Target Tumor Cells Research Articles

Abstract IA004: Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies

Abstract Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for the treatment of GBM. In this talk, we summarize recent clinical and pre-clinical efforts to develop immunotherapeutic and chimeric antigen receptor (CAR) T cell treatment strategies for GBM recurrence, including challenges in the form of fundamental mechanisms of therapy evasion by tumor cells, such as immense intratumoral heterogeneity, suppression of the tumor immune microenvironment, and low mutational burden. Insights from these advances and challenges have shaped our development of a translational research pipeline from initial target discovery, through target validation and exploration of mechanism, to building new biotherapeutics against novel cancer targets, and preclinical testing in our patient-derived animal models of treatment-resistant GBM. We have tracked GBM cell populations that undergo clonal evolution as a result of selective pressures exerted by standard treatments to identify the cellular composition of the recurrence, to allow us to determine the intracellular signaling pathways that drive GBM relapse. Ultimately, we will design rational combinations of therapeutics that can reignite the anti-tumor immune response, effectively and specifically target tumor cells, and reliably decrease tumor burden for GBM patients. Citation Format: Sheila K Singh. Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA004.

Abstract IA003: Advancing novel therapeutics through reverse translation

Abstract Background: The established paradigm for cancer drug development was designed to advance cytotoxic agents targeting tumor cells. An increased appreciation of the role of the tumor microenvironment in treatment efficacy and disease outcomes has identified tumor-extrinsic therapeutic targets. The different mechanisms of action employed by anti-angiogenic drugs or immunotherapeutics highlight the need for updated study endpoints to identify the maximally effective dose for clinical applications. These advances, and the translation of novel therapeutics, can be accelerated through reverse translation, a term used to describe research using patient samples to inform mechanistic studies – going from bedside-to-bench. Objective: To present an example of reverse translation in the development of an immune therapy combination for ovarian cancer. Preclinical studies demonstrated therapeutic synergy of CTLA4 immune checkpoint blockade and poly(ADP ribose) polymerase (PARP) inhibition in high grade serous ovarian cancer models. These results were translated to two clinical trials for the treatment of recurrent ovarian cancer. Tumor samples from study subjects have been collected to support ongoing mechanistic investigations and exploratory biomarker studies. Both targeted and unbiased approaches identified candidate biomarkers of response to treatment for further development. Ongoing mechanistic studies are examining the significance of top prognostic markers. Conclusions: Strategies are needed to support the integration of translational studies with clinical research to inform next generation trials and to optimize clinical applications of novel therapeutics. Citation Format: Sarah F. Adams. Advancing novel therapeutics through reverse translation [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA003.

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

High-Performance Photodynamic Therapy of Tongue Squamous Cell Carcinoma with Multifunctional Nano-Verteporfin.

The photodynamic therapy (PDT) showed promising potential in treating tongue squamous cell carcinoma (TSCC). The Food and Drug Administration approved Verteporfin (Ver) is a powerful alternative in this field for its penetrating power and high production of reactive oxygen species (ROS). However, its applications in the treatment of TSCC are still rare. Ver was loaded onto Poly (lactic-co-glycolic acid) (PLGA) nanoparticles, followed by the modification with RGD peptide as the ligand. The nanostructured was named as RPV. In vitro assessments were conducted to evaluate the cytotoxicity of RPV through the Live/Dead assay analysis and Cell Counting Kit-8 (CCK-8) assay. Using the reactive oxygen species assay kit, the potential for inducing targeted tumor cell death upon laser irradiation by promoting ROS production was investigated. In vivo experiments involved with the biological distribution of RPV, the administration with RPV followed by laser irradiation, and the measurement of the tumor volumes. Immunohistochemical analysis was used to detect the Ki-67 expression, and apoptosis induced by RPV-treated group. Systemic toxicity was evaluated through hematoxylin-eosin staining and blood routine analysis. Real-time monitoring was employed to track RPV accumulation at tumor sites. The in vitro assessments demonstrated the low cytotoxicity of RPV and indicated its potential for targeted killing TSCC cells under laser irradiation. In vivo experiments revealed significant tumor growth inhibition with RPV treatment and laser irradiation. Immunohistochemical analysis showed a notable decrease in Ki-67 expression, suggesting the effective suppression of cell proliferation, and TUNEL assay indicated the increased apoptosis in the RPV-treated group. Pathological examination and blood routine analysis revealed no significant systemic toxicity. Real-time monitoring exhibited selective accumulation of RPV at tumor sites. The findings collectively suggest that RPV holds promise as a safe and effective therapeutic strategy for TSCC, offering a combination of targeted drug delivery with photodynamic therapy.

