Poly(β-amino ester)–DNA complexes: Time-resolved fluorescence and cellular transfection studies

A large number of different polymers have been developed and studied for application as DNA carriers for non-viral gene delivery, but the DNA binding properties are not understood. This study describes the efficiency of nanoparticle formation by time-resolved fluorescence measurements for poly(β-amino esters), cationic biodegradable polymers with DNA complexation and transfection capability. From the large library of poly(β-amino esters) ten polymers with different transfection efficacies were chosen for this study. The binding constants for nanoparticle formation were determined and compared to with the same method. Although the DNA binding efficiency of the amine groups are similar for both types of polymers, the overall binding constants are an order of magnitude smaller for poly(β-amino esters) than for 25 kDa polyethylenimines, yet poly(β-amino esters) show comparable DNA transfection efficacy with polyethylenimines. Within this series of polymers the transfection efficacy showed increasing trend in association with relative efficiency of nanoparticle formation.Academy of FinlandNational Institutes of Health (U.S.) (Grant CA132091)National Institutes of Health (U.S.) (Grant CA115527

Longitudinal analysis of T2 relaxation time variations following radiotherapy for prostate cancer

Aim of this paper is to evaluate short and long-term changes in T2 relaxation times after radiotherapy in patients with low and intermediate risk localized prostate cancer. A total of 24 patients were selected for this retrospective study. Each participant underwent 1.5T magnetic resonance imaging on seven separate occasions: initially after the implantation of gold fiducials, the required step for Cyberknife therapy guidance, followed by MRI scans two weeks post-therapy and monthly thereafter. As part of each MRI scan, the prostate region was manually delineated, and the T2 relaxation times were calculated for quantitative analysis. The T2 relaxation times between individual follow-ups were analyzed using Repeated Measures Analysis of Variance that revealed a significant difference across all measurements (F (6, 120) = 0.611, p << 0.001). A Bonferroni post hoc test revealed significant differences in median T2 values between the baseline and subsequent measurements, particularly between pre-therapy (M0) and two weeks post-therapy (M1), as well as during the monthly interval checks (M2 - M6). Some cases showed a delayed decrease in relaxation times, indicating the prolonged effects of therapy. The changes in T2 values during the course of radiotherapy can help in monitoring radiotherapy response in unconfirmed patients, quantifying the scarring process, and recognizing the therapy failure

Acquired Angioedema with C1 Inhibitor Deficiency: Occurrence, Clinical Features, and Management: A Nationwide Retrospective Study in the Czech Republic Patients

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Acquired angioedema with C1 inhibitor deficiency (AAE-C1-INH) is rare but a potentially life-threatening disease. There are no official prevalence data, nor approved therapies for this condition. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; In this study, we aimed to collect and analyze clinical data on patients with AAE-C1-INH in the Czech Republic. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We have conducted a retrospective analysis of AAE-C1-INH patients from Czech referral centers for the treatment of hereditary angioedema with C1 inhibitor deficiency. The inclusion criteria involved recurrent episodes of angioedema with the first manifestation at or after the age of 40, negative family history of angioedema, and C1 inhibitor function 50% or less. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 14 patients (7 males and 7 females) met the inclusion criteria for AAE-C1-INH. The median age of the symptom onset was 59.5 years, and the median diagnosis delay was 1 year. The most common clinical manifestation was facial edema (100%) and upper airway swelling (85.7%). All patients responded to the acute attack treatment with icatibant and plasma-derived or recombinant C1 inhibitor concentrate. Lymphoid malignancy was identified in 9 patients (64%), monoclonal gammopathy of uncertain significance in 3 (21%), and in 1 patient autoimmune disease (ulcerative colitis) was considered causative (7%). We were not able to identify any underlying disease only in 1 patient (7%). In 6 of 7 patients (86%) treated for lymphoma, either a reduction in the frequency of angioedema attacks or both angioedema symptoms’ disappearance and complement parameter normalization was observed. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The prevalence of AAE-C1-INH in the Czech Republic is about 1:760,000. This rare condition occurs in approximately 8% of the patients with angioedema with C1 inhibitor deficiency. AAE-C1-INH is strongly associated with lymphoproliferative disorders, and treating these conditions may improve the control of angioedema symptoms. </jats:p

Melanin-Binding-Based Discovery of Topically Instilled Carbonic Anhydrase Inhibitors for Targeted Delivery and Prolonged Action in the Eye

Glaucoma is a vision-threatening disease that is currently treated with intraocular-pressure-reducing eyedrops that are instilled once or multiple times daily. Unfortunately, the treatment is associated with low patient adherence and suboptimal treatment outcomes. We developed carbonic anhydrase II inhibitors (CAI-II) for a prolonged reduction of intraocular pressure (IOP). The long action is based on the melanin binding of the drugs that prolongs ocular drug retention and response. Overall, 63 new CAI-II compounds were synthesized and tested for melanin binding in vitro. Carbonic anhydrase affinity and IOP reduction of selected compounds were tested in rabbits. Prolonged reduction of IOP in pigmented rabbits was associated with increasing melanin binding of the compound. Installation of a single eye drop of a high melanin binder carbonic anhydrase inhibitor (CAI) resulted in ≈2 weeks’ decrease of IOP, whereas the effect lasted less than 8 h in albino rabbits. Duration of the IOP response correlated with melanin binding of the compounds. Ocular pharmacokinetics of a high melanin binder compound was studied after eye drop instillation to the rat eyes. The CAI showed prolonged drug retention in the pigmented iris-ciliary body but was rapidly eliminated from the albino rat eyes. The melanin-bound drug depot maintained effective free concentrations of CAI in the ciliary body for several days after application of a single eye drop. In conclusion, melanin binding is a useful tool in the discovery of long-acting ocular drugs.Peer reviewe