Jul 2026· International journal of pharmaceutics· Vol 701, pp.
127190
· 0 citations· 47 references
Medicine
TL;DR
Evidence of the immune activation induced by A10 against BCa T24 cells is provided, and A10 could activate the cGAS-STING pathway, promote DAMPs release, and induce Immunogenic Cell Death (ICD) for anti-tumor activity against BCa cells in vitro.
Abstract
Bladder cancer (BCa) is one of the most prevalent malignancies worldwide, and the clinical treatment effect is limited due to the resistance and the associated low survival rates in patients. A10, as a novel camptothecin (CPT) derivative, possesses potent anti-tumor activity by targeting Topo Ⅰ/DDX5 (p68). However, the poor aqueous solubility and low bioavailability of A10 restrict its further application. We developed a Soluplus® - based solid dispersion (A10-SD) to enhance solubility by 389-fold and oral bioavailability by 14.38-fold. This research provided evidence of the immune activation induced by A10 against BCa T24 cells, and A10 could activate the cGAS-STING pathway, promote DAMPs release, and induce Immunogenic Cell Death (ICD) for anti-tumor activity against BCa cells in vitro. A10-SD meanwhile demonstrated remarkable tumor-suppressive efficacy in vivo with TGI of 99.84%, and its immune activation was preliminarily confirmed in vivo. A10-SD also showed good safety. This strategy provides an effective approach for the development of orally administered poorly soluble compounds, helping to unlock their therapeutic potential and promote their application.
Because of its poor aqueous solubility, low oral bioavailability, extensive cytochrome P450 3A4 (CYP3A4)-mediated metabolism, and acquired resistance, ibrutinib, a first-in-class covalent Bruton's tyrosine kinase (BTK) inhibitor, has shown limited efficacy in solid tumors despite revolutionizing the treatment of B-cell malignancies. Despite growing evidence linking BTK and 65-kDa Bruton's tyrosine kinase isoform (p65BTK) signaling to nuclear factor kappa-B (NF-κB) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-mediated tumor progression, immune evasion, and therapeutic resistance, these limitations have limited its therapeutic repurposing in breast, lung, colorectal cancer (CRC), and glioblastoma. While acknowledging the variable clinical applicability of the enhanced permeability and retention (EPR) effect in human tumors, this review critically assesses recent developments in polymeric nanoparticle (PNP)-based delivery systems for Ibrutinib, highlighting their potential to improve drug stability, enable sustained and stimuli-responsive release, enhance tumor accumulation, and facilitate active ligand-mediated targeting. A thorough literature search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar found studies published between 2010 and 2026. Preclinical data collectively show that PNPs improve antitumor efficacy, alter the tumor microenvironment, inhibit drug resistance and cancer stemness, lower systemic toxicity, and offer a promising platform for the clinical translation of precision BTK-targeted nanomedicine in solid tumors.
Y. Sonawane, Sankha Bhattacharya· Therapeutic delivery· 0 citations
Histopathological and toxicity studies confirm the antiproliferative effects and safety of the transdermal LLT formulation and support the potential of transdermal LLT formulation to be an effective and safe treatment for BC.
Naifa Alenazi, Z. Khired, Hussam M Shubaily et al.· Journal of liposome research· 0 citations
Taxol and Abraxane, the US Food and Drug Administration-approved paclitaxel (PTX) formulations, have revealed hypersensitivity due to excipients and mediocre efficacy due to insufficient tumor penetration, respectively. Here we developed a sphingolipid-derived PTX nanovesicle (paclitaxome) via covalently conjugating PTX to sphingomyelin, which improved pharmacokinetics and enhanced efficacy in metastatic triple-negative breast cancer and pancreatic cancer female mice and reduced myelosuppression. To bolster tumor penetration and reduce phagocytosis, we engineered a cationization-enabled transcytosis machinery by installing an ultra-pH-sensitive azepane (AZE) probe into paclitaxome and masked nanovesicle surface with a CD47 ‘self’ peptide (CD47p). The resulting CD47p/AZE–paclitaxome synchronized the co-delivery of gemcitabine or carboplatin to boost tumor inhibition and eradicate metastasis in late-stage KPC-Luc pancreatic cancer model and prevent tumor relapse and extend survival in postsurgical 4T1-Luc2 triple-negative breast cancer model in female mice. CD47p/AZE–paclitaxome also outperformed previous promising PTX nanoformulations. Finally, the series of nanoparticle modifications was applied to camptothecin, demonstrating its generalizability.