Rapidly determine venetoclax in plasma sample using an LC-MS/MS method and apply it in TDM for acute leukemia children patient

AbstractVenetoclax is the first oral Bcl-2 inhibitor with high affinity targeting tumor cell apoptosis mechanism. In this study we developed a simple, sensitive and reliable LC–MS/MS method to determine venetoclax in children's hemolytic or lipemic samples. The method utilized an electrospray ion source and operated in multiple reaction monitoring mode. Venetoclax-d8 was used as an internal standard. Plasma samples were precipitated by acetonitrile containing 10% dimethyl sulfoxide and were separated by a Hypersil GOLD column (2.1 mm × 150 mm, 5 μm). The mobile phase consisted of acetonitrile-2 mM ammonium acetate (30:70, v/v) containing 0.4% formic acid. The quantification for venetoclax and venetoclax-d8 were m/z 868.1 → 636.1, m/z 876.1 → 644.1, respectively. The linear range was 10–2,000 ng mL−1 for venetoclax. The matrix in normal plasma, hemolytic or lipemic plasma had no significant effect on the detection results. The specificity, recovery and stability also met the acceptance criteria of guiding principles for the validation of biological sample quantitative analysis presented in the Chinese Pharmacopoeia (2015). As a result, this method is particularly suitable for determining venetoclax in hemolytic or lipemic samples from children with acute myeloid leukemia. The method, with the application of monitoring drug concentrations in pediatric patients, was successful.

Investigation of NK cell function against two target hematological cell line using radioactive chromium assay

NK (Natural killer) cells are a special population of peripheral blood lymphocytes that kill virus-infected cells as well as tumor cells. For testing NK cell function, the classic gold standard assay has been used for a long time, determining the activity from target tumor cells using radioactive chromium in cell cultures for 4h. In this study two hematological cell lines K562 and MDS where used and target and results showed different sensitivity to killing by NK cells separated from healthy volunteers. Results have been shown that MDS release significantly more radioactive chromium indicating higher degree of necrosis during cell culture. In addition, K562 cell line is better target for NK killing in all different E:T ratio in comparison to MDS cell line previously described. Based on this, it is suggested that K562 cells be continues used in the future as better target for investigation NK killing.

Transformable Magnetic Liquid-Metal Nanoplatform for Intracellular Drug Delivery and MR Imaging-Guided Microwave Thermochemotherapy.

Improved techniques for the administration of chemotherapeutic drugs are required to enhance tumor therapy efficacy and reduce the side effects of chemotherapy due to insufficient targeting and limited intratumoral drug release. Controlled drug delivery systems combined with thermotherapy are expected to play an important role in personalized tumor therapy. Herein, a novel microwave-responsive transformable magnetic liquid-metal (MLM) nanoplatform is designed for effective endosomal escape that facilitates intracellular drug delivery and enhanced anticancer therapy. The MLM nanoplatform exhibits a sensitive magnetic resonance imaging function for imaging-guided therapy and brilliant synergistic effects of chemotherapy with microwave thermal therapy to kill tumor cells. Once endocytosed by targeted tumor cells, the deep penetration of microwave energy can be absorbed by the MLM nanoplatform to convert heat and reactive oxygen species, which induces the shape transformation from nanospheres to large rods, resulting in the physical disruption of the endosomal membrane for intracellular drug release. Furthermore, the MLM nanoplatform synergistic therapy could activate immunomodulatory effects by M1 macrophage polarization and T cell infiltration, thus inhibiting tumor growth and lung metastasis. This work based on microwave-driven transformable magnetic liquid-metal nanoplatform provides novel ways to precisely control drug delivery and high-efficiency cancer therapy.

Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

Классические и активирующие химерные антигенные рецепторы PD-1 как элемент мультитаргетного подхода в лечении гематологических и солидных новообразований

Aim. To generate anti-PD-L1 CAR-T effectors carrying extracellular domain PD-1 as antigen-recognizing site and to study their cytolytic activity as well as to functionally assess the anti-PD-L1 CAR-T effectors in vitro with a view to apply them in multi-targeted tumor therapy.
 Materials & Methods. Chimeric antigen receptor PD-1 was constructed using molecular cloning of PD-1 antigen-recognizing region (12–170 amino acids) into mammalian expression plasmid vector adding activation and co-stimulatory domains. Primary Т-lymphocytes of healthy donor peripheral blood mononuclear fraction were derived by expanding monoclonal antibody combination on surface markers CD3/CD28. Anti-PD-L1 CAR-T effectors were obtained by lentiviral transduction of primary T-lymphocyte genome of a healthy donor. Chimeric antigen receptor PD-1 expression and transduction efficiency were assessed by flow cytofluorometry. Specific cytotoxicity of the anti-PD-L1 CAR-T effectors was analyzed in vitro by means of real-time cytotoxicity assay (RTCA) with HeLa_PD-L1 target cell line co-cultivation. The level of cytokines IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A was assessed by flow cytofluorometry using Human Th1/Th2/Th17 CBA Kit (BD, USA).
 Results. The efficiency of lentiviral transduction and the proportion of the anti-PD-L1 CAR-T effectors were 42 %. The specificity of cytotoxic response of the anti-PD-L1 CAR-T effectors with a low effector/tumor ratio (1:20) was verified during HeLa_PD-L1 co-cultivation by a 1.5-fold decrease in the cell index (CI = 0.738) versus control (CI = 1.0645). The increase in synthesis of cytokines IL-2 (1000 pg/mL), IL-6 (438.5 pg/mL), TNF-α (44 pg/mL), and IFN-γ (1034 pg/mL) during HeLa_PD-L1 target cell line co-cultivation confirms the functionality of the analyzed effector cells.
 Conclusion. Anti-PD-L1 chimeric antigen receptor was constructed and tested in vitro. Anti-PD-L1 CAR-T lymphocytes specifically recognize and promote the cytolysis of tumor target cells by increased secretion of pro-inflammatory cytokines IFN-γ, TNF-α, IL-6, and IL-2. Chimeric antigen receptor PD-1 can be modified into chimeric switch receptor (CSR) by deleting CD3ζ-domain and can be used together with other CARs without predicted non-specific toxicity.

Cancer‑associated fibroblasts under therapy‑induced senescence in the tumor microenvironment (Review).

Current cancer treatments target tumor cells; however, the tumor microenvironment (TME) induces therapeutic resistance, tumor development and metastasis, thus rendering these treatments ineffective. Research on the TME has therefore concentrated on nonmalignant cells. Cancer-associated fibroblasts (CAFs) are a major TME component, which contribute to cancer progression due to their diverse origins, phenotypes and functions, including cancer cell invasion and migration, extracellular matrix remodeling, tumor metabolism modulation and therapeutic resistance. Standard cancer treatment typically exacerbates the senescence-associated secretory phenotype (SASP) of senescent cancer cells and nonmalignant cells that actively leak proinflammatory signals in the TME. Therapy-induced senescence may impair cancer cell activity and compromise treatment responsiveness. CAFs and SASP are well-studied in the formation and progression of cancer. The present review discusses the current data on CAF senescence caused by anticancer treatment and assesses how senescence-like CAFs affect tumor formation. The development of senolytic medication for aging stromal cells is also highlighted. Combining cancer therapies with senolytics may boost therapeutic effects and provide novel possibilities for research.

