Therapeutic efficacy for malignancies and neurological disorders is fundamentally restricted by biological barriers, particularly the complex tumor microenvironment (TME) and selective blood-brain barrier (BBB). This review analyzes advanced drug delivery technologies engineered to overcome these obstacles. For TME penetration, stimuli-responsive nanocarriers enable spatiotemporally controlled drug release, while tumor-penetrating peptide functionalized nanoparticles enhance deep tumor diffusion; metal-organic frameworks further facilitate combinatorial therapy via microenvironment-triggered payload release. Regarding BBB transcendence, receptor-mediated transcytosis strategies significantly improve brain uptake, and physical-assisted approaches achieve localized barrier modulation. Bioinspired platforms-notably cell-membrane-coated nanoparticles and exosomes-demonstrate superior immune evasion and tissue-specific accumulation. Despite promising clinical progress exemplified by ANG1005 and focused ultrasound-assisted liposomal doxorubicin, translation challenges persist, including TME heterogeneity, scalable manufacturing complexities, and long-term biosafety. Future development prioritizes multifunctional theranostic systems integrating barrier-remodeling agents, artificial intelligence (AI)-optimized nanocarrier design, and sustainable manufacturing processes. Collectively, these innovations are transforming advanced drug delivery into a core therapeutic paradigm for intractable diseases.

Liposomal Nanocarriers in Precision Oncology: Advances and Prospects.

Background/Objectives: Solid tumors are characterized by a dense stromal structure and heterogeneous microenvironments that limit intratumoral drug penetration and contribute to immune exclusion. We developed perfluoropentane (PFP)-based phase-change nanodroplets (IMP700) and aimed to identify focused ultrasound (FUS) parameters that enhance cavitation and sonoporation to improve drug delivery and immune engagement in tumor models. Methods: IMP700 was prepared as lipid-shelled PFP nanodroplets and physicochemically characterized. Acoustic droplet vaporization (ADV), echogenicity, and cavitation were evaluated in vitro and in vivo using ultrasound imaging and cavitation analysis under varying FUS parameters, including acoustic intensity, duty cycle, and pulse repetition frequency (PRF), in PANC-1 xenograft tumors. Sonoporation was assessed by co-administering an ultrasound-responsive doxorubicin liposome (IMP301), and intratumoral drug distribution was analyzed by confocal imaging. Immune responses were evaluated in a syngeneic 4T1 tumor model by quantifying CD8+ T-cell infiltration after repeated treatments. Results: IMP700 exhibited nanoscale size and high PFP encapsulation efficiency and underwent ADV with increased echogenicity and intensity-dependent cavitation. In vivo, a 2% duty cycle and 10 Hz PRF produced strong and reproducible cavitation. Under these conditions, IMP700 markedly increased inertial cavitation and enhanced intratumoral drug penetration compared to FUS alone. Combined IMP700 and FUS treatment also increased intratumoral CD8+ T-cell infiltration. Conclusions: IMP700 amplifies FUS-induced cavitation, improves sonoporation-mediated drug delivery, and promotes CD8+ T-cell infiltration, which supports the use of FUS-activated nanodroplets as a strategy to overcome stromal and immunological barriers in solid tumors.

Comparing the Delivery of Free and Liposomal Doxorubicin Across the Blood-Brain Barrier Following Microbubble-Mediated Focused Ultrasound.

Nudge strategies are well-established in behavioral economics as effective approaches for promoting desirable behaviors. However, the potential benefits of integrating nudge-based strategies into pharmacist-led patient education have not yet been demonstrated. Here, we present a study protocol for an interventional trial to address this issue. The PHARM-NUDGE study is a multicenter, randomized, parallel-group, single-blind, controlled trial prospectively designed to evaluate whether nudge-based pharmacist-led education can promote patients' preventive behaviors against skin toxicities associated with cancer chemotherapy. The key inclusion criteria are as follows: (1) patients who are men or women and aged 18 years or older and (2) patients scheduled to receive a chemotherapy regimen containing capecitabine, liposomal doxorubicin, lenvatinib, cetuximab, or panitumumab in outpatient chemotherapy units or during hospitalization. The enrolled patients are randomly assigned in a 2:1 ratio to the nudge-based education or standard education groups. Pharmacists responsible for patient education utilize special educational tools that incorporate nudge strategies and provide skincare education to patients assigned to the nudge-based education group. Patients assigned to the standard education group receive skincare education with equivalent content but without nudges. The primary endpoint is the proportion of patients in each group who achieve four or more of the five predefined behavioral criteria. The PHARM-NUDGE study is the first randomized controlled trial to evaluate the potential benefits of integrating nudge strategies into pharmacist-led skincare education for patients undergoing cancer chemotherapy with a high risk of skin toxicity, with patient enrollment initiated on October 15, 2025. Completion of the trial and acquisition of the final results are eagerly anticipated. This trial was registeredwith the Japan Registry of Clinical Trials (clinical trial number: jRCT1040250089, registration date: September 3, 2025).

