Pavan Balabathula

Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform

UNLABELLED The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core-shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core-shell-type lipid-polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics. FROM THE CLINICAL EDITOR This comprehensive review covers the current applications of core-shell-type lipid-polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.

Development and in vitro evaluation of core-shell type lipid-polymer hybrid nanoparticles for the delivery of erlotinib in non-small cell lung cancer.

Core-shell type lipid-polymer hybrid nanoparticles (CSLPHNPs) have emerged as a multifunctional drug delivery platform. The delivery system combines mechanical advantages of polymeric core and biomimetic advantages of the phospholipid shell into a single platform. We report the development of CSLPHNPs composed of the lipid monolayer shell and the biodegradable polymeric core for the delivery of erlotinib, an anticancer drug, clinically used to treat non-small cell lung cancer (NSCLC). Erlotinib loaded CSLPHNPs were prepared by previously reported single-step sonication method using polycaprolactone (PCL) as the biodegradable polymeric core and phospholipid-shell composed of hydrogenated soy phosphatidylcholine (HSPC) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 (DSPE-PEG2000). Erlotinib loaded CSLPHNPs were characterized for physicochemical properties including mean particle size, polydispersity index (PDI), zeta potential, morphology, thermal and infrared spectral analysis, drug loading, in vitro drug release, in vitro serum stability, and storage stability. The effect of critical formulation and process variables on two critical quality attributes (mean particle size and drug entrapment efficiency) of erlotinib loaded CSLPHNPs was studied and optimized. In addition, in vitro cellular uptake, luminescent cell viability assay and colony formation assay were performed to evaluate efficacy of erlotinib loaded CSLPHNPs in A549 cells, a human lung adenocarcinoma cell line. Optimized erlotinib loaded CSLPHNPs were prepared with mean particle size of about 170nm, PDI<0.2, drug entrapment efficiency of about 66% with good serum and storage stability. The evaluation of in vitro cellular efficacy results indicated enhanced uptake and efficacy of erlotinib loaded CSLPHNPs compared to erlotinib solution in A549 cells. Therefore, CSLPHNPs could be a potential delivery system for erlotinib in the therapy of NSCLC.

Effect of sucrose as a lyoprotectant on the integrity of paclitaxel-loaded liposomes during lyophilization

Abstract Context: The stability of liposomes in the form of dispersion is a major concern due to drug leakage and fusion or aggregation. The stability can be improved by lyophilization, but the stress induced by the lyophilization process can affect the integrity of liposomes. Objective: The objective of this study was to evaluate the lyoprotective effect of sucrose on drug leakage and vesicle size of paclitaxel-loaded liposomes during the lyophilization process. Materials and methods: Paclitaxel-loaded liposomal dispersions were prepared with sucrose at several lipid–sugar ratios, and internal–external sugar ratios, and then lyophilized. The entrapped paclitaxel content and vesicle size were monitored before and after lyophilization. The stability of the formulation was evaluated at 5 and 25 °C. Results: A significant increase in free paclitaxel and vesicle size was observed with the liposomes lyophilized without sucrose. Inclusion of sucrose in the formulation significantly reduced the free paclitaxel concentration and minimized the changes in vesicle size. The extent of protection improved further when sucrose was also present in the internal portion of the bilayer. The lyophilized formulation was stable at 5 °C for 3 months. Discussion: A significant (p < 0.05) correlation was observed between free paclitaxel content and the average diameter of the liposomes with respect to sucrose concentrations in the formulation. Sucrose protected the liposomes from drug leakage and aggregation/fusion induced by the lyophilization process in a concentration dependent manner. Conclusion: The integrity of paclitaxel-loaded liposomes was preserved during lyophilization by optimal levels of lyoprotectant sucrose in the formulation.

Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes

Abstract The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration–extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated–unsaturated lipid ratio, drug–lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug–lipid ratios demonstrated that 1:60 as the optimum drug–lipid ratio to achieve a loading of 1–1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

Targeted liposomal drug delivery systems for the treatment of B cell malignancies.

Abstract Nanoparticulate systems have demonstrated significant potential for overcoming the limitations of non-specific adverse effects related to chemotherapy. The treatment of blood malignancies employing targeted particulate drug delivery systems presents unique challenges and considerable research has been focused towards the development of targeted liposomal formulations for B cell malignancies. These formulations are aimed at achieving selectivity towards the malignant cells by targeting several cell surface markers which are over-expressed in that specific malignancy. CD19, CD20, CD22 and CD74 are few of such markers of which CD19, CD22 and CD74 are internalizing and CD20 is non-internalizing. Systems which have been developed to target both types of these cell surface markers are discussed. Specifically, the efficacy and development of targeted liposomes is considered. A number of studies have demonstrated the advantages of targeted liposomal systems encapsulating doxorubicin or vincristine. However, liposomal encapsulation of newer anti-neoplastic agents such as AD 198 which are superior to doxorubicin should be considered.

Potency and Stability of Intradermal Capsaicin: Implications for Use as a Human Model of Pain in Multicenter Clinical Trials

Intradermally injected capsaicin has been used extensively both as a human pain model and to assess analgesic efficacy. Factors such as dose, formulation, route, and site are known to affect its sensitivity. We determined whether potency and stability of capsaicin solutions were further sources of variability when following strict manufacturing guidelines. Capsaicin solution (1.0 mg/mL) was prepared according to Current Good Manufacturing Practice (cGMP) guidelines and aseptically filled into sterile amber borosilicate vials and stored at 5°C, 25°C, and 30°C. All samples were analyzed at one, three, six, and twelve months. Chemical stability was determined using HPLC and physical stability was evaluated by visual inspection of color changes, clarity, particulate matter, and product/ container closure abnormalities during each sampling time. Capsaicin intradermal injection was found to be sterile and retained 95% of the initial concentration for at least one year, regardless of studied storage temperatures (P<0.0001). Visual inspection indicated no changes in color, clarity, particulate matter, and product/ container closure abnormalities in all samples. These data show that capsaicin solutions (1.0 mg/mL) maintain their potency and stability over one year when manufactured according to cGMP guidelines. These results suggest that in clinical trials manufacturing of capsaicin solutions is recommended over extemporaneous compounding.

Formulation, Development, and In Vitro Evaluation of a CD22 Targeted Liposomal System Containing a Non-Cardiotoxic Anthracycline for B Cell Malignancies

Doxorubicin cardiotoxicity has led to the development of superior chemotherapeutic agents such as AD 198. However, depletion of healthy neutrophils and thrombocytes from AD 198 therapy must be limited. This can be done by the development of a targeted drug delivery system that delivers AD 198 to the malignant cells. The current research highlights the development and in vitro analysis of targeted liposomes containing AD 198. The best lipids were identified and optimized for physicochemical effects on the liposomal system. Physiochemical characteristics such as size, ζ-potential, and dissolution were also studied. Active targeting to CD22 positive cells was achieved by conjugating anti-CD22 Fab’ to the liposomal surface. Size and ζ-potential of the liposomes was between 115 and 145 nm, and −8 to−15 mV. 30% drug was released over 72 h. Higher cytotoxicity was observed in CD22+ve Daudi cells compared to CD22−ve Jurkat cells. The route of uptake was a clathrin- and caveolin-independent pathway. Intracellular localization of the liposomes was in the endolysosomes. Upon drug release, apoptotic pathways were activated partly by the regulation of apoptotic and oncoproteins such as caspase-3 and c-myc. It was observed that the CD22 targeted drug delivery system was more potent and specific compared to other untargeted formulations.

Combination Therapy in Glaucoma Treatment

Copyright: