Triple-negative Breast Cancer Research Articles

Design, Screening and Development of Asymmetric siRNAs Targeting the MYC Oncogene in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks hormone receptor and Her2 (ERBB2) expression, leaving chemotherapy as the only treatment option. The urgent need for targeted therapy for TNBC patients has led to the investigation of small interfering RNAs (siRNAs), which can target genes in a sequence-specific manner, unlike other drugs. However, the clinical translation of siRNAs has been hindered by the lack of an effective delivery system, except in the case of liver diseases. The MYC oncogene is commonly overexpressed in TNBC compared to other breast cancer subtypes. In this study, we used siRNA to target MYC in MDA-MB-231, MDA-MB-157, MDA-MB-436 and Hs-578T cells. We designed various symmetric and asymmetric (asiRNAs), screened them for in vitro efficacy, modified them for enhanced nuclease resistance and reduced off-target effects, and conjugated them with cholesterol (ChoL) and docosanoic acid (DCA) as a delivery system. DCA was conjugated to the 3' end of asiRNA by a cleavable phosphodiester linker for in vivo delivery. Our findings demonstrated that asiRNA-VP and Mod_asiRNA10-6 efficiently downregulated MYC and its downstream targets, including RRM2, RAD51 and PARP1. Moreover, in a tumor xenograft model, asiRNA-VP-DCA effectively knocked down MYC mRNA and protein expression. Remarkably, durable knockdown persisted for at least 46 days postdosing in mouse tumor xenografts, with no visible signs of toxicity, underscoring the safety of DCA-conjugated asiRNAs. In conclusion, this study developed novel asiRNAs, design platforms, validated modification patterns, and in vivo delivery systems specifically targeting MYC in TNBC.

Bifunctional Oxaliplatin (IV) Prodrug Based pH-Sensitive PEGylated Liposomes for Synergistic Anticancer Action Against Triple Negative Breast cancer.

Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and in-vivo performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200nm and higher drug loading (~ 4.26 ± 0.18%). In-vitro release displayed pH-dependent sustained release for up to 48h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC50 in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. In-vivo efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC.

Biomimetic Nanovesicles Synergize with Short-Term Fasting for Enhanced Chemotherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer among women. Chemotherapy acts as the standard regimen for TNBC treatment but suffers from limited drug accumulation in tumor regions and undesired side effects. Herein, we developed a synergistic strategy by combining a red blood cell (RBC) membrane-liposome hybrid nanovesicle with short-term fasting (STF) for improved chemotherapy of TNBC. The biomimetic nanovesicles exhibited reduced phagocytosis by macrophages while displaying a significant increase in tumor cell uptake through caveolae/raft-mediated endocytosis under nutrient-deprivation conditions. Importantly, drug-loaded nanovesicles and STF treatment synergistically increased the cytotoxicity of tumor cells by inhibiting their cell cycles and aerobic glycolysis as well as amplifying the reactive oxygen species (ROS) and autophagosomes generation. In the STF-treated mice, biomimetic nanovesicles greatly improved the antitumor efficacy at a lower drug dosage and inhibited the undesired metastasis of TNBC. Overall, we demonstrated that biomimetic nanovesicles synergizing with STF therapy serve as a promising therapeutic strategy for enhanced chemotherapy of malignant TNBC.

Natural lung-tropic TH9 cells: a sharp weapon for established lung metastases

BackgroundLung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (TH9) cells have shown promise in treating solid...

A plain language summary of results from the TORCHLIGHT trial of toripalimab plus chemotherapy for metastatic or recurrent triple-negative breast cancer.

A plain language summary of results from the TORCHLIGHT trial of toripalimab plus chemotherapy for metastatic or recurrent triple-negative breast cancer.

Discovery of a molecular glue for EGFR degradation.

Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.

Design Principles of an Engineered Metastatic Niche for Monitoring of Cancer Progression.