Covalent coupling of functionalized outer membrane vesicles (OMVs) to gold nanoparticles

Outer membrane vesicle-functionalized nanoparticles (OMV-NPs) have attracted significant interest, especially regarding drug delivery applications and vaccines. Here, we report on novel OMV-NPs by applying bioorthogonal click reaction for encapsulating gold nanoparticles (NPs) within outer membrane vesicles (OMVs) by covalent coupling. For this purpose, outer membrane protein A (OmpA), abundant in large numbers (due to 100,000 copies/cell [1]) in OMVs, was modified via the incorporation of the unnatural amino acid p–azidophenylalanine. The azide group was covalently coupled to alkyne-functionalized NPs after incorporation into OmpA. A simplified procedure using low-speed centrifugation (1,000 x g) was developed for preparing OMV-NPs. The OMV-NPs were characterized by zeta potential, Laurdan-based lipid membrane dynamics studies, and the enzymatic activity of functionalized OMVs with surface-displayed nicotinamide adenine dinucleotide oxidase (Nox). In addition, OMVs from attenuated bacteria (ClearColiTM BL21(DE3), E. coli F470) with surface-displayed Nox or antibody fragments were prepared and successfully coupled to AuNPs. Finally, OMV-NPs displaying single-chain variable fragments from a monoclonal antibody directed against epidermal growth factor receptor were applied to demonstrate the feasibility of OMV-NPs for tumor cell targeting.

Antibody-Drug Conjugate Overview: a State-of-the-art Manufacturing Process and Control Strategy.

Antibody-drug conjugates (ADCs) comprise an antibody, linker, and drug, which direct their highly potent small molecule drugs to target tumor cells via specific binding between the antibody and surface antigens. The antibody, linker, and drug should be properly designed or selected to achieve the desired efficacy while minimizing off-target toxicity. With a unique and complex structure, there is inherent heterogeneity introduced by product-related variations and the manufacturing process. Here this review primarily covers recent key advances in ADC history, clinical development status, molecule design, manufacturing processes, and quality control.The manufacturing process, especially the conjugation process, should be carefully developed, characterized, validated, and controlled throughout its lifecycle. Quality control is another key element to ensure product quality and patient safety. A patient-centric strategy has been well recognized and adopted by the pharmaceutical industry for therapeutic proteins, and has been successfully implemented for ADCs as well, to ensure that ADC products maintain their quality until the end of their shelf life. Deep product understanding and process knowledge defines attribute testing strategies (ATS). Quality by design (QbD) is a powerful approach for process and product development, and for defining an overall control strategy. Finally, we summarize the current challenges on ADC development and provide some perspectives that may help to give related directions and trigger more cross-functional research to surmount those challenges.

Preparation of green Ag@SiO2 microcapsule with long-acting antibacterial activity and tumor cell-targeting potential using carboxymethyl chitosan, halide ion, and sunlight

In this study, the photolysis of AgCl and mesoporous silica microspheres was used to prepare small green Ag nanoparticles (AgNPs) and Ag@SiO2 microcapsules. Transmission electron microscopy images of the Ag@SiO2 microcapsules indicated that the particle sizes of most of the AgNPs were 5–50 nm. Inductively coupled plasma mass spectrometry results indicated that the Ag dissolution amount of the Ag@SiO2 microcapsules was significantly larger than that of commercial AgNPs, and the Ag dissolution amount of the Ag@SiO2 microcapsules decreased more slowly after multiple soaking cycles. In a bactericidal test, most of the soaking solutions of the Ag@SiO2 microcapsules exhibited an obvious bacteriostatic circle for gram-negative and gram-positive bacteria and fungi. The cytotoxicity of the Ag@SiO2 microcapsules was more pronounced in tumor cells. Thus, these microcapsules can target tumor cells.

Enhanced cisplatin chemotherapy sensitivity by self-assembled nanoparticles with Olaparib.

