Fluence-dependent degradation of fibrillar type I collagen by 222 nm far-UVC radiation.

For more than 100 years, germicidal lamps emitting 254 nm ultraviolet (UV) radiation have been used for drinking-water disinfection and surface sterilization. However, due to the carcinogenic nature of 254 nm UV, these lamps have been unable to be used for clinical procedures such as wound or surgical site sterilization. Recently, technical advances have facilitated a new generation of germicidal lamp whose emissions centre at 222 nm. These novel 222 nm lamps have commensurate antimicrobial properties to 254 nm lamps while producing few short- or long-term health effects in humans upon external skin exposure. However, to realize the full clinical potential of 222 nm UV, its safety upon internal tissue exposure must also be considered. Type I collagen is the most abundant structural protein in the body, where it self-assembles into fibrils which play a crucial role in connective tissue structure and function. In this work, we investigate the effect of 222 nm UV radiation on type I collagen fibrils in vitro. We show that collagen's response to irradiation with 222 nm UV is fluence-dependent, ranging from no detectable fibril damage at low fluences to complete fibril degradation and polypeptide chain scission at high fluences. However, we also show that fibril degradation is significantly attenuated by increasing collagen sample thickness. Given the low fluence threshold for bacterial inactivation and the macroscopic thickness of collagenous tissues in vivo, our results suggest a range of 222 nm UV fluences which may inactivate pathogenic bacteria without causing significant damage to fibrillar collagen. This presents an initial step toward the validation of 222 nm UV radiation for internal tissue disinfection.

Potential of a Second-Generation Dual-Layer Spectral CT for Dose Calculation in Particle Therapy Treatment Planning.

In particle therapy treatment planning, dose calculation is conducted using patient-specific maps of tissue ion stopping power ratio (SPR) to predict beam ranges. Improving patient-specific SPR prediction is therefore essential for accurate dose calculation. In this study, we investigated the use of the Spectral CT 7500, a second-generation dual-layer spectral computed tomography (DLCT) system, as an alternative to conventional single-energy CT (SECT) for patient-specific SPR prediction. This dual-energy CT (DECT)-based method allows for the direct prediction of SPR from quantitative measurements of relative electron density and effective atomic number using the Bethe equation, whereas the conventional SECT-based method consists of indirect image data-based prediction through the conversion of calibrated CT numbers to SPR. The performance of the Spectral CT 7500 in particle therapy treatment planning was characterized by conducting a thorough analysis of its SPR prediction accuracy for both tissue-equivalent materials and common non-tissue implant materials. In both instances, DLCT was found to reduce uncertainty in SPR predictions compared to SECT. Mean deviations of 0.7% and 1.6% from measured SPR values were found for DLCT- and SECT-based predictions, respectively, in tissue-equivalent materials. Furthermore, end-to-end analyses of DLCT-based treatment planning were performed for proton, helium, and carbon ion therapies with anthropomorphic head and pelvic phantoms. 3D gamma analysis was performed with ionization chamber array measurements as the reference. DLCT-predicted dose distributions revealed higher passing rates compared to SECT-predicted dose distributions. In the DLCT-based treatment plans, measured distal-edge evaluation layers were within 1 mm of their predicted positions, demonstrating the accuracy of DLCT-based particle range prediction. This study demonstrated that the use of the Spectral CT 7500 in particle therapy treatment planning may lead to better agreement between planned and delivered dose compared to current clinical SECT systems.

Elucidating the fate of nanoparticles among key cell components of the tumor microenvironment for promoting cancer nanotechnology.

Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake, retention, and toxicity in cancer cells, FBs, and CAFs to further understand the fate of NPs in a real tumor-like environment. The outcome of this would guide designing of NP-based delivery systems to fully exploit the TME for a better therapeutic outcome. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. A cervical cancer cell line, HeLa, and a triple-negative breast cancer cell line, MDA-MB-231 were chosen as cancer cell lines. For this study, a clinically feasible 0.2 nM concentration of GNPs was employed. According to our results, the cancer cells and CAFs had over 25- and 10-fold higher NP uptake per unit cell volume compared to FBs, respectively. Further, the cancer cells and CAFs had over 30% higher NP retention compared to FBs. There was no observed significant toxicity due to GNPs in all the cell lines studied. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of "smart" nanomedicines that would constitute the next generation of cancer therapeutics.

Modulation of the Microtubule Network for Optimization of Nanoparticle Dynamics for the Advancement of Cancer Nanomedicine.

Nanoparticles (NPs) have shown promise in both radiotherapy and chemotherapy. NPs are mainly transported along cellular microtubules (MTs). Docetaxel (DTX) is a commonly used chemotherapeutic drug that can manipulate the cellular MT network to maximize its clinical benefit. However, the effect of DTX on NP behaviour has not yet been fully elucidated. We used gold NPs of diameters 15 and 50 nm at a concentration of 0.2 nM to investigate the size dependence of NP behaviour. Meanwhile, DTX concentrations of 0, 10 and 50 nM were used to uphold clinical relevance. Our study reveals that a concentration of 50 nM DTX increased NP uptake by ~50% and their retention by ~90% compared to cells treated with 0 and 10 nM DTX. Smaller NPs had a 20-fold higher uptake in cells treated with 50 nM DTX vs. 0 and 10 nM DTX. With the treatment of 50 nm DTX, the cells became more spherical in shape, and NPs were redistributed closer to the nucleus. A significant increase in NP uptake and retention along with their intracellular distribution closer to the nucleus with 50 nM DTX could be exploited to target a higher dose to the most important target, the nucleus in both radiotherapy and chemotherapy.