Across many types of cancer, metastatic disease is associated with a substantial decrease in 5-year survival rates relative to only a localized primary tumor. Many patients self-report metastatic disease due to disruption of normal organ or tissue function, and earlier detection could enable treatment with a lower burden of disease. We have previously reported a subcutaneous biomaterial implant for early detection by serving as an engineered metastatic niche, which has been reported to recruit tumor cells before colonization of solid organs. In this report, we investigated the design principles of the scaffold and defined the conditions for use in disease detection. Using the metastatic 4T1 triple-negative breast cancer model, we identified that a porous structure was essential to capture tumor and immune cells. Scaffolds of multiple diameters were investigated for their ability to serve as a metastatic niche, with a porous scaffold with a diameter as small as 2 mm identifying disease accurately. Additionally, scaffolds that had been in vivo for 1-5 weeks were able to identify disease accurately. Finally, the sensitivity of the scaffold relative to liquid biopsies was analyzed, with scaffolds accurately detecting disease at earlier time points than liquid biopsy. Collectively, these studies inform the design principles and use conditions for porous scaffolds to detect metastatic disease.

Synergistic Anticancer Efficacy of Curcumin and Doxorubicin Combination Treatment Inducing S-phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells: An In Vitro Study

Synergistic Anticancer Efficacy of Curcumin and Doxorubicin Combination Treatment Inducing S-phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells: An In Vitro Study

Predictive value of 18F-fluorodeoxyglucose uptake for axillary lymph node metastasis in operable breast cancer: impact of molecular subtypes.

To evaluate the predictive value of standardized uptake value (SUV) in both primary tumors and axillary lymph nodes (ALNs) using FDG PET/CT for lymph node metastasis in breast cancer patients, and to assess the influence of molecular subtypes on this predictive performance. This retrospective study included 287 patients with invasive ductal carcinoma (IDC) who underwent FDG PET/CT prior to surgery between September 2016 and December 2019. The maximum standardized uptake value (SUVmax)of primary tumors (SUV-B) and ALNs (SUV-LN) were analyzed. Molecular subtypes were classified as hormone receptor-positive, HER2-positive, and triple-negative breast cancer (TNBC). Receiver operating characteristic (ROC) curve analysis was performed to assess and compare the diagnostic performance of SUV-B and SUV-LN for predicting ALN metastasis. Among the 287 patients, 62 (21.6%) had confirmed ALN metastasis. The median SUV-LN was significantly higher in patients with metastasis compared to those without metastasis(1.5 vs. 0.9; P < 0.001). SUV-LN demonstrated good discriminative performance for ALN metastasis (AUC: 0.796), whereas SUV-B did not show significant predictive value (AUC: 0.536). The SUV_LN demonstrated significantly lower predictive performance for ALN metastasis in the hormone-positive group (AUC: 0.796) compared to the excellent discriminative performance in the HER2-positive (AUC: 0.923, P = 0.018) and TNBC (AUC: 0.940, P = 0.004) groups. Hormone receptor-positive tumors also exhibited lower FDG uptake in metastatic lymph nodes compared to HER2-positive and TNBC subtypes (P = 0.031). FDG PET/CT SUV-LN effectively predicts ALN metastasis in HER2-positive and TNBC subtypes. Hormone receptor-positive breast cancers show lower FDG uptake in metastatic ALNs, reducing diagnostic accuracy. This finding may aid in selecting the most appropriate diagnostic modality based on tumor characteristics in the era of personalized medicine.

Pirfenidone promotes cell cycle arrest and apoptosis of triple‑negative breast cancer cells by suppressing Hedgehog/GLI1 signaling.