Introduction Lyso-thermosensitive liposomal doxorubicin (LTLD) is a thermosensitive nanomedicine designed to release doxorubicin rapidly at mild hyperthermic temperatures. Unlike systemic doxorubicin, which is limited by cardiotoxicity and poor tumor penetration, LTLD enables targeted drug delivery enhanced by localized hyperthermia through heat-triggered release. While LTLD has demonstrated improved drug delivery with tumor-localized hyperthermia, comparative analyses of intravenous (IV) versus intra-arterial (IA) delivery routes for rectal targeting remain unexplored. This study evaluates doxorubicin pharmacokinetics and rectal tissue accumulation following LTLD administration via IV or IA routes, with or without localized rectal hyperthermia in swine, to identify the optimal delivery strategy for maximizing rectal drug concentrations while minimizing systemic exposure. Methods Eight healthy swine were assigned to four groups: IV LTLD with or without rectal hyperthermia, IA free doxorubicin with hyperthermia, or IA LTLD with hyperthermia. Animals received 30-min drug infusions (0.7 mg/kg) via the jugular vein or by bilateral selective catheterization of the internal iliac arteries. Serial blood samples were collected for 1 hour, followed by post-mortem tissue collection from the rectal wall, heart, and perirectal fat. A custom rectal heating device produced homogeneous localized hyperthermia. Results IV and IA LTLD combined with localized hyperthermia markedly increased doxorubicin accumulation (µg/g) in rectal tissue (7.45 ± 6.18, 8.41 ± 5.15, respectively) compared with normothermic IV LTLD (0.49 ± 0.16) or hyperthermic IA free-drug controls (0.67 ± 0.46). Plasma AUC 0–60min (µg/mL·min) was lowest with IA administration of free drug (12.7 ± 8.36) compared to IV LTLD with and without hyperthermia (424 ± 85.6, 544 ± 148, respectively) and IA LTLD with hyperthermia (305 ± 221). Doxorubicin concentrations in the heart did not differ among treatment groups. Fluorescence microscopy confirmed enhanced doxorubicin distribution within the rectal wall when LTLD was delivered via either route and combined with rectal hyperthermia. Conclusion Intravenous and intra-arterial LTLD combined with localized rectal hyperthermia produced similar increases in rectal doxorubicin concentrations in a swine model. These findings support the feasibility of integrating thermosensitive liposomal drug delivery with localized rectal hyperthermia and intra-arterial catheter-based delivery.

