BODIPY-Based Molecules for Biomedical Applications.

BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) derivatives have attracted attention as probes in applications like imaging and sensing due to their unique properties like (1) strong absorption and emission in the visible and near-infrared regions of the electromagnetic spectrum, (2) strong fluorescence and (3) supreme photostability. They have also been employed in areas like photodynamic therapy. Over the last decade, BODIPY-based molecules have even emerged as candidates for cancer treatments. Cancer remains a significant health issue world-wide, necessitating a continuing search for novel therapeutic options. BODIPY is a flexible fluorophore with distinct photophysical characteristics and is a fascinating drug development platform. This review provides a comprehensive overview of the most recent breakthroughs in BODIPY-based small molecules for cancer or disease detection and therapy, including their functional potential.

Intermittent alternating magnetic fields diminish metal-associated biofilm in vivo.

Prosthetic joint infection (PJI) is a complication of arthroplasty that results in significant morbidity. The presence of biofilm makes treatment difficult, and removal of the prosthesis is frequently required. We have developed a non-invasive approach for biofilm eradication from metal implants using intermittent alternating magnetic fields (iAMF) to generate targeted heating at the implant surface. The goal of this study was to determine whether iAMF demonstrated efficacy in an in vivo implant biofilm infection model. iAMF combined with antibiotics led to enhanced reduction of biofilm on metallic implants in vivo compared to antibiotics or untreated control. iAMF-antibiotic combinations resulted in a > 1 - log further reduction in biofilm burden compared to antibiotics or iAMF alone. This combination effect was seen in both S. aureus and P. aeruginosa and seen with multiple antibiotics used to treat infections with these pathogens. In addition, efficacy was temperature dependent with increasing temperatures resulting in a greater reduction of biofilm. Tissue damage was limited (< 1 mm from implant-tissue interface). This non-invasive approach to eradicating biofilm could serve as a new paradigm in treating PJI.

Quantifying the relationship between biofilm reduction and thermal tissue damage on metal implants exposed to alternating magnetic fields.

AIM: Metal implant infections are a devastating problem due to the formation of biofilm which impairs the effectiveness of antibiotics and leads to surgical replacement as definitive treatment. Biofilm on metal implants can be reduced using heat generated by alternating magnetic fields (AMF). In this study, the relationship between implant surface biofilm reduction and surrounding tissue thermal damage during AMF exposure is investigated through numerical simulations. METHODS: Mathematical models of biofilm reduction with heat were created based on in vitro experiments. Simulations were performed to predict the spatial and temporal heating on the implant surface and surrounding tissue when exposed to AMF. RESULTS: The modeling results show that intermittent and slow heating can achieve biofilm reduction with a narrow zone of tissue damage around an implant of less than 3 mm. The results also emphasize that uniformity of implant heating is an extremely important factor impacting the effectiveness of biofilm reduction. For a knee implant, using a target temperature of 75 °C, an intermittent treatment strategy of 15 exposures (10 s to target temperature followed by cooldown) achieved a bacterial CFU reduction of 6-log10 across 25% of the implant surface with less than 3 mm of tissue damage. Alternatively, a single 60 s heating exposure to same temperature achieved a bacterial reduction of 6-log10 across 85% of the implant surface, but with 4 mm of tissue damage. CONCLUSION: Overall, this study demonstrates that with uniform heating to temperatures above 70 °C, an implant surface can be largely reduced of biofilm, with only a few mm of surrounding tissue damage.

Feasibility of heating metal implants with alternating magnetic fields (AMF) in scaled up models.

Aim: Treatment of infected orthopedic implants remains a major medical challenge, involving prolonged antibiotic therapy and revision surgery, and adding a >$1 billion annual burden to the health care system in the US alone. Exposure of metallic implants to alternating magnetic fields (AMF) generates heat that can provide a noninvasive means to target biofilm adhered to the surface. In this study, an AMF system with a solenoid coil was constructed for targeting a metal plate surgically implanted in a sheep model.Methods: A tissue-mimicking phantom of the sheep leg was developed along with simulation model of phantom and the live sheep leg. This was used evaluate heating with the AMF system and to compare experimental results with numerical simulations. Comparative AMF exposures were performed/simulated in these model for feasibility of design, verification, and validation of simulations.Results: The system produced magnetic field strengths up to 12mT and achieved plate temperatures of 65-80 °C within 10-14 s. Single and intermittent AMF exposures of a tissue-mimicking phantom agreed with numerical simulations within 5 °C. Similar agreement between experimental measurements and simulations was also observed in the live sheep metal implant model. The simulations also predicted 2-3 mm of tissue damage using a CEM43 thermal dose model for 1-h AMF exposures targeting 65 °C for pulse delays of 2.5 and 5 mins.Conclusion: This study confirmed that AMF technology can be scaled up to treat implants in a large animal model with the same rates of heating and peak temperatures achieved in prior in vitro studies. Further, numerical simulations provided accurate predictions of the heating produced by AMF on metal implants and surrounding tissues, and can be used to design AMF coils for treating human prosthetic joint implants with more complex geometrical shapes.

