Breast Tumor Model Research Articles

Abstract B060: Enhanced therapeutic efficacy of a bioflavonoid loaded lipid nanoparticles via remodeling tumor microenvironment (TME) and KEAP1-NRF2 signaling in a murine breast tumor model

Abstract B060: Enhanced therapeutic efficacy of a bioflavonoid loaded lipid nanoparticles via remodeling tumor microenvironment (TME) and KEAP1-NRF2 signaling in a murine breast tumor model

Cetuximab functionalized chitosan/hyaluronic acid-based nanoparticles loaded with cabazitaxel enhances anti-tumor efficacy in DMBA-induced breast cancer model in rats through spatial targeting

The article discusses the ionic gelation of cationic chitosan (CS) with anionic hyaluronic acid (HA) sodium salt to form nanoparticles in the range of 125 nm. The particles were further functionalized with cetuximab to endow it with the ability to spatially target the tumor over-expressing EGFR. Solid-state characterization of the particles using XRD, FTIR, and DSC revealed the formation of stable nanoparticles with Cabazitaxel loaded in the amorphous nanostructure. XPS study used to assess the surface characteristics indicated that the cetuximab was successfully anchored on the surface of the particle. The prepared CS-HA-Cmab-NP elicited a pH-responsive drug release behavior due to the presence of CS in the matrix. In vitro performance of the nanoparticles was evaluated on MDA-MB-231 breast cancer cell lines showed overall increase in efficacy. In vivo pharmacokinetic and anti-tumor effect evaluated in female Sprague Dawley rats indicated that the Cmab-conjugated nanoparticles improved half-life of cabazitaxel and tumor reduction capability with higher survival rate and lower reduction in body weight. The results indicate that CS/HA nanoparticles anchored with cetuximab show enhanced efficacy in reducing the breast cancer tumor in DMBA-induced breast tumor model through spatial targeting, consequently reducing the systemic toxicity.

Targeting erbB Pathways in Breast Cancer: Dual Kinase Inhibition for Brain Metastasis and Prevention of p185HER2/Neu Tumor Development.

Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2. The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models. The Herceptin-resistant breast cancer cell line JIMT-1 was used in an in vivo tumor model, and MMTV-erbB2 (Fo5) transgenic mice models were used to evaluate the efficacy and safety of ER121 as neoadjuvant. ER121 treatment focusing on experimental brain metastasis in TNBC, HER2+ model, was quantified by total flux employing the In Vivo Imaging System (IVIS). We also compared the brain tissue from the treated and the controls groups. Additionally, ER121 was evaluated in JIMT-1, a Herceptin-resistant breast cancer cell line, both in vitro and in vivo tumor model. We also administered ER121 orally in neoadjuvant model with the MMTV-erbB2 (Fo5) transgenic mice, the survival rates were compared with the control group. Tumor-free survival of multiple treated groups were analyzed by Kaplan-Meier analysis employing the log-rank test with the Bonferroni correction using R Statistical Software. In this study, we present findings indicating that ER121 treatment significantly attenuated breast tumor growth using a TNBC, HER2+ model, focusing on experimental brain metastasis, as quantified by total flux employing IVIS. These observations were further corroborated by analysis of brain tissue from the treatment group compared to controls. Data is presented as Mean ± S.D. statistical significance was calculated using Student t test (*p < 0.05). Additionally, ER121 significantly inhibited JIMT-1, a Herceptin-resistant breast cancer cell line was used in vivo xenograft model. Additionally, we used a neoadjuvant model with the MMTV-erbB2 (Fo5) transgenics and the tumor-free survival rates exhibited a remarkable difference between the control and treated groups when ER121 was administered orally. We found statistically significant p values of 0.048 employing log-rank test with Bonferroni Correction for comparing ER121high, ER121 Low, Herceptin and PBS groups. All analyses were performed using R Statistical Software. ER121 is a non-toxic small-molecule erbB kinase inhibitor and holds promise as an oral and systemic therapeutic agent for treating progressive erbB-driven tumors in therapeutic settings. Moreover, ER121 shows potential as a preventive therapy in neoadjuvant settings for erbB2-associated tumors and when administered systemically can dramatically limit erbB2 brain metastases in animal models.

Isoliquiritigenin Suppresses Breast Tumor Development by Enhancing Host Antitumor Immunity.

