical inter‐connective porous structure with noteworthy liquid absorption capacity and high antibody‐binding density, enabling reliable in vivo biomarkers enrichment and detection with nanomolar sensitivity to differentiate disease from benign biofluids. Furthermore, a groove structure allows concurrently detection of multiple tumor biomarkers at identical regions without cross‐influence in a single application, enhancing sensitivity and precision. This work advances the field of porous polymeric microneedles and offers a promising guideline for developing more accurate and noninvasive diagnostic systems.

Particles and Prejudice: Nanomedicine Approaches to Reducing Health Disparities in Endometrial Cancer

AbstractEndometrial cancer is the most common gynecological malignancy worldwide and unfortunately has a much higher mortality rate in Black women compared with White women. Many potential factors contribute to these mortality rates, including the underlying effects of systemic and interpersonal racism. Furthermore, other trends in medicine have potential links to these rates including participation in clinical trials, hormone therapy, and pre‐existing health conditions. Addressing the high incidence and disparate mortality rates in endometrial cancer requires novel methods, such as nanoparticle‐based therapeutics. These therapeutics have been growing in increasing prevalence in pre‐clinical development and have far‐reaching implications in cancer therapy. The rigor of pre‐clinical studies is enhanced by the likeness of the model to the human body. In systems for 3D cell culture, for example, the extracellular matrix mimics the tumor more closely. The increasing emphasis on precision medicine can be applied to cancer using nanoparticle‐based methods and applied to pre‐clinical models by using patient‐derived model data. This review highlights the intersections of nanomedicine, precision medicine, and racial disparities within endometrial cancer and provides insights into reducing health disparities using recent scientific advances on the nanoscale.

Engineering Nano‐Pills to Inhibit Ovarian Cancer Proliferation and Migration through a Combination of Chemical/Nucleic Acid Therapy

Abstract Ovarian cancer (OC) is the most fatal of all gynecological malignancies, presenting a significant threat to women's health. Its treatment is complicated by severe dose‐dependent chemotherapy toxicity, drug resistance, and tumor migration. Herein, an intelligent combination strategy of chemotherapy and nucleic acid therapy, named ApMEmiR&D is developed. This integrated system consists of three parts: the nano‐pill, the protective membrane, and the navigation element. Nano‐pills are nanospheres assembled from miRNA and doxorubicin (DOX) with the help of ferrous ions (Fe 2+ ). The protective membrane is derived from tumor‐associated macrophages (TAMs membrane) originating from the primary tumor microenvironment (TME). The navigation element is the cholesterol‐conjugated AS1411 aptamer. The resulting ApMEmiR&D nanoparticles exhibit uniform size, a well‐defined nanosphere structure, robust serum stability, and ultra‐high drug loading efficiency and capacity. The system can efficiently accumulate in the tumor, allowing for the synergistic inhibition of tumor growth and metastasis without apparent systemic toxicity. The results demonstrate the homing effect of tumor microenvironment‐derived macrophage cell membrane and the targeting effect of aptamer, leading to precise drug targeting and immune compatibility, thereby enhancing therapeutic efficacy. The success of this strategy paves the way for metastasis inhibition and targeted cancer therapy.

Nanotechnology Approaches for Prevention and Treatment of Chemotherapy‐Induced Neurotoxicity, Neuropathy, and Cardiomyopathy in Breast and Ovarian Cancer Survivors

AbstractNanotechnology has emerged as a promising approach for the targeted delivery of therapeutic agents while improving their efficacy and safety. As a result, nanomaterial development for the selective targeting of cancers, with the possibility of treating off‐target, detrimental sequelae caused by chemotherapy, is an important area of research. Breast and ovarian cancer are among the most common cancer types in women, and chemotherapy is an essential treatment modality for these diseases. However, chemotherapy‐induced neurotoxicity, neuropathy, and cardiomyopathy are common side effects that can affect breast and ovarian cancer survivors quality of life. Therefore, there is an urgent need to develop effective prevention and treatment strategies for these adverse effects. Nanoparticles (NPs) have extreme potential for enhancing therapeutic efficacy but require continued research to elucidate beneficial interventions for women cancer survivors. In short, nanotechnology‐based approaches have emerged as promising strategies for preventing and treating chemotherapy‐induced neurotoxicity, neuropathy, and cardiomyopathy. NP‐based drug delivery systems and therapeutics have shown potential for reducing the side effects of chemotherapeutics while improving drug efficacy. In this article, the latest nanotechnology approaches and their potential for the prevention and treatment of chemotherapy‐induced neurotoxicity, neuropathy, and cardiomyopathy in breast and ovarian cancer survivors are discussed.