Abstract Background: Patients with stage 1 triple negative breast cancer (TNBC) are at high risk of recurrence, given the aggressive nature of the disease. A SEER database review of patients diagnosed with Stage IA TNBC between 2010 and 2019 showed that chemotherapy use increased significantly from 2010-2019 among patients with T1b (p = 0.001) and T1c tumors (p < 0.0001), reaching ≥60% in patients with T1b and ≥70% in patients with T1c tumors across most years. In patients with T1c tumors, chemotherapy was associated with improved BCSS, with a 5-year BCSS of 94.5% for patients receiving chemotherapy vs. 91.2% in the no/unknown chemotherapy group (Adjusted HR = 0.64; 95% CI: 0.48-0.85). Other studies have shown the benefit of adjuvant chemotherapy for stage 1 triple negative breast cancers especially T1c tumors. Given the recurrence free survival and overall survival benefit seen with systemic therapy, guidelines recommend adjuvant chemotherapy for TNBC that are at least 0.6 cm in size. Standard anthracycline-based and taxanes based chemotherapy regimens that have shown benefit in stage II-III breast cancers are routinely used for stage 1 TNBC. However, these regimens are associated with significant risk of neuropathy, alopecia and neutropenia. An investigator-initiated trial at our institution studied the combination of liposomal doxorubicin and carboplatin in the neoadjuvant setting for patients with stage II-III TNBC (ClinicalTrials.gov Identifier: NCT02315196). This study showed that the combination achieved pathologic complete response (pCR) similar to standard regimens with good tolerability. The regimen was well tolerated with minimal risk of alopecia, reduced risk of neuropathy, and lower rates of neutropenia. Selection of liposomal doxorubicin has gained favor due to the lower degree of toxicity, including cardiotoxicity, as compared to conventional doxorubicin while retaining similar efficacy. Based on the results of this study, we are conducting a phase 2 study that will evaluate this regimen in the adjuvant setting for patients with Stage 1 and 2 TNBC. (ClinicalTrials.gov Identifier: NCT05949021) METHODS: The primary objective of this study is to evaluate the efficacy of liposomal doxorubicin and carboplatin in the adjuvant phase for patients with Stage 1 or 2 triple negative breast cancer, as measured by the 5-year disease-free survival (DFS) rate. The current 5-year recurrence-free survival (RFS) is 92.5% compared with 66.5% for patients treated without chemotherapy With 2 years of accrual and 5 years of additional follow-up, we will need 30 patients to achieve 80% power to detect an increase in the five-year survival rate from 66.5% to 84.5% using a 5% level test of survival. Patients diagnosed with early-stage (upto 2.5cm) breast cancer (Estrogen Receptor ≤ 20%; Progesterone receptor ≤ 20% and HER2 negative) who completed primary breast surgery with axillary staging are eligible for the study. Patients must have baseline Left ventricular ejection fraction >50%. Patients will receive liposomal doxorubicin (30mg/m2) and carboplatin (AUC 5) every 4 weeks for 4 cycles. Patients will undergo tumor-informed circulating tumor DNA (ctDNA) monitoring with the Haystack MRD test at baseline, cycles 2 and 4, and every 6 months thereafter for 24 months. After completion of chemotherapy, patient will receive adjuvant breast radiation. Patient will be on follow up for up to 5 years. The study is currently enrolling patients at Rutgers Cancer Institute and Robert Wood Johnson Barnabas Health (RWJBH) affiliate sites in New Jersey. Citation Format: M. George, C. Omene, A. Litvak, G. Raptis, A. Cruz, K. Toomey, S. Kumar, N. Ohri, L. Potdevin, K. Harper, E. L. Gramiccioni, B. Haffty, H. S. Sloane, D. Toppmeyer. Phase 2 study of adjuvant liposomal doxorubicin and carboplatin for early-stage triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-02.

Abstract Background: Immune checkpoint inhibitors deliver durable benefit to only a minority of individuals with metastatic breast cancer, in part due to a paucity of activated, antigen-presenting dendritic cells within the tumor microenvironment. Pre-clinical work from our group showed that combining pegylated liposomal doxorubicin (to release tumor antigens) with a CD40 agonist (to license dendritic cells and repolarize macrophages toward an anti-tumor phenotype) and recombinant Flt3 ligand (to expand dendritic cell precursors) produces markedly superior tumor control compared with chemotherapy alone. These findings underpin the first-in-human clinical evaluation of this triplet regimen. Methods: This is a single arm phase I pilot study of the combination of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) in patients with metastatic or unresectable locally advanced HER2 negative breast cancer (triple negative, TNBC; and hormone receptor positive, HR+). Two lead-in cohorts randomize participants in a 2:1 ratio to receive one cycle of either the triplet combination or pegylated liposomal doxorubicin alone, after which all patients transition to triplet therapy; paired tumor biopsies are obtained at baseline and after the lead-in to characterize early immunological changes. Eligibility originally limited enrollment to triple-negative disease but has been broadened to include HR+ tumors. Key eligibility criteria are unresectable stage III or stage IV HER2 negative breast cancer; for TNBC up to three prior therapies for metastatic disease allowed; for HR+ disease prior cyclin dependent kinase 4/6 inhibitors required and up to 3 prior lines of chemotherapy and/or antibody drug conjugates for metastatic disease allowed; and measurable disease by RECIST 1.1 criteria. Key exclusion criteria are prior exposure to an anti-CD40 antibody or Flt3 ligand, anthracycline treatment in the metastatic setting, progression on or within six months of (neo)adjuvant anthracyclines, and a history of non-infectious pneumonitis. CDX-301 is administered only during cycles 1 and 2, whereas pegylated liposomal-doxorubicin and CDX-1140 is continued until disease progression or clinically limiting toxicities. The primary endpoint is determination of a recommended phase II dose of CDX-1140 based on treatment-related adverse events and dose-limiting toxicities. Secondary endpoints include anti-tumor immune responses measured as CD8 T cell infiltration after triplet therapy and after liposomal doxorubicin alone, median progression-free survival, overall response rate, duration of response, and clinical benefit rate. As of June 24th, 2025 this trial is in dose expansion and has enrolled 23 of 30 evaluable patients (NCT05029999). The trial is currently open at University of Texas Southwestern Simmons Comprehensive Cancer Center, University of Chicago, University of Texas San Antonio Health Science Center, Johns Hopkins, and University of North Carolina. Citation Format: S. M. Reddy, C. A. Santa-Maria, N. Chen, V. Kaklamani, J. O’Shaughnessy, Y. Abdou, N. Unni, B. Santos, S. Syed, N. Sadeghi, J. Gruber, D. Klemow, Y. Fang, I. Chan, N. Peswani, I. Patel, S. Shakeel, M. Carter, K. Kyle, R. Nanda, H. McArthur, S. Conzen, C. L. Arteaga. Phase I pilot of pegylated liposomal doxorubicin, CD40 agonist antibody CDX-1140, and Flt3 ligand CDX-301 in advanced HER2-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-28.

