Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activatable Prodrug of Doxorubicin

Purpose

A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state.

Methods

The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process. The prodrug is a conjugate of doxorubicin and photocleavable biotin (DOX-PCB).

Results

These DOX-PCB nanoparticles are 30 times less toxic to cells than doxorubicin, but can be activated to release pure therapeutic doxorubicin when exposed to 365 nm light. These nanoparticles have an average diameter of around 100 nm and achieve the maximum possible prodrug loading capacity since no support structure or coating is required to prevent loss of prodrug from the nanoparticle.

Conclusions

These light activatable nanoparticles demonstrate tunable toxicity and can be used to facilitate future therapy development whereby light delivered specifically to the tumor tissue would locally convert the nanoparticles to doxorubicin while leaving nanoparticles accumulated in healthy tissue in the less toxic prodrug form.

     

Venous Thromboembolic Complications Following Air Travel: What's the Quantitative Risk? A Literature Review

OBJECTIVES: To quantify the risk of venous thromboembolism (VTE) following air travel and assess methods of prevention. DESIGN: Review of literature. METHODS: We reviewed Pubmed, Medline, Embase and Cochrane Databases for studies that have assessed the risk of VTE associated with air travel. RESULTS: There is an association of VTE with air travel with pooled odds ratio of 1.59 (confidence interval 1.04-2.43) from three case control studies and relative risk of 2.93 (confidence interval 1.5-5.58) from two controlled cohort studies. The incidence of symptomatic pulmonary embolism (PE) is extremely low but there is substantial increase when the distance travelled is more than 5,000 miles (1.5 PE per million passengers) or time of flight is more than 8h duration (2.57 PE per million passengers). The quantitative risk of lower limb venous thrombosis in high-risk subjects is 5% per flight and 1.6% per flight for low risk subjects following long haul flights. All six randomised trials to test the below knee compression stockings with ankle pressures of 14-30 mmHg have shown reduction in lower limb venous thrombosis. CONCLUSION: VTE is more common in those with additional risk factors when the risk is about 5% per air travel for long haul flights. Class I or II below knee compression stockings are effective in the prevention of lower limb venous thrombosis.     

Apnea testing with continuous positive airway pressure for the diagnosis of brain death in a patient with poor baseline oxygenation status

Apnea testing is a key component in the clinical diagnosis of brain death. Patients with poor baseline oxygenation may not tolerate the standard 8-10 min apnea testing with oxygen insufflation through tracheal tube. No studies have assessed the safety and feasibility of other methods of oxygenation during apnea testing in these types of patients. Here, we safely performed apnea testing in a patient with baseline PaO₂ of 99.1 mm Hg at 100% oxygen. We used continuous positive airway pressure (CPAP) of 10 cm of H₂O and 100% oxygen at the flow rate of 12 L/min using the circle system of anesthesia machine. After 10 min of apnea testing, PaO₂ decreased to 75.7 mm Hg. There was a significant rise in PaCO₂ and fall in pH, but without hemodynamic instability, arrhythmias, or desaturation. Thus, the apnea test was declared positive. CPAP can be a valuable, feasible and safe means of oxygenation during apnea testing in patients with poor baseline oxygenation, thus avoiding the need for ancillary tests.     

Preparation and drug release activity of scaffolds containing collagen and poly(caprolactone)

A new biodegradable polymeric scaffold was prepared by using collagen and poly(caprolatctone) (PCL). These scaffolds were found to be soft, spongy, and transparent in nature and characterized by thermogravimetric analysis and FTIR spectrum. To these biodegradable polymeric scaffolds, antibiotic drugs namely amikacin and gentamycin were incorporated separately to study their release pattern from scaffolds. Amikacin and gentamycin release activity of the scaffolds containing a constant quantity of collagen but different quantities of PCL were studied at various time intervals viz. 1, 4, 24, and 48 h by measuring the optical density at 257 and 255 nm, respectively.     