Isoliquiritigen (ISL), a constituent of licorice, has been shown to possess antitumorigenic effects in diverse cancer types. In this study, we observed that ISL suppressed breast tumor development significantly more effectively in immunocompetent mice than in immunocompromised ones. In exploring the cause of such a discrepancy, we detected robust tumor infiltration of CD8[Formula: see text] T lymphocytes in mice treated with ISL, not seen in tumors derived from vehicle-treated mice. Moreover, we found a dramatic reduction in PD-L1 in both experimental breast tumors and cultured breast cancer cells upon ISL treatment. In further experiments, we showed that ISL selectively elevated miR-200c in breast cancer and confirmed that PD-L1 mRNA is the target of miR-200c in both murine and human breast cancer cells. ISL suppression of PD-L1 was functionally linked to miR-200c/ZEB1/2 because (1) ISL diminished ZEB1/2; (2) knockdown of ZEB1/2 led to the disappearance of PD-L1; and (3) miR-200c antagomiR disabled ISL to reduce PD-L1. We found evidence that ISL reduced the level of PD-L1 by simultaneously intercepting the ERK and Src signaling pathways. In agreement with clinical finding that PD-L1 antibodies enhance efficacy of taxane-based therapy, we showed that ISL improved the tumoricidal effects of paclitaxel in an orthopedic murine breast tumor model. This study demonstrates that ISL-led tumor suppression acts through the augmentation of host antitumor immunity.

Harnessing Nature's ingenuity to engineer butterfly-wing-inspired photoactive nanofiber patches for advanced postoperative tumor treatment

Postoperative tumor treatment necessitates a delicate balance between eliminating residual tumor cells and promoting surgical wound healing. Addressing this challenge, we harness the innovation and elegance of nature's ingenuity to develop a butterfly-wing-inspired photoactive nanofiber patch (WingPatch), aimed at advancing postoperative care. WingPatch is fabricated using a sophisticated combination of electrostatic spinning and spraying techniques, incorporating black rice powder (BRP) and konjac glucomannan (KGM) into a corn-derived polylactic acid (PLA) nanofiber matrix. This fabrication process yields a paclitaxel-infused porous nanofiber architecture that mirrors the delicate patterns of butterfly wings. Meanwhile, all-natural composites have been selected for their strategic roles in postoperative recovery. BRP offers the dual benefits of photothermal therapy and antibacterial properties, while KGM enhances both antibacterial effectiveness and tissue regeneration. Responsive to near-infrared light, WingPatch ensures robust tissue adhesion and initiates combined photothermal and chemotherapeutic actions to effectively destroy residual tumor cells. Crucially, it simultaneously prevents infections and promotes wound healing throughout the treatment process. Its effectiveness has been confirmed by animal studies, and WingPatch significantly improves treatment outcomes in both breast and liver tumor models. Thus, WingPatch exemplifies our dedication to leveraging natural world's intricate patterns and inventiveness to propel postoperative care forward.

Platelet Angiopoietin-1 Protects Against Murine Models of Tumor Metastasis.

In addition to their fundamental roles in preserving vascular integrity, platelets also contribute to tumor angiogenesis and metastasis. However, despite being a reservoir for angiogenic and metastatic cytokines, platelets also harbor negative regulators of tumor progression. Angpt1 (angiopoietin-1) is a cytokine essential for developmental angiogenesis that also protects against tumor cell metastasis through an undefined mechanism. Although activated platelets release Angpt1 from α-granules into circulation, the contributions of platelet Angpt1 to tumor growth, angiogenesis, and metastasis have not been investigated. Using cytokine arrays and ELISAs, we first compared platelet Angpt1 levels in breast and melanoma mouse tumor models to tumor-free controls. We then assessed tumor growth and metastasis in mice lacking megakaryocyte and platelet Angpt1 (Angpt1Plt KO). The spontaneous metastasis of mammary-injected tumor cells to the lungs was quantified using RT-PCR (reverse transcription-polymerase chain reaction). The lung colonization of intravenously injected tumor cells and tumor cell extravasation were determined using fluorescent microscopy and flow cytometry. Platelet Angpt1 is selectively upregulated in the PyMT (polyoma middle tumor antigen) breast cancer mouse model, and platelets are the principal source of Angpt1 in blood circulation. While primary tumor growth and angiogenesis were unaffected, Angpt1Plt KO mice had both increased spontaneous lung metastasis and tumor cell lung colonization following mammary or intravenous injection, respectively. Although platelet Angpt1 did not affect initial tumor cell entrapment in the lungs, Angpt1Plt KO mice had increased tumor cell retention and extravasation. Serum from Angpt1Plt KO mice increased endothelial permeability and reduced VE (vascular endothelial)-cadherin expression at endothelial junctions compared with serum from control mice (Angpt1WT). Platelets provide an intravascular source of Angpt1 that restrains tumor metastasis by preserving the lung microvasculature to limit tumor cell extravasation.