Abstract Introduction: Triple-negative breast cancer (TNBC), accounting for 10%-15% of breast cancers and defined by ER-/PR-/HER2- status, exhibits aggressive biological behavior with high proliferative indices, genomic instability, and limited targeted therapies. BRCA1-mutated TNBC may respond to PARP inhibitors and DNA-damaging agents. However, a significant proportion of BRCA1-mutated TNBC patients experience disease progression, underscoring the urgent need for novel treatment strategies. This case report details a young female with BRCA1-mutated TNBC presenting with extensive systemic and brain metastases. The treatment strategy combining Sacituzumab Govitecan (SG), Anlotinib, and concurrent whole-brain radiotherapy (WBRT) provides unique insights into managing complex, relapsed TNBC. Case Report: In March 2011, a 28-year-old female was diagnosed with left breast invasive ductal carcinoma (ER-/PR-/HER2-, pT2N0M0). She underwent left modified radical mastectomy, followed by 8 cycles of adjuvant chemotherapy (epirubicin + cyclophosphamide, followed by paclitaxel). In March 2017, a 2×2 cm invasive carcinoma was detected (ER-/PR-/HER2 1+) in her right breast. She received 6 cycles of neoadjuvant TAC chemotherapy (docetaxel + liposomal doxorubicin + cyclophosphamide), and then underwent right nipple-areolar-sparing mastectomy, axillary dissection, and breast reconstruction on August 7, 2017, followed by radiotherapy. In December 2020, right chest wall recurrence was found, treated with local extended resection in January 2021, and followed by one-year oral capecitabine. In June 2023, she developed lung metastases (germline BRCA1 mutation),then enrolled in an IIT trial (NCT05085626) where she received Fluzoparib + Chidamide, achieving partial response (PR) with a progression-free survival (PFS) of 14 months. In August 2024, the patient developed widespread metastases (brain, lung, soft tissues, liver, spleen, bone, ileum). She declined brain surgery and received Bevacizumab + Trastuzumab Deruxtecan. After two cycles, symptoms of intracranial hypertension improved, and the disease was assessed as stable disease (SD), but grade 3 or 4 nausea/vomiting/fatigue led to discontinuation. In December 2024, original lesions (brain, lung, liver, ileum) progressed with new metastases in retroperitoneum, kidneys, left 4th metacarpal, and phalanges. Treatment with SG in combination with Anlotinib was initiated, accompanied by concurrent WBRT during the first cycle. After two cycles, the disease achieved a PR. Grade 3 anemia occurred during treatment but was managed symptomatically. The PFS has exceeded 7 months to date, and the patient remains under continuous treatment. Discussion: Preclinical studies have shown that SG delivers SN-38 to induce DNA damage in homologous recombination deficiency (HRD) tumors (e.g., BRCA-mutated) with impaired repair. Anti-angiogenics enhance SG’s efficacy via VEGF-targeted vascular normalization and blockade of survival signaling pathways. Additionally, SG can penetrate into intracranial tumors and exhibit promising activity. Combining SG with WBRT can further induce DNA damage and enhance treatment efficacy. The patient’s positive response to this combination regimen suggests potential benefit for metastatic TNBC, especially in those with brain metastases, though grade 3 anemia highlights the need for close toxicity monitoring. Conclusion: This case report highlights the potential efficacy of SG in combination with anti-angiogenic therapy and radiotherapy in treating BRCA1-mutated TNBC patients with multiple recurrences and brain metastases. However, further studies are needed to confirm these findings and to optimize the use of these agents in this subset of patients. Citation Format: C. Hao, Z. Jie. Sacituzumab Govitecan Combined with Anti-angiogenic Therapy and Radiotherapy in a BRCA1-Mutated Triple-Negative Breast Cancer Patient with Multiple Recurrences: A Case Report [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-19.

