Sun, T. C. | bioRxiv Science

bioRxiv2025

Antimetastatic Sulfonate-Functionalized Mesoporous Silica Nanoparticles Enhance Irinotecan Stability and Delivery for Colorectal Cancer Treatment

Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related mortality, with Irinotecan (IRI) serving as a backbone chemotherapeutic despite its dose-limiting toxicities, instability of the active lactone form, and lack of intrinsic antimetastatic activity. To overcome these barriers, we developed sulfonate-functionalized mesoporous silica nanoparticles (MSNs), referred to as (SO3-)-MSN-PEG/TA, as a multifunctional nanocarrier for IRI delivery. This nanoformulation markedly enhanced drug loading efficiency and preserved over 90% of the lactone form for up to six months, enabling sustained release and improved pharmacological stability. In vitro studies demonstrated superior cellular uptake, enhanced apoptosis, and a reduced IC50 compared to free IRI. Beyond drug delivery, (SO3-)-MSN-PEG/TA exhibited intrinsic antimetastatic activity by modulating focal adhesion kinase (FAK)/paxillin signaling, thereby impairing cell migration and suppressing angiogenesis, along with efficient tumor accumulation through the enhanced permeability and retention (EPR) effect. Pharmacokinetic analysis further revealed that IRI@(SO3-)-MSN-PEG/TA prolonged systemic retention, maintaining higher IRI plasma concentrations compared with free IRI. IRI@(SO3-)-MSN-PEG/TA significantly inhibited both primary tumor growth and metastatic dissemination in orthotopic and heterotopic colorectal cancer models, while markedly reducing systemic toxicities and preserving bone marrow cellularity relative to free IRI and liposomal IRI (Onivyde). Collectively, this dual-functional nanomedicine provides an innovative therapeutic strategy that not only augments IRI efficacy but also confers metastasis suppression and favorable pharmacokinetics, addressing critical unmet needs in mCRC treatment. These findings highlight the translational potential of IRI@(SO3-)-MSN-PEG/TA as a safer and more effective therapy for mCRC.

bioengineering↗

bioRxiv2022

Intracortical remodelling increases in highly-loaded bone after exercise cessation

Resorption within cortices of long bones removes excess mass and damaged tissue, and increases during periods of reduced mechanical loading. Returning to high-intensity exercise may place bones at risk of failure due to increased porosity caused by bone resorption. We used microradiographs of bone slices from highly-loaded (metacarpal, tibia) and minimally-loaded (rib) bones from 12 racehorses, 6 that died during a period of high-intensity exercise and 6 that had a period of intense exercise followed by at least 35 days of rest prior to death, and measured intracortical canal cross-sectional area (Ca.Ar) and number (N.Ca) to infer remodelling activity across sites and exercise groups. Large canals that are the consequence of bone resorption (Ca.Ar > 0.04 mm2) were 1.4x to 18.7x greater in number and area in the third metacarpal bone from rested than exercised animals (p = 0.005- 0.008), but were similar in number and area in ribs from rested and exercised animals (p = 0.575-0.688). An intermediate relationship was present in the tibia, and when large canals and smaller canals that result from partial bony infilling (Ca.Ar > 0.002 mm2) were considered together. The mechanostat may override targeted remodelling during periods of high mechanical load by enhancing bone formation, reducing resorption and suppressing turnover. Both systems may work synergistically in rest periods to remove excess and damaged tissue.

physiology↗