Sustained estradiol valerate delivery by microneedles: A new effective platform to construct estrogen-dependent tumor model

The establishment of an estrogen receptor-positive (ER+) breast tumor model plays a crucial role in the preliminary screening of anticancer drugs and understanding disease mechanism. However, the construction of this model requires exogenous estrogen supplementation. The current method of estrogen supplementation was limited by its high cost and potential side effects. Herein, we utilized Poly D, L-lactic-co-glycolic acid (PLGA) as substrate to develop the estradiol valerate microneedle patch (EVMP). The EVMP exhibited excellent drug loading capacity (46 μg/needle) and good mechanical strength (>0.2 N/needle). Importantly, the EVMP exhibited favorable sustained release of estradiol valerate ability in vitro. Subsequently, the EVMP successfully achieved sustained release in Balb/c nude mice, resulting in an average MCF-7 (ER+) tumor volume of approximately 300 mm3 at day 35. In addition, no significant inflammatory reaction or urinary calculi were observed during this process, which further demonstrated the efficacy and safety of the EVMP. Overall, these findings suggested that the EVMP held great potential as a safe and animal-friendly alternative platform for constructing the ER + breast cancer model.

Targeted Endoperoxides Delivering Singlet Oxygen to Cancer Cell Mitochondria: Exploration of the Therapeutic Potential.

The clinical practice of photodynamic therapy of cancer (PDT) is mostly limited to superficial types of cancer. The major reason behind this limited applicability is the need for light in the photogeneration of ROS, and in particular singlet oxygen. In order to circumvent this major roadblock, we designed and synthesized naphthalene-derived endoperoxides with mitochondria targeting triphenylphosphonium moieties. Here, we show that these compounds release singlet oxygen by thermal cycloreversion, and initiate cell death with IC50<10 μM in cancer cell cultures. The mouse 4T1 breast tumor model study, where the endoperoxide compound was introduced intraperitoneally, also showed highly promising results, with negligible systemic toxicity. Targeted delivery of singlet oxygen to cancer cell mitochondria could be the breakthrough needed to transform Photodynamic Therapy into a broadly applicable methodology for cancer treatment by keeping the central tenet and discarding problematic dependencies on oxygen or external light.

Dual A2A/A2B Adenosine Receptor Antagonist M1069 Counteracts Immunosuppressive Mechanisms of Adenosine and Reduces Tumor Growth In Vivo.

While A2A adenosine receptor (AR) was considered as a major contributor to adenosine-mediated immunosuppression, A2B, having the lowest affinity to adenosine, has also emerged as a potential contributor to tumor promotion. Therefore, in adenosine-rich tumor microenvironment (TME), where A2B could be complementary and/or compensatory to A2A, simultaneous targeting of A2A and A2B ARs can provide higher potential for cancer immunotherapy. We developed M1069-a highly selective dual antagonist of the A2A and A2B AR. In assays with primary human and murine immune cells, M1069 rescued IL2 production from T cells (A2A dependent) and inhibited VEGF production by myeloid cells (A2B dependent) in adenosine-high settings. M1069 also demonstrated superior suppression of the secretion of protumorigenic cytokines CXCL1, CXCL5, and rescue of IL12 secretion from adenosine-differentiated dendritic cells compared to an A2A-selective antagonist (A2Ai). In a one-way mixed lymphocyte reaction (MLR) assay, adenosine-differentiated human and murine dendritic cells treated with M1069 demonstrated superior T-cell stimulatory activity compared to dendritic cells differentiated in presence of A2Ai. In vivo, M1069 decreased tumor growth as a monotherapy and enhanced antitumor activity of bintrafusp alfa (BA) or cisplatin in syngeneic adenosinehi/CD73hi 4T1 breast tumor model, but not in the CD73 knockout 4T1 tumor model or in adenosinelow/CD73low MC38 murine colon carcinoma model. In summary, our dual A2A/A2B AR antagonist M1069 may counteract immune-suppressive mechanisms of high concentrations of adenosine in vitro and in vivo and enhance the antitumor activity of other agents, including BA and cisplatin.

Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth-by 100 to 140 times-in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.