Breast cancer is a common malignant tumor in women and triple-negative breast cancer (TNBC) is the most challenging type of breast cancer with poor prognosis. We aimed to elucidate the effects of pirfenidone, a FDA-approved oral anti-fibrotic drug which has recently shown antitumor potential, in the progression of TNBC and the underlying mechanisms. After TNBC cells were treated with pirfenidone, cell viability was evaluated using CCK-8 assay. The EDU staining was applied for reflecting the ability of cell proliferation. Additionally, cell cycle distribution and apoptotic rate of TNBC cells exposed to pirfenidone were determined by flow cytometry. The levels of proteins associated with cell cycle, apoptosis and Hedgehog/gliomaassociated oncogene homolog (GLI)1 signaling was examined through western blot. Then, GLI1 was upregulated to analyze the proliferation, cell cycle and apoptosis of TNBC cells in the presence of pirfenidone to reveal the regulatory mechanism. Pirfenidone dose-dependently decreased the viability and proliferation of MDA-MB-231 and HCC-1937 cells. Besides, the distribution of TNBC cells in G0/G1 phase was significantly elevated by pirfenidone, accompanied by downregulated levels of CyclinD1, CDK4 and CDK6. Simultaneously, pirfenidone caused remarkably increased apoptotic MDA-MB-231 and HCC-1937 cells, coupled with downregulated BCL2 expression as well as upregulated Bax, cleaved caspase3 and cleaved PARP expression. Expression of proteins related to Hedgehog/gliomaassociated oncogene homolog (GLI)1 signaling was tested through western blot. Particularly, GLI1 and PTCH1 levels were dose-dependently inhibited after pirfenidone exposure. Interestingly, GLI1 overexpression attenuated the influences of pirfenidone on the proliferation, cell cycle and apoptosis of TNBC cells. Collectively, pirfenidone arrests the cell cycle and promotes apoptosis of TNBC cells by suppressing Hedgehog/GLI1 signaling.

Triple Negative Breast Cancer: Immunohistochemistry-Based Sub-Classification and Correlation with Clinico-Demographic Profile and Survival in Indian Patients

Triple Negative Breast Cancer: Immunohistochemistry-Based Sub-Classification and Correlation with Clinico-Demographic Profile and Survival in Indian Patients

Progress of research on PD-L1 inhibitor adebrelimab usage in malignant tumors

Adebrelimab is a humanized monoclonal antibody against programmed death-ligand 1 (PD-L1) and is also a novel immune checkpoint inhibitor, which has been used in the first-line treatment of extensive stage small cell lung cancer (SCLC) with its unique mechanism of action and good clinical efficacy. Significant progress has been made in the treatment of adebrelimab in other malignancies such as non-small cell lung cancer, triple-negative breast cancer, esophageal squamous cell carcinoma, and the treatment of SCLC at different stages is also being explored. Therefore, adebrelimab emerges as a promising new treatment option for patients with small cell lung cancer (SCLC) and other types of malignant tumors.

Promising Anti-Microbial from Functionalized Magnesium Nickel Doped Cobalt Nano-Ferrites Structural and Optical Studies

Using low temperature solution combustion method, the magnesium-nickel doped cobalt nanoferrites of formula MgxNixCo1–2xFe2O4 (x values 0.0, 0.1, 0.2.) have been synthesized. The anticancer assessment was done on the nano ferrites using MTT assay on triple negative breast cancer MDAMB-231 cell line. The anti-inflammatory studies were to measure inhibition % of anti-inflammatory at different concentrations. The structural characterizations analyzed using XRD, FTIR, FE-SEM and TGA-DTA. The XRD results confirms that the samples have cubic spinel structures. The crystallite size is confirmed and it lies between 30 nm–36 nm. The FT-IR confirms the presence of a metal ion peak around 559 cm−1 to 587 cm−1. The formation of metal phase oxide in the TGA curve is the cause of the last stage of weight loss at temperatures between 600 and 800 °C. The SEM gives the aggregated grain boundaries with irregular distribution of particles with grain size around 27.5 nm. The optical spectral features confirmed as cut-off varied between 503 nm–534 nm; Indirect band gap varied between 1.94 eV–1.73 eV; direct band gap varied between 2.45–2.12 eV. The application-oriented studies of the present investigation led to the bio-related applications in various fields.