Abstract Background: Although immunotherapies deliver lasting remissions in many solid cancers, triple-negative breast cancers demonstrate limited immunity. One potential reason for this is functional impairment within the antigen-presenting cell (APC) compartment. Cross-presenting conventional dendritic cells (cDC1s) are essential for initiating effective CD8+ T cell responses but are frequently scarce or suppressed in breast tumors. We evaluated a rationally designed triplet regimen combining immunogenic anthracycline chemotherapy, Flt3 ligand to expand dendritic cell populations, and a CD40 agonist to activate them, aiming to reprogram the tumor microenvironment and promote durable anti-tumor T cell responses. Methods: EO771, AT3, or 4T1 tumors were implanted orthotopically in female mice. Once tumors reached ∼50 mm3, mice received pegylated liposomal doxorubicin (Doxil, day 1), recombinant Flt3 ligand (Flt3L, days 1-5), and a CD40 agonist antibody (CD40a, days 11, 14, 17) or monotherapy or doublet combinations. Tumor burden and survival were monitored longitudinally. Tumors and draining lymph nodes were analyzed using flow cytometry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing (TCR-seq). Mechanistic dependencies were assessed through genetic knockout models, antibody-mediated depletion, cytokine or chemokine blockade, and lymphocyte trafficking inhibition. Results: Triplet treatment significantly delayed tumor progression and prolonged survival compared to monotherapy or doublet combinations. To elucidate the underlying immune mechanisms, flow cytometry and scRNA-seq revealed robust activation across all three major APC lineages: dendritic cells (DCs), macrophages, and B cells. Specifically, Flt3L expanded cDC1s, cDC2s, and mature dendritic cells enriched in immunoregulatory features (mregDCs), while CD40a upregulated CD80, CD86, β2-microglobulin, and Il12b. Inflammatory macrophages expressing high levels of Cxcl9 were enriched, and B cells exhibited increased markers of activation and memory differentiation. Consistent with APC activation, triplet therapy increased intra-tumoral CD8+ T cell infiltration, reduced expression of exhaustion markers (LAG-3, TIM-3), and promoted stem-like features. TCR-seq demonstrated clonal expansion of T cells without changes in Shannon diversity, indicating predominant expansion of pre-existing T cell clones. Mechanistic studies demonstrated that cDC1s are essential for therapeutic efficacy, as tumor control was lost in Batf3-/- mice but remained intact following depletion of CSF1R+ macrophages or CD20+ B cells. CD8+ T cell depletion partially reduced efficacy, while co-depletion of CD8+ and CD4+ T cells resulted in complete loss of tumor control, indicating a cooperative role for both subsets. Removal of regulatory T cells further enhanced treatment response, suggesting they act as a barrier to optimal efficacy. Importantly, therapy remained effective despite FTY720-mediated inhibition of lymphocyte trafficking from the tumor draining lymph node, pointing to a role for pre-existing intra-tumoral T cells. Finally, neutralization of IL-12 completely abolished tumor control, whereas CXCL9 or CXCR3 blockade had little impact, underscoring the central role of IL-12 in mediating therapeutic response. Conclusion: This CD40 agonist-based triplet immunotherapy reprograms the tumor microenvironment through coordinated APC activation and IL-12-driven CD4+ and CD8+ T cell responses. cDC1s are essential mediators of therapeutic efficacy, while macrophages and B cells adopt inflammatory and activated states but are dispensable for treatment effect. Tregs constrain treatment potency and are a rational co-target to improve responses in breast cancer. Citation Format: P. L. Mylabathula, R. Ali, A. Alkhani, X. Qi, S. Hebbale, J. Zhu, I. Chan, S. M. Reddy. Targeting dendritic cells with CD40 agonist-based triplet immunotherapy induces IL12B-driven tumor control in triple-negative breast cancers [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-30.

Abstract Background: There is an unmet therapeutic need for patients with HR+/HER2− metastatic breast cancer who experience disease progression and recurrence after first-line standard of care treatment with a CDK4/6 inhibitor and endocrine therapy (ET). The main therapy options, for those patients who are not considered suitable for additional ET-based therapy, are chemotherapy and antibody-drug conjugates (ADCs). Human epidermal growth factor receptor 3 (HER3) is overexpressed in 50-70% of breast cancers, with highest expression in HR+/HER2− breast cancer, and its overexpression is associated with poor prognosis and drug resistance. Patritumab deruxtecan (HER3-DXd), a novel ADC that selectively binds HER3, is composed of a fully human anti-HER3 IgG1 antibody linked to a cytotoxic topoisomerase I inhibitor via a stable tetrapeptide-based linker that is selectively cleaved within tumor cells. In the phase 2 ICARUS-Breast01 study, HER3-DXd showed clinically meaningful antitumor activity (ORR, 53.5% [95% CI, 43.2-63.6]; median PFS, 9.4 months [95% CI, 8.1-13.4]) and manageable safety in patients with HR+/HER2− advanced breast cancer who progressed on CDK4/6 inhibitor treatment, and 1 line of chemotherapy. The phase 3, multicenter, open-label, HERTHENA-Breast04 study (NCTXXXXXXXX) evaluates efficacy and safety of HER3-DXd monotherapy vs treatment of physician’s choice (TPC) in participants with HR+/HER2− unresectable locally advanced or metastatic breast cancer after progression on one line of CDK 4/6 inhibitor treatment. Methods: Participants must be aged ≥18 y and have centrally confirmed HR+/HER2− (per most recent ASCO/CAP guidelines: HER2 IHC 0 or 1+ or IHC 2+/in situ hybridization negative) unresectable locally advanced or metastatic breast cancer. Participants must have experienced disease progression or recurrence following prior treatment with a CDK4/6 inhibitor and ET and must be eligible for at least 1 TPC option, as determined by the investigator. Participants must have measurable disease per RECIST version 1.1 and ECOG PS of 0 or 1. Participants who have received prior chemotherapy or are candidates for an additional line of ET-based therapy in the advanced setting are ineligible for the study. Participants are randomized 1:1 to Arm 1 or 2, with approximately 500 participants assigned to each arm. Participants in Arm 1 will receive HER3-DXd 5.6 mg/kg IV on day 1 Q3W, and participants in Arm 2 will receive TPC consisting of 1 of the following options: 1) paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 Q4W; 2) paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; 3) nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; 4) capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 Q3W; 5) liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or 6) trastuzumab deruxtecan 5.4 mg/kg IV on day 1 Q3W. Treatment will continue until radiographic disease progression, unacceptable toxicity, or participant withdrawal. The dual primary endpoints are PFS per RECIST version 1.1 by BICR and OS. Secondary endpoints are ORR and DOR per RECIST version 1.1 by BICR, safety, and patient-reported outcomes. AEs are graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Imaging assessments occur Q6W from randomization through week 60 and Q12W thereafter. Enrollment is planned to begin in Q3 2025 across North America, Latin America, Europe, and Asia Pacific. Citation Format: B. Pistilli, S. Hou, J. M. Collins, P. K. Sudheendra, V. Kaklamani. Herthena-breast04: a phase 3, randomized, open-label study evaluating the efficacy and safety of patritumab deruxtecan (HER3-DXd) versus treatment of physician’s choice in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) unresectable locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-22.