Advance in Nanomedicine for Improving Mucosal Penetration and Effective Therapy of Cervical Cancer

AbstractInsufficient intratumor drug distribution and serious adverse effects are often associated with systemic chemotherapy for cervical cancer. Considering the location of cervical cancer, access to the cervix through the vagina may provide an alternative administration route for high drug amounts at the tumor site, minimal systemic exposure as well as convenience of non‐invasive self‐medication. Enormous progress has been made in nanomedicine to improve mucosal penetration and enhance the effectiveness of therapy for cervical cancer. This review article first introduce the physiological state of cervicovaginal cavity and the characteristics of intravaginal environment in cervical cancers. Based on introduction to the physiological state of cervicovaginal cavity and the characteristics of intravaginal environment in cervical cancers, both “first mucus‐adhering then mucosal penetration” and “first mucus‐penetrating then mucosal penetration” strategies are discussed with respect to mechanism, application condition, and examples. Finally, existing challenges and future directions are envisioned in the rational design, facile synthesis, and comprehensive utilization of nanomedicine for local therapy of cervical cancer. This review is expected to provide useful reference information for future research on nanomedicine for intravaginally administered formulations for topical treatment of cervical cancer.

Reduction‐Sensitive Fluorinated‐Pt(IV) Universal Transfection Nanoplatform Facilitating CT45‐Targeted CRISPR/dCas9 Activation for Synergistic and Individualized Treatment of Ovarian Cancer

AbstractCompared to traditional clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated protein 9 (Cas9) system, CRISPR/dead Cas9 (dCas9) system can precisely regulate endogenous gene expression without damaging the host gene, representing a greater potential for cancer therapy. Cancer/testis antigen 45 (CT45) is proved to enhance platinum‐based chemosensitivity for individualized ovarian cancer therapy. However, the development of a single nanocarrier codelivering CRISPR/dCas9 system and chemotherapeutics for synergistic cancer therapy still faces challenges. Herein, a reduction‐sensitive fluorinated‐Pt(IV) universal transfection nanoplatform (PtUTP‐F) is developed for the CT45‐targeted CRISPR/dCas9 activation to achieve synergistic and individualized treatment of ovarian cancer. Overcoming multiple physiological barriers, PtUTP‐F condensed gene can efficiently transfect into different cells including 293T cells, A2780, SKOV3, A549, and A2780/cisplatin (DDP) cancer cells, which is superior to Lipofectamine 6000. With the responsive release of gene and Pt(II) in the intracellular reducing microenvironment, PtUTP‐F/dCas9‐CT45 can generate CRISPR/dCas9 activation of CT45 expression for protein phosphatase 4C (PP4C) activity inhibition to hinder the DNA repair pathway and thus enhances the sensitivity to Pt(II) drugs for individualized A2780 tumor therapy. The PtUTP‐F not only represents a powerful nanoplatform for CRISPR/dCas9 system delivery but also initiates a novel strategy for synergistic and individualized treatment of CRISPR/dCas9‐based gene therapy with chemotherapy.

Active Delivery of VLPs Promotes Anti‐Tumor Activity in a Mouse Ovarian Tumor Model

AbstractVirus‐like nanoparticles (VLPs) have been used as an attractive means in cancer immunotherapy because of their unique intrinsic immunostimulatory properties. However, for treating metastatic tumors in the peritoneal cavity, such as ovarian cancer, multiple injections of therapy are needed due to the large peritoneal space and fast excretion of therapy. Here, it is reported on the development of active VLP delivery vehicles for the treatment of peritoneal ovarian tumors using biocompatible Qβ VLPs‐loaded Mg‐based micromotors. The autonomous propulsion of such Qβ VLPs‐loaded Mg‐micromotors in the peritoneal fluid enables active delivery of intact immunostimulatory Qβ VLPs to the peritoneal space of ovarian tumor bearing mice, greatly enhancing the local distribution and retention of Qβ VLPs. Such improved distribution and longer retention time of Qβ in the peritoneal cavity leads to enhanced immunostimulation and therefore increased survival rate of tumor‐bearing mice compared to a passive Qβ treatment. For clinical translation, the active delivery of VLPs holds great promise for tumor immunotherapy toward the treatment of different types of primary and metastatic tumors in the peritoneal cavity.

Therapeutic Gene Silencing Using Targeted Lipid Nanoparticles in Metastatic Ovarian Cancer

AbstractOvarian cancer is an aggressive tumor owing to its ability to metastasize from stage II onward. Herein, lipid nanoparticles (LNPs) that encapsulate combination of small interfering RNAs (siRNAs), polo‐like kinase‐1 (PLK1), and eukaryotic translation‐initiation factor 3c (eIF3c), to target different cellular pathways essential for ovarian cancer progression are generated. The LNPs are further modified with hyaluronan (tNPs) to target cluster of differentiation 44 (CD44) expressing cells. Interestingly, hyaluronan‐coated LNPs (tNPs) prolong functional activity and reduce growth kinetics of spheroids in in vitro assay as compared to uncoated LNPs (uNPs) due to ≈1500‐fold higher expression of CD44. Treatment of 2D and 3D cultured ovarian cancer cells with LNPs encapsulating both siRNAs result in 85% cell death and robust target gene silencing. In advanced orthotopic ovarian cancer model, intraperitoneal administration of LNPs demonstrates CD44 specific tumor targeting of tNPs compared to uNPs and robust gene silencing in tissues involved in ovarian cancer pathophysiology. At very low siRNA dose, enhanced overall survival of 60% for tNPs treated mice is observed compared to 10% and 20% for single siRNA‐, eIF3c‐tNP, and PLK1‐tNP treatment groups, respectively. Overall, LNPs represent promising platform in the treatment of advanced ovarian cancer by improving median‐ and overall‐survival.