Bioreducible heparin-based nanogel drug delivery system

Bioreducible heparin (HEP)-based nanogels were prepared by derivatizing HEP with vinyl group followed by copolymerizing with cystamine bisacrylamide in aqueous medium in the absence of surfactant. The hydrodynamic diameter of the HEP nanogels could be tuned in the range from 80 to 200 nm. Doxorubicin (DOX) was loaded into the HEP nanogels, and high drug loading content (30%) and efficiency (90%) were achieved. In vitro drug release test revealed that this drug delivery system exhibited strongly redox-sensitive drug release behavior that would greatly favor the in vivo drug delivery performance of the nanogels. After injected into tumor-bearing mice through tail vein, the DOX-loaded HEP nanogels showed remarkable accumulation in tumors as demonstrated by in vivo near infared fluorescence imaging and ex vivo DOX concentration measurements. The doxorubicin accumulation at tumor site goes beyond 9% injected dose per gram of tumor through such delivery system, making that DOX-loaded HEP nanogels have significantly superior in vivo antitumor activity.     

A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.     

Contribution of components of the quadriceps femoris muscle for producing external torque in patients with patellofemoral pain syndrome

IntroductionDifferent muscular activities of the quadriceps components for producing necessary torque may change in patients with patellofemoral pain syndrome (PFPS). The aim of the current study, therefore, was to assess the contribution of each component of the quadriceps femoris muscle for producing external torque in patients with PFPS.MethodTwelve females with PFPS (24.7 ± 2.3 years) and twelve healthy matched females (25.4 ± 2.4 years) performed three consecutive knee flexion and extension movements with maximum effort at 45°/s and 300°/s using a Biodex system 3 dynamometer. Simultaneously, electromyographic (EMG) activities of the vastus medialis oblique (VMO), RF (rectus femoris) and vastus lateralis (VL) muscles were recorded using a DataLog instrument. Standard multiple regressions were used to assess the ability of EMG activities of the VMO, RF and VL muscles to predict normalized quadriceps femoris isokinetic concentric and eccentric torques at 45°/s and 300°/s in the normal and patient groups.ResultsIn the normal group, the VL and the VMO were the good predictors of quadriceps concentric torque at 45°/s and 300°/s, respectively. The VL and the RF were the good predictors of quadriceps eccentric torque at 300°/s in the patient group. No other conditions showed a considerable prediction for quadriceps torque in the normal or patient group.ConclusionFemales with PFPS differ with normal females in terms of the contribution of each component of the quadriceps femoris for producing external torque. Training the VMO for concentric contraction at both high and low velocities should be included in the management of the patients with PFPS.     

Evaluation of a deep learning model on coronary CT angiography for automatic stenosis detection

PurposeThe purpose of this study was to evaluate a deep-learning model (DLM) for classifying coronary arteries on coronary computed tomography -angiography (CCTA) using the Coronary Artery Disease-Reporting and Data System (CAD-RADS).Materials and methodsThe DLM was trained with 10,800 curved multiplanar reformatted (cMPR) CCTA images classified by an expert radiologist using the CAD-RADS. For each of the three main coronary arteries, nine cMPR images 40° apart acquired around each arterial circumference were then classified by the DLM using the highest probability. For the validation set composed of 159 arteries from 53 consecutive patients, the images were read by two senior and two junior readers; consensus of the two seniors was the reference standard. With the DLM, the majority vote for the nine images was used to classify each artery. Three groups (CAD-RADS 0, 1–2, or 3–4–5) and 2 groups CAD-RADS 0–1–2 or 3–4–5 (<50% vs. ≥50% stenosis) were used for comparisons with readers and consensus. Performance of the model and readers was compared to the consensus reading using the intraclass coefficient (ICC) and Cohen's kappa coefficient at the artery and patient levels.ResultsWith the three groups at the artery level, the ICC of the DLM was 0.82 (95% CI: 0.75–0.88) and not significantly different from those of 3/4 readers; accuracy was 81%. With the binary classification, Cohen kappa coefficient of the DLM was 0.85 (95% CI: 0.69–0.94) and not significantly different from that of 3/4 readers; accuracy was 96%. At the patient level, sensitivity and specificity were 93% and 97% respectively, and the negative predictive value was 97%.ConclusionThe DLM detected ≥50% stenoses with performances similar to those achieved by senior radiologists.