Jianqin Lu. A sphingolipid-derived paclitaxel nanovesicle enhances efficacy of combination therapies in triple-negative breast cancer and pancreatic cancer [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B068.
Colorectal cancer (CRC) ranks among the top three most commonly diagnosed cancers worldwide and remains a leading cause of cancer-related deaths, accounting for nearly 10% of global cancer incidence. Despite advances in treatment, chemotherapy with 5-fluorouracil (5-FU) continues to be a mainstay; however, its rapid systemic clearance, limited tumor selectivity, and gastrointestinal toxicity significantly compromise therapeutic efficacy. To address these limitations, this study aimed to design and optimize a pH- and microflora-activated colon-targeted tablet containing 5-FU-loaded, folic acid-conjugated chitosan (FA-CS) nanoparticles for site-specific CRC therapy. The nanoparticles were prepared using ionic gelation with sodium tripolyphosphate (STPP) as a cross-linking agent and optimized through a Box–Behnken design (BBD). The optimized batch containing 0.45 mg/mL folic acid-conjugated chitosan, 0.50 mg/mL STPP, and 10.0 mg 5-FU exhibited a particle size of 232.5 nm, a polydispersity index of 0.307, and an entrapment efficiency of 81.3%. The nanoparticles were compressed into core tablets and sequentially coated with Eudragit E100, hydroxypropyl methylcellulose K15M (HPMC K15M), and Eudragit S100 to achieve delayed colon-targeted release. In vitro studies showed minimal drug release in gastric and intestinal media, followed by nearly complete release (approximately 96%) under simulated colonic conditions. The formulation also remained stable under accelerated conditions, supporting its potential for CRC therapy.
The clinical utility of combining cabazitaxel (CBZ) and camptothecin (CPT) for advanced prostate cancer is hindered by emerging drug resistance and the absence of optimized nanocarriers for co-delivery. We investigated the potential of novel Tf-targeted nanocarriers to encapsulate CBZ and CPT, aiming to selectively augment their synergistic anti-cancer activity within in vitro prostate cancer models. Our findings demonstrate a robust synergistic interaction between CBZ and CPT (with a growth inhibition percentage of 87.42% and a combination index of 0.12) in PC3-Luc cells at CBZ:CPT molar ratio of 1:8. Transferrin-bearing PEGylated cholesterol-based poly(amidoamine) dendrimers were successfully synthesized and observed their assembly at a threshold aggregation concentration of around 10 µg/mL. CBZ was encapsulated with 88.35% efficiency and over 70% of the payload released under acidic tumor conditions (pH 5.5-6.4). When fluorescent CBZ was mixed with CPT and delivered by Tf-targeted PPSSCH, its cellular uptake among PC3-Luc, DU145, and LNCaP cells enhanced by 16.50-, 17.20-, and 21.18-times, respectively. Encapsulation of the CBZ/CPT combination using optimized synergistic ratio within transferrin-functionalized, PEGylated cholesterol-based poly(amidoamine) dendrimers significantly potentiated the antiproliferative activity of CBZ by 3.93-, 4.72-, and 5.06-fold in these three cell lines, respectively. These promising in vitro findings support further preclinical (in vivo) evaluation of transferrin-targeted PEGylated cholesterol-based PAMAM dendrimers for CBZ-CPT co-delivery.
Musa Albatsh, Yousef Ijjeh, Nowar Alsarayreh et al.· Biomedicine & pharmacotherap...· 0 citations
In vivo validation in PC-3 xenograft mice confirmed that 11 M exerted robust tumor growth suppression with low systemic toxicity, accompanied by DNMT3A downregulation and MAPK pathway activation, substantiating its multi-target therapeutic mechanism.