The cardio-oncologic burden of breast cancer: molecular mechanisms and importance of preclinical models.

Breast cancer, the most prevalent cancer affecting women worldwide, poses a significant cardio-oncological burden. Despite advancements in novel therapeutic strategies, anthracyclines, HER2 antagonists, and radiation remain the cornerstones of oncological treatment. However, each carries a risk of cardiotoxicity, though the molecular mechanisms underlying these adverse effects differ. Common mechanisms include DNA damage response, increased reactive oxygen species, and mitochondrial dysfunction, which are key areas of ongoing research for potential cardioprotective strategies. Since these mechanisms are also essential for effective tumor cytotoxicity, we explore tumor-specific effects, particularly in hereditary breast cancer linked to BRCA1 and BRCA2 mutations. These genetic variants impair DNA repair mechanisms, increase the risk of tumorigenesis and possibly for cardiotoxicity from treatments such as anthracyclines and HER2 antagonists. Novel therapies, including immune checkpoint inhibitors, are used in the clinic for triple-negative breast cancer and improve the oncological outcomes of breast cancer patients. This review discusses the molecular mechanisms underlying BRCA dysfunction and the associated pathological pathways. It gives an overview of preclinical models of breast cancer, such as genetically engineered mouse models, syngeneic murine models, humanized mouse models, and various in vitro and ex vivo systems and models to study cardiovascular side effects of breast cancer therapies. Understanding the underlying mechanism of cardiotoxicity and developing cardioprotective strategies in preclinical models are essential for improving treatment outcomes and reducing long-term cardiovascular risks in breast cancer patients.

The association of HIV status with triple-negative breast cancer in patients with breast cancer in South Africa: a cross-sectional analysis of case-only data from a prospective cohort study

Breast cancer is the most common malignancy diagnosed among women in South Africa, with the aggressive triple-negative subtype comprising approximately 15% of breast cancers in this population. South Africa has the largest population of people with HIV in the world. This study aims to evaluate the association between HIV status and the proportion of patients with breast cancer with the triple-negative subtype. We did a cross-sectional analysis of case-only data from the South African Breast Cancer and HIV Outcomes (SABCHO) study, a prospective cohort study recruiting patients with newly diagnosed breast cancer at six public hospitals in South Africa. We analysed data from patients who enrolled in SABCHO between Jan 1, 2015, and Jan 18, 2022. Women aged 18 years or older with newly diagnosed and histologically confirmed invasive breast cancer were eligible. Participants were classified as HIV-positive or HIV-negative by use of an ELISA-based HIV test done at the time of enrolment. We developed multivariable logistic regression models to test for an association between HIV status and the proportion of triple-negative relative to non-triple-negative breast cancers while adjusting for demographic and reproductive risk factors. Of the 4122 patients enrolled in the SABCHO cohort within our study timeframe, 239 patients were excluded due to unknown breast cancer subtype (n=141), HIV status (n=97), or race (n=1). 3883 women with breast cancer were included in the study, of whom 637 (16·4%) had triple-negative breast cancer, 894 (23·0%) were HIV-positive, and 186 (4·8%) had triple-negative breast cancer and HIV. Triple-negative breast cancer accounted for 186 (20·8%) of 894 breast cancers among women who were HIV-positive and 451 (15·1%) of 2989 breast cancers among women who were HIV-negative (p<0·0001). In the fully adjusted logistic regression model, HIV-positive status was associated with an increased proportion of triple-negative breast cancer (adjusted odds ratio [OR] 1·39, 95% CI 1·12-1·74, compared with women who were HIV-negative). When compared with women who were HIV-negative, the association between HIV-positive status and the proportion of triple-negative breast cancer was strongest among the subgroup of women with a duration of HIV infection of 2 years or longer (1·57, 1·23-2·00) and those on antiretroviral therapy (ART; 1·47, 1·16-1·87). Patients with breast cancer and chronic HIV who are on ART are more likely to have triple-negative breast cancer than patients with breast cancer without HIV. This association is independent of age, race, and reproductive factors. US National Institutes of Health, University of the Witwatersrand, South Africa Medical Research Council Common Epithelial Cancers Research Center, Conquer Cancer Foundation, and Varmus Global Scholars Fund.

