Sustained Release of an Anti-Glaucoma Drug: Demonstration of Efficacy of a Liposomal Formulation in the Rabbit Eye

Topical medication remains the first line treatment of glaucoma; however, sustained ocular drug delivery via topical administration is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Currently, daily topical administration for lowering the intra-ocular pressure (IOP), has many limitations, such as poor patient compliance and ocular allergy from repeated drug administration. Poor compliance leads to suboptimal control of IOP and disease progression with eventual blindness. The delivery of drugs in a sustained manner could provide the patient with a more attractive alternative by providing optimal therapeutic dosing, with minimal local toxicity and inconvenience. To investigate this, we incorporated latanoprost into LUVs (large unilamellar vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by the film hydration technique. Relatively high amounts of drug could be incorporated into this vesicle, and the drug resides predominantly in the bilayer. Vesicle stability monitored by size measurement and DSC (differential scanning calorimetry) analysis showed that formulations with a drug/lipid mole ratio of about 10% have good physical stability during storage and release. This formulation demonstrated sustained release of latanoprost in vitro, and then tested for efficacy in 23 rabbits. Subconjunctival injection and topical eye drop administration of the latanoprost/liposomal formulation were compared with conventional daily administration of latanoprost eye drops. The IOP lowering effect with a single subconjunctival injection was shown to be sustained for up to 50 days, and the extent of IOP lowering was comparable to daily eye drop administration. Toxicity and localized inflammation were not observed in any treatment groups. We believe that this is the first demonstration, in vivo, of sustained delivery to the anterior segment of the eye that is safe and efficacious for 50 days

Biocompatibility and Biodegradation Studies of Subconjunctival Implants in Rabbit Eyes

Sustained ocular drug delivery is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Biodegradable subconjunctival implants with controlled drug release may circumvent these two problems. In our study, two microfilms (poly [d,l-lactide-co-glycolide] PLGA and poly[d,l-lactide-co-caprolactone] PLC were developed and evaluated for their degradation behavior in vitro and in vivo. We also evaluated the biocompatibility of both microfilms. Eighteen eyes (9 rabbits) were surgically implanted with one type of microfilm in each eye. Serial anterior-segment optical coherence tomography (AS-OCT) scans together with serial slit-lamp microscopy allowed us to measure thickness and cross-sectional area of the microfilms. In vitro studies revealed bulk degradation kinetics for both microfilms, while in vivo studies demonstrated surface erosion kinetics. Serial slit-lamp microscopy revealed no significant inflammation or vascularization in both types of implants (mean increase in vascularity grade PLGA50/50 12±0.5% vs. PLC70/30 15±0.6%; P = 0.91) over a period of 6 months. Histology, immunohistochemistry and immuno-fluorescence also revealed no significant inflammatory reaction from either of the microfilms, which confirmed that both microfilms are biocompatible. The duration of the drug delivery can be tailored by selecting the materials, which have different degradation kinetics, to suit the desired clinical therapeutic application

Risk and resilience among mothers and fathers of primary school age children with ASD in Malaysia: a qualitative constructive grounded theory approach

Little is known about the coping and resilience experiences of parents of children with autism spectrum disorder (ASD) in the Malaysian cultural context. This study utilized a qualitative methodological approach adopting constructive grounded theory. The study sought to address the lack of research to date exploring the risk and protective experiences that contribute to parental stress and resilience for parents of primary school age children with ASD in the Malaysian setting. Twenty-two parents of children with ASD (13 mothers and 9 fathers) participated in semi-structured interviews. A strength of the study was the inclusion of both mother and father participant perspectives. The interviews lasted 50–80 min (mean: 67.5 min). The 22 parents had a total of 16 children (12 males; 4 females) formally diagnosed with ASD. Child age ranged between 5 and 12 years (mean age: 8.44). Overall, analysis of the 22 interviews revealed four prominent themes – “initial reaction to child’s ASD symptoms and diagnosis,” “family life affected by a child with ASD,” “awareness about ASD in Malaysia,” and “coping strategies, wellbeing, and becoming resilient.” The first three themes revolved around stress and adversity, and, the adaptability and acceptance of the parents. These processes illustrated the risks experienced by the parents of children with ASD in Malaysia. The last theme especially highlighted the strengths and determination of the parents and illustrated the protective experiences and processes that helped parents to develop and enhance resilience. Overall, the findings revealed that resilience develops synergistically and dynamically from both risk and protective experiences across different levels – individual, family, community, society and government. The findings motivated the development of our theoretical model of resilience that can help health and education professionals tailor assessment and interventions for parents of children with ASD in the Malaysian context. Clinical, policy, and research suggestions were discussed

From flab to fab : transforming surgical waste into an effective bioactive coating material

Cellular events are regulated by the interaction between integrin receptors in the cell membrane and the extracellular matrix (ECM). Hence, ECM, as a material, can potentially play an instructive role in cell–material interactions. Currently, adipose tissue in the form of lipoaspirate is often discarded. Here, it is demonstrated how our chemical-free decellularization method could be used to obtain ECM from human lipoaspirate waste material. These investigations show that the main biological components are retained in the lipoaspirate-derived ECM (LpECM) material and that this LpECM material could subsequently be used as a coating material to confer bioactivity to an otherwise inert biodegradable material (i.e., polycaprolactone). Overall, lipoaspirate material, a complex blend of endogenous proteins, is effectively used a bioactive coating material. This work is an important stepping-stone towards the development of biohybrid scaffolds that contain cellular benefits without requiring the use of additional biologics based on commonly discarded lipoaspirate material

Nox4-dependent ROS modulation by amino endoperoxides to induce apoptosis in cancer cells

Tumor metastasis is the main cause of death in cancer patients. Anoikis resistance is one critical malefactor of metastatic cancer cells to resist current clinical chemotherapeutic treatments. Although endoperoxide-containing compounds have long been suggested as anticancer drugs, few have been clinically employed due to their instability, complex synthesis procedure or low tumor cell selectivity. Herein, we describe a one-pot strategy to synthesize novel amino endoperoxides and their derivatives with good yields and stabilities. In vitro cell-based assays revealed that 4 out of the 14 amino endoperoxides selectively induce metastatic breast carcinoma cells but not normal breast cells to undergo apoptosis, in a dose-dependent manner. Mechanistic studies showed that the most potent amino endoperoxide, 4-Me, is selective for cancer cells expressing a high level of Nox4. The anticancer effects are further shown to be associated with reduced O2−:H2O2 ratio and increased ·OH level in the cancerous cells. Animal study showed that 4-Me impairs orthotopic breast tumor growth as well as tumor cell metastasis to lymph nodes. Altogether, our study suggests that anticancer strategies that focus on redox-based apoptosis induction in tumors are clinically viable.Published versio

Change of film thickness of PLGA50/50 and PLC70/30 in vitro (PBS, pH 7.4).

<p>Change of film thickness of PLGA50/50 and PLC70/30 in vitro (PBS, pH 7.4).</p

In vitro weight loss of PLGA50/50 and PLC70/30, immersed in PBS buffer (pH 7.4).

<p>In vitro weight loss of PLGA50/50 and PLC70/30, immersed in PBS buffer (pH 7.4).</p

Photographs with fluorescence microscopy of sections of PLGA50/50 and PLC70/30 with immunofluorescence stains for T cells.

<p>A, B: 1– Section of eye implanted with PLGA50/50 microfilm at 3 and 6 months respectively. A, B: 2 – Section of eye implanted with PLC70/30 microfilm at 3 and 6 months respectively.</p