Cisplatin (CDDP) is widely used as one kind of chemotherapy drugs in cancer treatment. It functions by interacting with DNA, leading to the DNA damage and subsequent cellular apoptosis. However, the presence of intracellular PARP1 diminishes the anticancer efficacy of CDDP by repairing DNA strands. Olaparib (OLA), a PARP inhibitor, enhances the accumulation of DNA damage by inhibiting its repair. Therefore, the combination of these two drugs enhances the sensitivity of CDDP chemotherapy, leading to improved therapeutic outcomes. Nevertheless, both drugs suffer from poor water solubility and limited tumor targeting capabilities. To address this challenge, we proposed the self-assembly of two drugs, CDDP and OLA, through hydrogen bonding to form stable and uniform nanoparticles. Self-assembled nanoparticles efficiently target tumor cells and selectively release CDDP and OLA within the acidic tumor microenvironment, capitalizing on their respective mechanisms of action for improved anticancer therapy. In vitro studies demonstrated that the CDDP-OLA NPs are significantly more effective than CDDP/OLA mixture and CDDP at penetrating cancer cells and suppressing their growth. In vivo studies revealed that the nanoparticles specifically accumulated at the tumor site and enhanced the therapeutic efficacy without obvious adverse effects. This approach holds great potential for enhancing the drugs' water solubility, tumor targeting, bioavailability, and synergistic anticancer effects while minimizing its toxic side effects.

Antibody-Drug Conjugates: Advancing from Magic Bullet to Biological Missile.

Precision drug development is focusing on targeting tumor cell surface proteins for therapeutic delivery, maximizing biomarker identified on-target damage to the tumor while minimizing toxicity. A recent article demonstrated high expression of B7-H4 antigen on resistant ovarian cancer cells and described preclinical activity of B7-H4-directed antibody-drug conjugate. See related article by Gitto et al., p. 1567.

Redox-responsive Nanomicelles with Intracellular Targeting and Programmable Drug Release for Targeted Tumor Therapy.

Anti-inflammatory medications, in particular aspirin, have chemopreventive and anticancer adjuvant effects on specific types of cancers, according to ongoing anti-tumor research. Additionally, efforts have been made to transform Poly(salicylic acid) (PSA) into delivery-related nanocarriers. to transport anticancer medications into nanocarriers. However, tumor cell targeting and tumor selectivity were lacking in the salicylic acid polymer-based nanocarriers, preventing them from performing to their full potential. The objective of this study is to prepare targeting and reduction-responsive poly pre-drug nanocarriers (HA-ss-PSA NPs) and to investigate the feasibility of delivering adriamycin (DOX) as nanocarriers. The structures of the polymers were confirmed by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR) and infrared spectroscopy (IR); the encapsulation rate and drug loading of DOX-loaded nanoparticles were determined by HPLC; and the anti-tumor effects of the carriers were evaluated by MTT experiments and in vivo</i> experiments. The prepared nanocarriers had uniform particle size distribution. The drug release rate was up to 80% within 48 h in the tumor environment. DOX/HA-ss-PSA NPs showed significant cytostatic effects. In addition, HA-ss-PSA NPs showed significant targeting and inhibition of cell migration in cell uptake and scratch assays. In vivo</i> experiments showed that the prepared carriers had high tumor inhibition rates, good targeting effects on the liver and tumor, and significantly reduced toxicity to other tissues. The prepared HA-ss-PSA NPs could effectively inhibit the growth of HepG2 cells and tumors in vivo</i>, indicating that PSA could be used as a backbone component of a safe and reliable drug delivery system, providing a new strategy for the treatment of liver cancer.

Better safe than sorry: dual targeting antibodies for cancer immunotherapy.

Antibody-based therapies are revolutionizing cancer treatment and experience a steady increase from preclinical and clinical pipelines to market share. While the clinical success of monoclonal antibodies is frequently limited by low response rates, treatment resistance and various other factors, multispecific antibodies open up new prospects by addressing tumor complexity as well as immune response actuation potently improving safety and efficacy. Novel antibody approaches involve simultaneous binding of two antigens on one cell implying increased specificity and reduced tumor escape for dual tumor-associated antigen targeting and enhanced and durable cytotoxic effects for dual immune cell-related antigen targeting. This article reviews antibody and cell-based therapeutics for oncology with intrinsic dual targeting of either tumor cells or immune cells. As revealed in various preclinical studies and clinical trials, dual targeting molecules are promising candidates constituting the next generation of antibody drugs for fighting cancer.

Natural Polymers as a Carrier for the Effective Delivery of Antineoplastic Drugs.