FAM83H regulated by glis3 promotes triple-negative breast cancer tumorigenesis and activates the NF-κB signaling pathway.

Triple-negative breast cancer (TNBC) is a highly aggressive and invasive form of breast cancer (BC) with a high mortality rate and a lack of effective targeted drugs. Family with sequence similarity 83 member H (FAM83H) is critically implicated in tumorigenesis. However, the potential role of FAM83H in TNBC remains elusive. Here, we discovered that FAM83H exhibited high expression in tumor tissues of patients with TNBC and was associated with TNM stage. Gain- or loss-of-function experiments were conducted to explore the biological role of FAM83H in TNBC. Subsequently, functional enrichment analysis confirmed that FAM83H overexpression promoted TNBC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), accompanied by upregulation of cyclin E, cyclin D, Vimentin, N-cadherin and Slug. As observed, FAM83H knockdown showed anti-cancer effects, such as fostering apoptosis and inhibiting tumorigenicity and metastasis of TNBC cells. Mechanistically, FAM83H activated the NF-κB signaling pathway. Moreover, a dual-luciferase reporter assay demonstrated that GLIS family zinc finger 3 (GLIS3) bound to the promoter of FAM83H and enhanced its transcription. Notably, overexpression of GLIS3 significantly stimulated TNBC cell proliferation and invasion, and all of this was reversed by rescue experiments involving the knockdown of FAM83H. Overall, FAM83H exacerbates tumor progression, and in-depth understanding of FAM83H as a therapeutic target for TNBC will provide clinical translational potential for intervention therapy.

Simultaneous targeting and suppression of heat shock protein 60 to overcome heat resistance and induce mitochondrial death of tumor cells in photothermal immunotherapy

As the most aggressive and metastatic subtype of breast cancer, clinical demands of triple negative breast cancer (TNBC) have far not been met. Heat shock protein 60 (HSP60) is over expressed in tumor cells and impair the efficacy of photothermal therapy. In this work, a conjugate composed of self-designed peptide targeting HSP60 and gold nanorods was constructed, referred to as AuNR-P17. Results showed that AuNR-P17 was able to simultaneously down regulate the level of HSP60 and locate in the mitochondria where HSP60 is enriched in the tumor cells of TNBC, which also impeded the interaction between HSP60 and integrin α3, thereby reducing the tumor cells' heat tolerance and metastatic capabilities. At the same time, AuNR-P17 induced remarkable mitochondrial apoptosis when exposed to the laser irradiation of 808 nm. The dual functions of AuNR-P17 led to the decrement of BCL-2 and the activation of p53 and cleaved caspase-3. The danger associated molecular patterns (DAMPs) generated from the mitochondrial apoptosis elicited strong and long-term specific immune responses against TNBC in vivo and ultimately inhibited the tumor metastasis and recurrence with significantly prolonged survival (>100 days) on TNBC mice. In conclusion, this study demonstrated HSP60 a promising potential therapeutic target for triple negative breast cancer and exhibited powerful capacity of AuNR-P17 in photothermal immune therapy.

