Stealth Liposomal Chemotherapeutic Agent for Triple Negative Breast Cancer with Improved Pharmacokinetics.

Triple-negative breast cancer is one of the most lethal cancers. Chemotherapeutics for targeting CDK4 and CDK6 like Palbociclib (PAB) in triple-negative breast cancer was widely explored. However, poor bioavailability and severe side effects profile limiting its clinical usage in the field of cancer chemotherapy. Herein, we set out to develop the stealth liposomes (LPS) of PAB by rotary thin film evaporation with a vesicle size of less than 100 nm. In vitro, drug release studies were performed and fitted into different release kinetic models. LPS were characterized by electron microscopic techniques for morphology. The engineered nanotherapeutics agents were further evaluated in 4T1 triple-negative breast cancer cell lines for its anti-cancer potential and cellular uptake. The hemolytic potential and pharmacokinetic (PK) behavior of developed LPS-PAB and PAB were analyzed by using robust UHPLC-QTOF-MS method. LPS-PAB demonstrates biphasic release profile with first-order release kinetics. Further, LPS-PAB has shown less IC50 value (1.99 µM) compared to PAB alone (3.24 µM). The designed nanoliposomes were tagged with fluorescent FITC dye to check rapid cellular uptake. Importantly, stealth LPS-PAB has shown a 1.75-fold reduction in hemolytic potential as compared to PAB plain drug at 100 µg/mL concentration. The PK results obtained was displayed 2.5-fold increase in Cmax, 1.45-fold increase in AUCtot, 1.8-fold increase in half-life and 1.3-fold increase in MRT with LPS-PAB when compared to orally administered PAB suspension. These findings suggest that novel LPS-PAB can be employed as an alternate therapeutic strategy to eradicate triple-negative breast cancer.

Development of Imatinib Mesylate-Loaded Liposomes for Nose to Brain Delivery: In Vitro and In Vivo Evaluation.

Neurodegenerative diseases like Alzheimer's disease require treatment where it is essential for drug to reach brain. Nose to brain delivery of drugs enables direct transport to brain bypassing blood brain barrier. Imatinib mesylate, an anti-cancer agent, was found to have potential anti-Alzheimer's activity and thus repurposed for the same. However, the drug has severe side effects, poor brain bioavailability which may hinder effective treatment of Alzheimer's disease. In the current work, imatinib mesylate-loaded liposomes were prepared with particle size below 150 nm with sustained drug release up to 96 h. The liposomal drug formulation was compared with plain drug solution for cytotoxicity on N2a cells and did not show any kind of toxicity at concentrations up to 25 µg/mL. The nanocarrier formulation was then evaluated for brain deposition by nose to brain administration in comparison with drug solution in rats. The liposomes effectively improved the brain deposition of drug in brain from formulation compared to pure drug solution as indicated by AUC from in vivo experiments. These results indicate that the nose to brain delivery of liposomal imatinib mesylate improved the drug deposition and residence time in brain compared to drug solution administered through oral and intranasal routes.

Dithranol-loaded nanostructured lipid carrier-based gel ameliorate psoriasis in imiquimod-induced mice psoriatic plaque model.

OBJECTIVE: The aim of this study was to formulate nanostructured lipid carriers (NLCs) of dithranol-loaded in gel for ease of application and to evaluate its anti-psoriatic efficacy vis-a-vis conventional ointment formulation. SIGNIFICANCE: This study will provide an insight about the use of nanocarriers, esp. NLCs loaded with dithranol for the effective treatment of psoriasis. METHODS: Dithranol-loaded NLCs were prepared by hot melt homogenization method and characterized for particle size and percentage entrapment efficiency. The optimized NLCs were loaded into gel and evaluated for drug release, spreadability, rheological behavior, and staining. Anti-psoriatic efficacy of the NLC gel was evaluated in imiquimod (IMQ) induced psoriatic plaque model in comparison with prepared conventional ointment formulation (1.15% w/w dithranol). RESULTS: NLCs were prepared with particle size below 300 nm, polydispersity index (PDI) below 0.3 and percentage entrapment efficiency of ∼100%. The prepared NLC gel was then compared with the ointment for drug release, staining property, and efficacy. Topical application of dithranol-loaded NLC gel on IMQ-induced psoriatic plaque model reduced the symptoms of psoriasis assessed by both Psoriasis area severity index (PASI) scoring and enzyme-linked immunosorbent assay. There was a significant reduction in disease severity and cytokines like Interleukins-17, 22, 23 and Tumor necrosis factor-α by the developed system in comparison to the negative control. CONCLUSIONS: To conclude dithranol-loaded NLCs in gel base was efficacious in management of psoriasis at the same drug concentration and also offer less cloth staining to that of the ointment product.

Cabazitaxel and thymoquinone co-loaded lipospheres as a synergistic combination for breast cancer.

Cabazitaxel as microtubule inhibitor and thymoquinone as HDAC inhibitor affects the important genes like p53, STAT3, Bax, BCL-2, p21 and down regulation of NF-κB are reported for potential activity against breast tumors. However, poor aqueous solubility and permeability hinders the delivery of these drugs to target site. To address the delivery challenges cabazitaxel and thymoquinone co-loaded lipospheres were developed. Lipospheres are the lipid based self-assemblies of particle size below 150 nm were prepared with more than 90% entrapment efficiency for both the drugs. In vitro drug release studies revealed there was a sustained diffusion controlled drug release from liposphere matrix leading to decrease in particle size with increase in zeta potential. Cytotoxicity studies on MCF-7 and MDA-MB-231 cells demonstrated cabazitaxel and thymoquinone as synergistic combination for the treatment of breast cancer which was proved by CompuSyn software. Enhanced efficacy of developed lipospheres can be due to rapid cellular internalization which was observed in confocal laser scanning microscopy. Drastic changes in cancer cell morphology such as nuclear fragmentation were observed upon treatment with these lipospheres in comparison to combination solution as observed in fluorescent imaging which are the hall marks of apoptosis. Cell cycle analysis and apoptosis studies confirmed the increased Sub G1 phase arrest as well as cell death due to apoptosis. Thus, as per observed results, it can be concluded that cabazitaxel and thymoquinone co-loaded lipospheres are the efficient delivery vehicles in management of breast cancer.

Non-polymer drug-eluting coronary stents.

Cardiovascular complications are leading causes of most fatalities. Coronary artery disease and surgical failures contribute to the death of the majority of patients. Advanced research in the field of medical devices like stents has efficiently resolved these problems. Clinically, drug-eluting stents have proven their efficacy and safety compared to bare metal stents, which have problems of in-stent restenosis. However, drug-loaded stents coated with polymers have shown adverse effects related to the stability and deterioration of the polymer coating over time. This results in late stent thrombosis and immunogenicity. These reasons laid the foundation for the development of non-polymeric drug-eluting stents. This review focuses on non-polymer drug-eluting stents loaded with different drugs like anti-inflammatory agents, anti-thrombotic, anti-platelet agents, immune suppressants and others. Surface modification techniques on stents like crystalline coating; microporous, macroporous, and nanoporous coatings; and chemically modified self-assembled monolayers are described in detail. There is also an update on clinically approved products and those under development.