Mitigating Breast Cancer with Intratumoral In Situ pH-responsive Abemaciclib-loaded Novasome Hydrogel.

The closer, the better: intratumoral delivery of a thermoresponsive gemcitabine-loaded hydrogel in preclinical PDAC models.

Current treatments for pancreatic ductal adenocarcinoma (PDAC) patients are typically restricted to (neo)adjuvant chemotherapy, surgery or palliative care. Mainly due to a late diagnosis and highly desmoplastic environment, these treatments have limited efficacy and patient prognosis is very poor. Intratumoral delivery of chemotherapeutic agents using hydrogel technology might boost treatment efficacy and reduce side effects. Here, we aimed to investigate the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell, loaded with the chemotherapeutic agent gemcitabine. We explored this in vitro, using patient-derived organoids and surgically obtained tumor explants, and in vivo, using a human patient-derived xenograft (PDX) and syngeneic KPC3 mouse models. Upon intratumoral injections of gemcitabine-loaded ChemoGell, respective survival, peripheral blood and end-stage tumor histological analyses were performed. Intratumoral injection of gemcitabine-loaded ChemoGell in in vitro and in vivo models showed decreased tumor growth and increased cytotoxicity compared to blank ChemoGell and saline control intratumoral injections. In contrast, systemic administration of gemcitabine did not show therapeutic benefits. Intratumoral ChemoGell injections induced interesting lymphocyte and monocyte dynamics overtime, showing an intratumoral influx of NK cells and monocytes and an in-depot infiltration of activated fibroblasts, macrophages and activated CD8 + T cells. Our findings establish a foundation for integrating localized treatment modalities, addressing critical challenges in PDAC and improving patient prognosis through more effective, localized therapeutic strategies.

Ultrasound-responsive PLGA nanoparticles co-loaded with celecoxib and catalase enhance the therapeutic efficacy of imatinib in gastrointestinal stromal tumors.

The therapeutic efficacy of imatinib (IM) in gastrointestinal stromal tumors (GISTs) is often limited by inadequate intratumoral drug accumulation and an abnormal tumor microenvironment. In this study, an ultrasound-responsive poly(lactic-co-glycolic acid) (PLGA) nanoparticle system, designated CXB/CAT@PFP-PLGA NPs, was developed for the co-delivery of celecoxib (CXB) and catalase (CAT) to enhance the antitumor efficacy of IM. The nanoparticles were characterized in terms of their physicochemical properties, ultrasound responsiveness, and oxygen-generating capability. Their ability to potentiate IM therapy was evaluated both in vitro and in vivo, while biodistribution and biosafety were assessed in vivo. The results showed that CXB/CAT@PFP-PLGA NPs exhibited a relatively uniform size distribution and successfully co-encapsulated CXB and CAT. Upon ultrasound irradiation, the nanoparticles underwent phase transition, thereby triggering drug release. In vitro, CXB/CAT@PFP-PLGA NPs enhanced the inhibitory effect of IM by reducing cell viability, promoting apoptosis, and inhibiting cell migration. In vivo, the nanosystem improved the antitumor efficacy of IM, accumulated at the tumor site, suppressed tumor growth, and showed no evident systemic toxicity. Collectively, these findings suggest that CXB/CAT@PFP-PLGA NPs may represent a promising strategy for enhancing IM therapy in GIST.

Nano drug delivery of a new scfv-based immunotoxin by chitosan nanoparticles upgrades its efficiency against breast cancer

In Vivo Multimodal Self-Immolative Prodrug Nanomicelle-Hydrogel Modulate Key Intratumoral and Metastatic Genomic Signaling Pathways in Pancreatic Cancer

To address the critical challenge of high-lethality pancreatic ductal adenocarcinoma and poor response to conventional chemotherapies, this study introduces a self-immolative micelle encapsulating paclitaxel (PTX) or gemcitabine (GEM), two frontline chemotherapeutic agents. These chemotherapeutic agents present a 2.3-fold reduction for GEM and a 61.7-fold reduction for PTX in IC50 values when conjugated to the micelle system, compared to their free drug counterparts. Through longitudinal bioluminescence imaging, we observed a significant reduction in peritoneal tumor implants versus metastatic tumor deposits growth and a decrease in metastatic spread in the GEM- and GEM+PTX-micelle (micelle@GEM and micelle@GEM+PTX)-treated groups compared with the free drug formulations. Gene expression analysis of treated tumors revealed interesting oncogenic pathways, including PI3K-Akt and MAPK signaling, suggesting a targeted action at the molecular level. Our results identified the dual roles of PSMA1 and UBE2C as poor prognostic markers of pancreatic cancer progression and as candidate genes of interest, with key roles in the ubiquitination and proteasome degradation pathways in the pathophysiology of the disease. These data suggest that encapsulation of PTX and GEM in these micelles embedded within a hydrogel could alter the pharmacokinetics and pharmacodynamics of these agents, thereby modulating their interactions with cellular targets. Such targeted approaches could transform the treatment of pancreatic cancer by providing tailored therapies based on the unique genomic landscape of an individual’s tumor, thus optimizing the clinical outcomes.

Tumor microenvironment improved by nanostructured lipid carriers co-deliverying paclitaxel and ubenimex to treat breast cancer.

OBJECTIVE The aim of this research was to design nanostructured lipid carriers co-delivering paclitaxel and ubenimex to improve the tumor microenvironment and enhance efficacy against breast cancer. SIGNIFICANCE Nanostructured lipid carriers (NLC) offer unique advantages for co-delivery of anti-tumor drugs, including high drug-loading capacity, controlled-release performance, and facile functionalization. This study developed a nanostructured lipid carrier (NLC) co-loaded with paclitaxel and ubenimex to achieve synergistic therapeutic effects on breast cancer by improving the immunosuppressive tumor microenvironment. METHODS Ubenimex (Uben) was conjugated to vitamin E polyethylene glycol succinate (TPGS) via ester bonds, after which the synthetic conjugate, paclitaxel, and lipid materials were formulated into the nanostructured lipid carrier (PTX/Uben-NLC) by the emulsified solvent evaporation-low-temperature curing method and subsequently characterized and evaluated for improved anti-tumor efficacy. RESULTS The prepared PTX/Uben-NLC was approximately spherical with a negative potential and a particle size of about 161 nm. The formulation demonstrated sustained drug release. Uben exhibited pH-responsive release in the weakly acidic tumor microenvironment (TME) and induced immune cell activation and secretion of anti-tumor cytokines (IFN-γ, TNF-α, IL-12), while secretion of immunosuppressive cytokines (TGF-β and IL-10) was concurrently inhibited. PTX exerted direct anti-tumor effects on tumor cells. Consequently, the PTX/Uben-NLC alleviated TME immunosuppression and enhanced anti-breast-cancer activity. CONCLUSION Dual-drug-loaded nanostructured lipid carriers alleviated TME immunosuppression to enhance synergistic anti-breast cancer therapy and provided a feasible solution for breast cancer treatment.

Engineered Multifunctional Nanococktail of Sorafenib for Targeted Therapy in Hepatic Cancer: In Vivo Study