Plant-derived extracellular vesicles release combined with systemic DOX exhibits synergistic effects in 3D bioprinted triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, lacking targeted therapeutic options. Hydrogels, particularly gelatin methacrylate (GelMA), have emerged as promising materials for localized drug delivery due to their biocompatibility and tunable properties. This study investigates a dual-delivery system for enhancing the treatment efficacy of triple-negative breast cancer (TNBC) using a combination of extracellular vesicles (EVs) derived from Citrus limon L. and the chemotherapeutic drug doxorubicin (DOX). We fabricated 3D bioprinted GelMA scaffolds to achieve localized and controlled release of EVs and evaluated their synergistic effects with systemic DOX delivery on both primary and metastatic 3D TNBC models.The GelMA scaffolds, especially those with 95 % methacrylation, exhibited higher stiffness, which enhanced their sustained release. Following 48-h incubation, the combination of EVs and DOX significantly increased cytotoxicity in the primary 3D TNBC model, reducing cell viability to approximately 30 % compared to controls. This was notably more effective than treatments with DOX or EVs alone. During the extended 7-day incubation period, the combination treatment continued to show superior efficacy, with persistently high levels of ROS generation and further reduction in cell viability. In a metastatic 3D TNBC model, a significant sensitivity to the combined treatment was observed, which notably inhibited aggregate formation and migration. Importantly, EVs-embedded scaffolds promoted the proliferation of human fibroblasts, highlighting their non-toxic nature, while concurrently inhibiting TNBC cell growth. This approach provides a promising strategy to improve the treatment outcomes of TNBC by exploiting the synergistic effects of local EVs release and systemic chemotherapy.

Innovative Nanomaterials for Targeting Hypoxia to Improve Treatment for Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer with a high rate of metastases, a short overall survival time, and a poor response to targeted therapy. Improving tumor hypoxia by lowering the oxygen consumption rate of breast tumor cells is a powerful strategy. A viable way to address this issue is to improve therapeutic efficacy by improving the effectiveness of radiation and overcoming drug resistance in TNBC treatment by controlling hypoxia in the tumor microenvironment. The failure of radiation and chemotherapy in TNBC is frequently caused by hypoxia. In TNBC therapy, novel nanomaterials are used for oxygen delivery or generation to affect the tumor microenvironment to improve the effects of ionizing radiation using nanoplatforms. One of the growing fields is novel nano-based drug delivery devices for hypoxic regions and hypoxia- inducible factor-1 (HIF1) targeted therapeutics. Biocompatible nanoparticles may be used in the treatment of TNBC patients in the clinic. Because of the rising market and competition, intellectual property rights (IPR), patents, and tactics may be critically considered. To better comprehend the current state of IPR and patents in cancer nanotechnology, this overview examines recent advances and sophisticated protection measures in this area.

Enhanced antitumor activity of lapatinib against triple-negative breast cancer via loading in human serum albumin

Triple-negative breast cancer (TNBC) presents significant treatment challenges due to its aggressive nature. Human serum albumin (HSA) is a promising drug delivery platform, offering high binding capacity, biocompatibility, and reduced toxicity. Lapatinib (LAP), a tyrosine kinase inhibitor for TNBC, is hindered by poor water solubility and toxicity. To address these issues, LAP was encapsulated within HSA (HSA-LAP), and its structural, drug release, and therapeutic properties were evaluated in cellular and animal TNBC models. HSA-LAP demonstrated efficient drug loading and pH-dependent tumor-targeted release, favoring acidic tumor microenvironments. Structural and microscopic studies confirmed LAP binding to HSA, with only minor structural and no significant morphological changes observed. In 4 T1 breast cancer cells, HSA-LAP exhibited superior anti-proliferative, pro-apoptotic, and anti-migratory effects compared to free LAP, which were further amplified when combined with VGB3, a VEGFR1/2-targeting peptide, indicating an effective dual-targeting strategy for TNBC. In vivo, HSA-LAP showed greater tumor inhibition and improved survival rates, especially in combination with VGB3 through apoptosis induction. Biodistribution studies using technetium-99 m (99mTc) labeling revealed enhanced tumor targeting. These findings highlight the potential of HSA as a delivery vehicle for LAP, particularly in combination with anti-angiogenic agents like VGB3, offering a promising therapeutic strategy for TNBC.