Cancer is a broad term for a set of disorders marked by the development of physically and functionally changed cells that proliferate uncontrollably, infect neighboring tissues, and result in malignant tumours, 'neoplasm'. Cancer remains a difficult disease to treat because of the significant adverse effects and poor pharmacokinetic profile of antineoplastic drugs, despite advancements in our understanding of the features and behavior of tumor cells in recent decades. In this series, the role of natural polymers is prominent as a component of a novel delivery system of anticancer drugs. These natural polymeric drug delivery systems (NPDDS) have many advantages over synthetic polymers like controlled delivery, biodegradability, inexpensive, low toxicity profile, and easily obtainable. These polymers further modify for the targeting of tumour cells. This review discusses and critically analyses the different natural polymers, such as chitosan, cellulose, starch, albumin, dextran, fucoidan, gelatin, etc., in terms of natural ingredient-based polymeric nanocarriers specifically for cancer therapy. It also describes benefits, drawbacks, and opinions and provides insights about the efficacy of NPDDS as well as its future perspectives and tabulated recent patents and cases under clinical trials exploited for cancer treatment.

Nanoparticles for the Treatment of Bone Metastasis in Breast Cancer: Recent Advances and Challenges.

Although the frequency of bone metastases from breast cancer has increased, effective treatment is lacking, prompting the development of nanomedicine, which involves the use of nanotechnology for disease diagnosis and treatment. Nanocarrier drug delivery systems offer several advantages over traditional drug delivery methods, such as higher reliability and biological activity, improved penetration and retention, and precise targeting and delivery. Various nanoparticles that can selectively target tumor cells without causing harm to healthy cells or organs have been synthesized. Recent advances in nanotechnology have enabled the diagnosis and prevention of metastatic diseases as well as the ability to deliver complex molecular "cargo" particles to metastatic regions. Nanoparticles can modulate systemic biodistribution and enable the targeted accumulation of therapeutic agents. Several delivery strategies are used to treat bone metastases, including untargeted delivery, bone-targeted delivery, and cancer cell-targeted delivery. Combining targeted agents with nanoparticles enhances the selective delivery of payloads to breast cancer bone metastatic lesions, providing multiple delivery advantages for treatment. In this review, we describe recent advances in nanoparticle development for treating breast cancer bone metastases.

Efficient Sequential Co-Delivery Nanosystem for Inhibition of Tumor and Tumor-Associated Fibroblast-Induced Resistance and Metastasis.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. However, the effect of current treatment strategies by inducing tumor cell apoptosis alone is not satisfactory. The growth, metastasis and treatment sensitivity of tumors can be strongly influenced by cancer-associated fibroblasts (CAFs) in the microenvironment. Effective cancer therapies may need to target not only the tumor cells directly but also the CAFs that protect them. Celastrol and small-sized micelles containing betulinic acid were co-encapsulated into liposomes using the thin-film hydration method (CL@BM). Folic acid was further introduced to modify liposomes as the targeting moiety (F/CL@BM). We established a novel NIH3T3+4T1 co-culture model to mimic the tumor microenvironment and assessed the nanocarrier's inhibitory effects on CAFs-induced drug resistance and migration in the co-culture model. The in vivo biological distribution, fluorescence imaging, biological safety evaluation, and combined therapeutic effect evaluation of the nanocarrier were carried out based on a triple-negative breast cancer model. In the present study, a novel multifunctional nano-formulation was designed by combining the advantages of sequential release, co-loading of tretinoin and betulinic acid, and folic acid-mediated active targeting. As expected, the nano-formulation exhibited enhanced cytotoxicity in different cellular models and effectively increased drug accumulation at the tumor site by disrupting the cellular barrier composed of CAFs by tretinoin. Notably, the co-loaded nano-formulations proved to be more potent in inhibiting tumor growth in mice and also showed better anti-metastatic effects in lung metastasis models compared to the formulations with either drug alone. This novel drug delivery system has the potential to be used to develop more effective cancer therapies. Targeting CAFs with celastrol sensitizes tumor cells to chemotherapy, increasing the efficacy of betulinic acid. The combination of drugs targeting tumor cells and CAFs may lead to more effective therapies against various cancers.