Abstract Background: Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancers and disproportionately contributes to breast cancer mortality due to its aggressive clinical course, high propensity for visceral and brain metastases, and lack of targeted therapies. While TNBC lacks estrogen receptor alpha (ERα), up to 80% of tumors express estrogen receptor beta (ERβ), and a similar proportion harbor TP53 mutations. Pioneering work by our group demonstrated that ERβ directly interacts with p53, exerting tumor-suppressive effects in the presence of mutant p53 (mut-p53), but potential oncogenic effects in wild-type p53 settings (Mukhopadhyay et al., J Natl Cancer Inst, 2019). We have also showed that tamoxifen (Tam), a selective estrogen receptor modulator, stabilizes ERβ and enhances its binding to mut-p53, sequestering it away from TP73 and restoring TP73’s tumor suppressor activity. In vitro, Tam synergistically enhances the cytotoxicity of doxorubicin in ERβ/mut-p53 positive TNBC cell lines, while in vivo xenograft models demonstrate superior tumor regression with the combination. Therapeutic proof-of-concept was observed in a patient with metastatic Erβ/mut-p53 expressing TNBC who had marked tumor regression following Tam treatment (Scarpetti et al., The Oncologist, 2023). Given the frequent co-expression of ERβ and mut-p53 in TNBC and the favorable safety profile of tamoxifen and pegylated liposomal doxorubicin (PLD), we have initiated a phase II clinical trial evaluating this combination in patients with metastatic(m) or unresectable TNBC. Methods: This is an open-label, single-arm, phase II study (NCT06434064) enrolling patients(pts) ≥18 years with mTNBC characterized by ERα-low (≤10%) expression and progression on ≥2 prior lines of systemic therapy. Pts will receive Tam 20 mg orally once daily and PLD 50mg/m2 intravenously every 28 days. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. Tam is continued unless dose-limiting toxicity occurs, as no dose reductions are allowed. The primary endpoint is overall response rate (ORR) as assessed by RECIST v1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety/tolerability per CTCAE v5.0. Exploratory endpoints include changes in circulating tumor DNA (ctDNA), ERβ-mut-p53 interaction assessed by proximity ligation assay (PLA), differential gene expression analysis by RNA-seq, immune deconvolution via CIBERSORT, and peripheral immune profiling through cytokine analysis and flow cytometry. A safety lead-in will be conducted in the first 6 pts. The study uses a Simon two-stage design to detect an increase in ORR from 16% to 33%, with 80% power and α = 0.10 (n1 = 12, n2 = 18). This design ensures early stopping for futility and supports efficient evaluation of efficacy. Technical and analytic validation of ER-beta expression as a possible biomarker of response is ongoing. Significance: If successful, this study will establish a novel, mechanism-driven treatment option for previously treated mTNBC. Correlative analyses will uncover molecular and immune pathways linked to therapeutic response. Erβ and mut-p53 interaction profiling may support future patient selection for Tam based therapies. Future studies will explore potential synergy between antibody-drug conjugates that induce DNA-damage e.g. Sacituzumab govitecan and Tam as well as adding immune checkpoint inhibition to Tam and Doxil to improve patient outcomes. Status: The study is currently open to enrollment. Clinical trial information: (NCT 06434064) Citation Format: Z. Shah, C. C. Oturkar, I. Aijaz, H. Yu, M. L. Tarquini, G. M. Das, S. Kabraji. A Pilot, Single-Arm, Phase II Trial of Tamoxifen plus Pegylated Liposomal Doxorubicin in Patients with Metastatic Triple Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-09.

Doxorubicin (Dox) is a widely used chemotherapeutic agent, but its clinical application is limited by severe dose-dependent toxicities, particularly cardiotoxicity. To overcome these challenges, two novel formulations-liposomal doxorubicin (Dox-Lip) and proliposomal doxorubicin (Dox-P-Lip) -were developed and systematically compared with the reference listed drug (RLD), focusing on physicochemical comparability and in vitro bioequivalence in accordance with FDA guidance. Dox-Lip was prepared using alternative lipid compositions and a modified pH gradient-based active loading method, while Dox-P-Lip was obtained by lyophilization of the liposomal formulation. Characterization studies included encapsulation efficiency (EE%), lipid content, drug-to-lipid ratio, internal pH, morphology, bilayer phase behavior, PEG surface density, particle size, zeta potential, and PEG layer thickness determined using the Fixed Aqueous Layer Thickness (FALT) model. In vitro drug release was evaluated under simulated plasma, variable pH and temperature, and ultrasound exposure. Both formulations exhibited high encapsulation efficiencies (EE%) exceeding 90%, comparable to those of the RLD. Moreover, these formulations demonstrated approximately 2.1-fold thicker PEG layers, indicating improved steric stabilization. Although these formulations exhibited slightly higher leakage under stress conditions, the encapsulation efficiency (EE%) consistently remained above 90%, confirming their structural integrity. Overall, the novel formulations demonstrated physicochemical similarity and stability relative to the RLD, supporting their potential as bioequivalent and clinically viable liposomal Dox alternatives.

Enhancing nanomedicine efficacy in KPC pancreatic tumors through ketotifen-mediated tumor microenvironment remodeling

Light-responsive α-TOS liposomal nanocarriers Co-delivering TiO2 and doxorubicin for the treatment of breast cancer.

Self-propelled biomotors co-deliver doxorubicin liposomes and aPD-1 antibody to fight breast cancer