A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy

The antitumor performance of PROteolysis-TArgeting Chimeras (PROTACs) is limited by its insufficient tumor specificity and poor pharmacokinetics. These disadvantages are further compounded by tumor heterogeneity, especially the presence of cancer stem-like cells, which drive tumor growth and relapse. Herein, we design a region-confined PROTAC nanoplatform that integrates both reactive oxygen species (ROS)-activatable and hypoxia-responsive PROTAC prodrugs for the precise manipulation of bromodomain and extraterminal protein 4 expression and tumor eradication. These PROTAC nanoparticles selectively accumulate within and penetrate deep into tumors via response to matrix metalloproteinase-2. Photoactivity is then reactivated in response to the acidic intracellular milieu and the PROTAC is discharged due to the ROS generated via photodynamic therapy specifically within the normoxic microenvironment. Moreover, the latent hypoxia-responsive PROTAC prodrug is restored in hypoxic cancer stem-like cells overexpressing nitroreductase. Here, we show the ability of region-confined PROTAC nanoplatform to effectively degrade BRD4 in both normoxic and hypoxic environments, markedly hindering tumor progression in breast and head-neck tumor models.

CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.

Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.

Patient-specific vascularized tumor model: Blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment. Our findings demonstrate that macrophages in vascularized breast and lung tumor models can enhance monocyte recruitment via CCL7 and CCL2, mediated by CSF-1R. Additionally, a multispecific antibody targeting CSF-1R, CCR2, and neutralizing TGF-β (CSF1R/CCR2/TGF-β Ab) repolarizes TAMs towards an anti-tumoral M1-like phenotype, reduces monocyte chemoattractant protein secretion, and blocks monocyte migration. This antibody also inhibits monocyte recruitment in patient-specific vascularized tumor models. In summary, this vascularized tumor model recapitulates the monocyte recruitment cascade, enabling functional testing of innovative therapeutic antibodies targeting TAMs in the tumor microenvironment.

Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy

BackgroundThe combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon.MethodsConstructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels.ResultsThe abscopal effect was further amplified in the “cold” tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response.ConclusionsBi was used as an artificially implanted anaerobic target to cause a transient “infection” at the tumor, causing the tumor to become locally inflamed and “hot”, and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.

Ultra-wideband Imaging of Breast Tumors Based on Global Back Projection Algorithm

Abstract Tumor imaging in medicine requires consideration of human safety, image quality clarity, and cost of imaging. Ultra-wideband (UWB) technology employs large bandwidth channels that enable high-speed data transmission. This determines that it can provide high-quality images quickly while still being a harmless imaging method. Therefore, it is essential to construct a UWB microwave detection tumor system. The creation of a vector network analyzer (VNA) based microwave imaging system in this work. To adapt to breast imaging, this paper improved the imaging algorithm of global back projection (GBP) based on the classical back projection algorithm. To verify the system’s feasibility, this paper performed UWB detection experiments using a breast tumor model. By comparing the simulation results, the final imaging results show that the UWB imaging system can detect tumors located at two different locations in the model and that high-quality images can be obtained in the near field using the GBP algorithm. This paper provides a reliable and low-cost method for medical diagnosis.

Intermittent fasting boosts antitumor immunity by restricting CD11b+Ly6ClowLy6Glow cell viability through glucose metabolism in murine breast tumor model

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy. However, it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting. Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis, as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer. During this process, both the immunosuppressive monocytic- (M-) and granulocytic- (G-) myeloid-derived suppressor cell (MDSC) decreased, accompanied by an increase in interleukin (IL) 7R+ and granzyme B+ T cells in the tumor microenvironment. Interestingly, we observed that Ly6Glow G-MDSC sharply decreased after fasting treatment, and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets. Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocyte-monocyte progenitor and the generation of colony-stimulating factors and IL-6, which both contributed to the accumulation of G-MDSC. On the other hand, glucose metabolism restriction can directly induce the apoptosis of Ly6Glow G-MDSC, but not Ly6Ghigh subsets. In summary, these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3+ T cells, providing potential solutions for enhancing immune-based cancer interventions.

Synchronized Codelivery of Combination Chemotherapies Intratumorally Using a Lipidic Lyotropic Liquid Crystal System.