Alternating magnetic fields and antibiotics eradicate biofilm on metal in a synergistic fashion.

Hundreds of thousands of human implant procedures require surgical revision each year due to infection. Infections are difficult to treat with conventional antibiotics due to the formation of biofilm on the implant surface. We have developed a noninvasive method to eliminate biofilm on metal implants using heat generated by intermittent alternating magnetic fields (iAMF). Here, we demonstrate that heat and antibiotics are synergistic in biofilm elimination. For Pseudomonas aeruginosa biofilm, bacterial burden was reduced >3 log with iAMF and ciprofloxacin after 24 h compared with either treatment alone (p < 0.0001). This effect was not limited by pathogen or antibiotic as similar biofilm reductions were seen with iAMF and either linezolid or ceftriaxone in Staphylococcus aureus. iAMF and antibiotic efficacy was seen across various iAMF settings, including different iAMF target temperatures, dose durations, and dosing intervals. Initial mechanistic studies revealed membrane disruption as one factor important for AMF enhanced antibacterial activity in the biofilm setting. This study demonstrates the potential of utilizing a noninvasive approach to reduce biofilm off of metallic implants.

Role of Simulations in the Treatment Planning of Radiofrequency Hyperthermia Therapy in Clinics.

Hyperthermia therapy is a treatment modality in which tumor temperatures are elevated to higher temperatures to cause damage to cancerous tissues. Numerical simulations are integral in the development of hyperthermia treatment systems and in clinical treatment planning. In this study, simulations in radiofrequency hyperthermia therapy are reviewed in terms of their technical development and clinical aspects for effective clinical use. This review offers an overview of mathematical models and the importance of tissue properties; locoregional mild hyperthermia therapy, including phantom and realistic human anatomy models; phase array systems; tissue damage; thermal dose analysis; and thermoradiotherapy planning. This review details the improvements in numerical approaches in treatment planning and their application for effective clinical use. Furthermore, the modeling of thermoradiotherapy planning, which can be integrated with radiotherapy to provide combined hyperthermia and radiotherapy treatment planning strategies, are also discussed. This review may contribute to the effective development of thermoradiotherapy planning in clinics.

Quantitative Estimation of the Equivalent Radiation Dose Escalation using Radiofrequency Hyperthermia in Mouse Xenograft Models of Human Lung Cancer.

Hyperthermia is a potent radiosensitizer, and its effect varies according to the different types of cancer cells. In the present study, the radiosensitizing effect of hyperthermia on lung cancer cell lines A549 and NCI-H1299 was determined based on the equivalent radiation dose escalation. In vitro cell experiments were conducted using lung cancer cell lines A549 and NCI-H1299 to determine thermal radiosensitivity. In vivo experiments were conducted using mouse heterotopic xenograft models to determine the treatment response and increase in the temperature of tumors using a 13.56 MHz radiofrequency (RF) hyperthermia device. Using the α and ß values of the linear-quadratic equations of cell survival curves, numerical simulations were performed to calculate the equivalent radiation dose escalations. The dielectric properties of tumors were measured, and their effect on the calculated equivalent radiation dose was analyzed. Hyperthermia increased the equivalent radiation dose of lung cancer xenografts and a higher escalation was found in NCI-H1299 cells compared with that observed in A549 cells. An underestimation of the calculated equivalent radiation dose was observed when the dielectric property of the tumor was varied. This study may contribute to the effective planning of thermoradiotherapy in clinics.

Effect of tumor properties on energy absorption, temperature mapping, and thermal dose in 13.56-MHz radiofrequency hyperthermia.

Computational techniques can enhance personalized hyperthermia-treatment planning by calculating tissue energy absorption and temperature distribution. This study determined the effect of tumor properties on energy absorption, temperature mapping, and thermal dose distribution in mild radiofrequency hyperthermia using a mouse xenograft model. We used a capacitive-heating radiofrequency hyperthermia system with an operating frequency of 13.56 MHz for in vivo mouse experiments and performed simulations on a computed tomography mouse model. Additionally, we measured the dielectric properties of the tumors and considered temperature dependence for thermal properties, metabolic heat generation, and perfusion. Our results showed that dielectric property variations were more dominant than thermal properties and other parameters, and that the measured dielectric properties provided improved temperature-mapping results relative to the property values taken from previous study. Furthermore, consideration of temperature dependency in the bio heat-transfer model allowed elucidation of precise thermal-dose calculations. These results suggested that this method might contribute to effective thermoradiotherapy planning in clinics.