Doxorubicin (DOX) is one of the most potent chemotherapeutic agents for cancer treatment. However, its cumulative and often irreversible, life-threatening cardiotoxicity significantly limits its clinical applications. While strategies like dose reduction, iron chelation, and liposome encapsulation have aided in mitigating cardiotoxicity to certain extent, they are associated with decreased therapeutic efficacy and potential cancer relapse, the risk of developing secondary malignancy, and the incidence of the Hand-foot syndrome. Exosomes (Exo) are naturally occurring nanoparticles that can be engineered to display targeting moieties on their surface, thereby enhancing drug delivery efficacy. We aimed to develop an exosomal DOX formulation targeting broad epidermal growth factor receptor (EGFR) variants to enhance its anti-tumor efficacy and minimize cardiotoxicity. The native 53-amino-acid EGF was decorated on the surface of exosomes by genetically engineering exosome-producing A549 cells. The EGF-Exo was effectively internalized by tumor cell lines in a manner dependent on EGFR expression levels, and exhibited enhanced accumulation in xenograft A549 tumors relative to the heart, with minimal cardiac accumulation. When loaded with DOX, these engineered exosomes were rapidly internalized, inducing higher apoptosis in A549 cells compared to liposomal-DOX. Upon systemic administration in an A549 xenograft mouse model, EGF-Exo-DOX exhibited enhanced accumulation in tumors relative to the heart, with minimal cardiac accumulation, significantly reducing tumor burden, mitigating DOX-induced cardiotoxicity, and exhibiting no tumorigenic effects. This favorable therapeutic profile is primarily attributed to DOX-induced apoptosis. Our findings demonstrate that tumor-derived exosomes engineered with EGF on their surface enable targeted drug delivery to tumors with high EGFR expression. Although the exosomes modestly increase cell proliferation in vitro, the EGF-Exo-DOX formulation exhibits enhanced tumor accumulation relative to the heart, minimal cardiac uptake, and shows no tumorigenic effects in vivo. Compared to Lipo-DOX, a widely used clinical formulation of liposomal DOX in China, EGF-Exo-DOX demonstrates superior cellular uptake, greater induction of tumor cell apoptosis, and improved anti-tumor efficacy. These results highlight the potential of engineered exosomes as a targeted drug delivery platform for patients with EGFR-overexpressing tumors.

To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in the treatment of desmoid tumors (DTs). In this investigator-initiated, double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with advanced or refractory DTs to receive either PLD (50 mg/m² intravenously) or placebo every 4 weeks for 6 cycles. Crossover from placebo to PLD was permitted upon disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response and safety. From November 2020 to March 2023, a total of 73 patients were assigned to receive PLD (49 patients) or placebo (24 patients). With a median follow-up of 16.1 months, PLD had a significantly longer PFS over placebo (not reached vs. 4.3 months), with a hazard ratio (HR) of 0.05 (95% CI, 0.01-0.17; P<0.001). The 2-year PFS rates were 90.4% with the PLD group and 19.6% with placebo. PFS benefit favored PLD across most prespecified subgroups. The confirmed objective response was observed in 19 (40.4%) patients in the PLD group and 1 (4.3%) in the placebo group (P=0.002). Common grade 3 or higher adverse events with PLD included neutrophil count decreased (10.6%), mucositis oral (6.4%), and white-cell decreased (4.3%). Significant between-group differences in certain patient-reported toxicities were observed (P<0.05). PLD significantly prolonged PFS and induced durable responses than placebo, with a favorable safety profile, for patients with progressive or symptomatic desmoid tumors.

Elderly patients with recurrent ovarian cancer are often underrepresented in clinical trials, complicating treatment decisions because of comorbidities and altered drug tolerance. Trabectedin plus pegylated liposomal doxorubicin is a non-platinum option for patients with a platinum-free interval of 6–12 months. This single-center retrospective study evaluated the efficacy and safety of this combination in 23 patients aged ≥65 years with partially platinum-sensitive relapsed ovarian cancer treated between 2018 and 2022. Median age was 68 years. The median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 18 months (95% CI: 12–101). Treatment was generally well tolerated, with mostly grade 1–2 hematologic toxicities, particularly anemia and neutropenia, and no treatment-related deaths. These findings suggest that trabectedin plus pegylated liposomal doxorubicin has clinically meaningful activity and an acceptable safety profile in this elderly population, although confirmation in larger cohorts is needed.

Chemotherapy remains indispensable in the treatment of malignant tumors but is often limited by the prevailing "one size fits all" approach, which neglects inter-patient variablity in pharmacokinetics and treatment response, often resulting in suboptimal outcomes. In this study, we explored individualized chemotherapy protocols in a clinically relevant mouse model of breast cancer using a novel algorithm-assisted therapy design (AATD). Two strategies were applied: a two-stage computational therapy protocol designed to stabilize blood concentrations of pegylated liposomal doxorubicin (PLD); and a model-predictive approach that optimizes dosing based on individual tumor characteristics. Compared to the standard maximum tolerated dose protocol, AATD-based personalized chemotherapy, guided by real-time monitoring of treatment response, tumor growth, and drug concentrations, significantly improved overall survival. Our findings in a mouse model of triple-negative breast cancer provide compelling evidence that chemotherapy can be personalized and optimized through algorithm-assisted therapy design.