In this work, an injectable in situ depot-forming lipidic lyotropic liquid crystal (L3C) system is developed to codeliver a precisely synchronized combination of chemotherapeutics intratumorally. The developed L3C system is composed of amphiphilic lipids and surfactants, including monoolein, phosphatidylcholine, tocopherol acetate, and d-α-tocopherol polyethylene glycol 1000 succinate. Owing to its amphiphilic nature, the developed formulation can coaccommodate both hydrophobic and hydrophilic chemotherapeutic moieties simultaneously. The study presents a proof of concept by designing a combination chemotherapy regimen in vitro and demonstrating its in vivo translation using doxorubicin and paclitaxel as model hydrophilic and hydrophobic drug moieties, respectively. The synchronized combination of the two chemotherapeutics with maximum synergistic activity was identified, coloaded in the developed L3C system at predefined stoichiometric ratios, and evaluated for antitumor efficacy in the 4T1 breast tumor model in BALB/c mice. The drug-loaded L3C formulation is a low-viscosity injectable fluid with a lamellar phase that transforms into a hexagonal mesophase depot system upon intratumoral injection. The drug-loaded depot system locally provides sustained intratumoral delivery of the chemotherapeutics combination at their precisely synchronized ratio for over a period of one month. Results demonstrate that the exposure of the tumor to the precisely synchronized intratumoral chemotherapeutics combination via the developed L3C system resulted in significantly higher antitumor activity and reduced cardiotoxicity compared to the unsynchronized combination chemotherapy or the synchronized but uncoordinated drug delivery administered by a conventional intravenous route. These findings demonstrate the potential of the developed L3C system for achieving synchronized codelivery of the chemotherapeutics combination intratumorally and improving the efficacy of combination chemotherapy.

Photothermal-controlled NO-releasing Nanogels reverse epithelial-mesenchymal transition and restore immune surveillance against cancer metastasis

Metastasis leads to high mortality among cancer patients. It is a complex, multi-step biological process that involves the dissemination of cancer cells from the primary tumor and their systemic spread throughout the body, primarily through the epithelial-mesenchymal transition (EMT) program and immune evasion mechanisms. It presents a challenge in how to comprehensively treat metastatic cancer cells throughout the entire stage of the metastatic cascade using a simple system. Here, we fabricate a nanogel (HNO-NG) by covalently crosslinking a macromolecular nitric oxide (NO) donor with a photothermal IR780 iodide-containing hyaluronic acid derivative via a click reaction. This enables stable storage and tumor-targeted, photothermia-triggered release of NO to combat tumor metastasis throughout all stages. Upon laser irradiation (HNO-NG+L), the surge in NO production within tumor cells impairs the NF-κB/Snail/RKIP signaling loop that promotes the EMT program through S-nitrosylation, thus inhibiting cell dissemination from the primary tumor. On the other hand, it induces immunogenic cell death (ICD) and thereby augments anti-tumor immunity, which is crucial for killing both the primary tumor and systemically distributed tumor cells. Therefore, HNO-NG+L, by fully leveraging EMT reversal, ICD induction, and the lethal effect of NO, achieved impressive eradication of the primary tumor and significant prevention of lung metastasis in a mouse model of orthotropic 4T1 breast tumor that spontaneously metastasizes to the lungs, extending the NO-based therapeutic approach against tumor metastasis.

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.

Immunogenic Treatment of Metastatic Breast Cancer Using Targeted Carbon Nanotube Mediated Photothermal Therapy in Combination with Anti-Programmed Cell Death Protein-1.

The high prevalence of breast cancer is a global health concern, compounded by the lack of safe or effective treatments for its advanced stages. These facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells and the tumor vasculature. Here, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of single-walled carbon nanotubes (SWCNTs) to ANXA5-the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition, creating a systemic anticancer immune response. In vitro ablation of cells incubated with the conjugate promoted cell death in a dose-dependent and targeted manner. This treatment strategy was tested in vivo with the orthotopic EMT6 breast tumor model in female balb/cJ mice. Enhanced therapeutic effects were achieved by using intratumoral injection of the conjugate and treating tumors at a lower PTT temperature (45°C). Intratumoral injection prevented the accumulation of the SWCNTs in major clearance organs. When combined with checkpoint inhibition of anti-programmed cell death protein-1, SWCNT-ANXA5-mediated PTT increased survival and 80% of the mice survived for 100 days. Evidence of immune system activation by flow cytometry of splenic cells strengthens the hypothesis of an abscopal effect as a mechanism of prolonged survival. SIGNIFICANCE STATEMENT: This study demonstrated a relatively high survival rate (80% at 100 days) of mice with aggressive breast cancer when treated with photothermal therapy using the SWCNT-ANXA5 conjugate injected intratumorally and combined with immune stimulation using the anti-programmed cell death protein-1 checkpoint inhibitor. Photothermal therapy was accomplished by maintaining the tumor temperature at a relatively low level of 45°C and avoiding accumulation of the nanotubes in the clearance organs by using intratumoral administration.