Use of genetically engineered Salmonella typhimurium OY1002/1A2 strain coexpressing human cytochrome P450 1A2 and NADPH-cytochrome P450 reductase and bacterial O-acetyltransferase in SOS/umu assay

The major pathway of bioactivation of procarcinogenic heterocyclic aromatic amines (HCAs) is cytochrome P450 1A2 (CYP1A2)-catalyzed N-hydroxylation and subsequent esterification by O-acetyltransferase (O-AT). We have previously reported that an umu tester strain, Salmonella typhimurium OY1001/1A2, endogenously coexpressing human CYP1A2 and NADPH-P450 reductase (reductase), is able to detect the genotoxicity of some aromatic amines [Aryal et al., 1999, Mutat Res 442:113-120]. To further enhance the sensitivity of the strain toward HCAs, we developed S. typhimurium OY1002/1A2 by introducing pCW"/1A2:hNPR (a bicistronic construct coexpressing human P450 1A2 and the reductase) and pOA102 (constructed by subcloning the Salmonella O-AT gene in the pOA101-expressing umuC"lacZ gene) in S. typhimurium TA1535. In addition, as an O-AT-deficient strain, we developed the OY1003/1A2 strain by introducing pCW"/1A2:hNPR and pOA101 into O-AT-deficient S. typhimurium TA1535/1,8-DNP. Strains OY1001/1A2, OY1002/1A2, and OY1003/1A2 expressed, respectively, about 150, 120, and 140 nmol CYP1A2/l culture (in whole cells), and respective cytosolic preparations acetylated 15, 125, and > or = 0 nmol isoniazid/min/mg protein as the O-AT activities of cytosolic preparations, respectively. We compared the induction of umuC gene expression as a measure of genotoxicity and observed that the OY1002/1A2 strain was more sensitive than OY1001/1A2 strain toward the genotoxicity of 2-amino-1,4-dimethylimidazo[4,5-f]quinol ine(MeIQ), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ),2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx),2-aminoanthracene, 2-amino-6-methyldipyrido[1,2-a::3,2'-d]i midazole,3-amino-1, 4-dimethyl-5H-pyrido[4,3-b]indole, and 3-amino-1-methyl-5H-pyrido[4, 3-a]indole. However, the genotoxicity of MeIQ, IQ, and MeIQx was not detected with the OY1003/1A2 strain. These results indicate that the newly developed strain OY1002/1A2 can be employed in detecting potential genotoxic aromatic amines requiring bioactivation by CYP1A2 and O-acetyltransferase.     

Retrospective reporting of the duration of post-partum amenorrhea: A survival analysis

Introduction: Duration of post-partum amenorrhoea (PPA) is the period from the end of pregnancy to begin of menstruation. It is a temporary infecundable period. The attainment of first menstruation after delivery is treated as the termination of PPA. Objectives: The main aim of this paper is to investigate the differentials of the duration of PPA according to the characteristics of mothers and their child. Methods: The data are taken from a sample survey of Palpa and Rupandehi districts. A total of 1019 ever-married mothers were interviewed. 481 mothers were provided information on the duration of PPA to their last but one born child (retrospective status reporting). Survival analysis technique has been used. Results: It was found that the distribution of PPA showed a heaping at the multiple of three months. Mean duration of PPA was found to be ten months and it was higher among mothers of higher parity, older mothers and higher age at birth of child. Younger mothers have lower duration than that of the older. Mean duration was increased with the increased parity of mothers. A strong positive association was observed between the duration of PPA and breastfeeding (BF). The increased duration of PPA was found with the increased birth interval. The survival status of child was found a strong consequence on amenorrheaic period. Inverse association was found with education as well as high socioeconomic status of the family. A significant association was found with residential as well as caste/ethnic groups. Conclusion: Mean duration of PPA was found to be 10.6 months. Amenorrheaic period was found higher among mothers of higher parity, older ages, and higher age at birth of the child. A positive relationship was found with BF whereas inverse association was found with the level of education. Duration of PPA was decreased with the increased level of socio-economic status.