Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor.

Itraconazole (ITA), an old and widely prescribed antifungal drug with excellent safety profile, has more recently been demonstrated to be a multitarget antiangiogenesis agent affecting multiple angiogenic stimulatory signals and pathways, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and mammalian target of rapamycin (mTOR). In this study, we developed two nanoparticle formulations, i.e., polymer micelles (IP2K) and albumin nanoparticles (IBSA), to solubilize the extremely hydrophobic and insoluble ITA to allow intravenous administration and pharmacokinetics (PK)/pharmacodynamics (PD) comparisons. Although none of the formulations showed strong antiproliferation potency against non-small cell lung cancer (NSCLC) cells in vitro, when administrated at the equivalent ITA dose to a NSCLC patient-derived xenograft (PDX) model, IBSA retarded while IP2K accelerated the tumor growth. We attributed the cause of this paradox to formulation-dependent PK and vascular manipulation: IBSA demonstrated a more sustained PK with a Cmax of 60-70% and an AUC ∼2 times of those of IP2K, and alleviated the tumor hypoxia presumably through vascular normalization. In contrast, the high Cmax of IP2K elevated tumor hypoxia through a strong angiogenesis inhibition, which could have aggravated cancer aggressiveness and accelerated tumor growth. Furthermore, IBSA induced minimal hepatic and hematologic toxicities compared to IP2K and significantly enhanced the in vivo tumor inhibition activity of paclitaxel albumin nanoparticles when used in combination. These findings suggest that formulation and pharmacokinetics are critical aspects to be considered when designing the ITA angiogenesis therapy, and IBSA could potentially be assessed as a novel and safe multitarget angiogenesis therapy to be used in combination with other anticancer agents.

Current Advances of Tubulin Inhibitors in Nanoparticle Drug Delivery and Vascular Disruption/Angiogenesis.

Extensive research over the last decade has resulted in a number of highly potent tubulin polymerization inhibitors acting either as microtubule stabilizing agents (MSAs) or microtubule destabilizing agents (MDAs). These inhibitors have potent cytotoxicity against a broad spectrum of human tumor cell lines. In addition to cytotoxicity, a number of these tubulin inhibitors have exhibited abilities to inhibit formation of new blood vessels as well as disrupt existing blood vessels. Tubulin inhibitors as a vascular disrupting agents (VDAs), mainly from the MDA family, induce rapid tumor vessel occlusion and massive tumor necrosis. Thus, tubulin inhibitors have become increasingly popular in the field of tumor vasculature. However, their pharmaceutical application is halted by a number of limitations including poor solubility and toxicity. Thus, recently, there has been considerable interests in the nanoparticle drug delivery of tubulin inhibitors to circumvent those limitations. This article reviews recent advances in nanoparticle based drug delivery for tubulin inhibitors as well as their tumor vasculature disruption properties.

Nanoparticle Drug Delivery Systems for α-Mangostin.

α-Mangostin, a xanthone derivative from the pericarp of Garcinia mangostana L., has numerous bioactivities and pharmacological properties. However, α-mangostin has low aqueous solubility and poor target selectivity in the human body. Recently, nanoparticle drug delivery systems have become an excellent technique to improve the physicochemical properties and effectiveness of drugs. Therefore, many efforts have been made to overcome the limitations of α-mangostin through nanoparticle formulations. Our review aimed to summarise and discuss the nanoparticle drug delivery systems for α-mangostin from published papers recorded in Scopus, PubMed and Google Scholar. We examined various types of nanoparticles for α-mangostin to enhance water solubility, provide controlled release and create targeted delivery systems. These forms include polymeric nanoparticles, nanomicelles, liposomes, solid lipid nanoparticles, nanofibers and nanoemulsions. Notably, nanomicelle modification increased α-mangostin solubility increased more than 10,000 fold. Additionally, polymeric nanoparticles provided targeted delivery and significantly enhanced the biodistribution of α-mangostin into specific organs. In conclusion, the nanoparticle drug delivery system could be a promising technique to increase the solubility, selectivity and efficacy of α-mangostin as a new drug candidate in clinical therapy.

Mechanisms of the effectiveness of lipid nanoparticle formulations loaded with anti-tubercular drugs combinations toward overcoming drug bioavailability in tuberculosis.

Dual-drug-loaded lipid nanoparticle formulations (LNFs) namely solid lipid nanoparticles (SLNs) and nanostructured lipid carrier (are also solid lipid nanoparticles- a new generation of traditional SLNs) were developed and delivered to differentiated THP-1 cells. Developed LNFs have smooth and spherical surface morphology and nano range in size. In vitro drugs release profiles from these LNFs were slow and sustained. Particles were well co-localised in a different compartment (lysosome and endosome) of polarised macrophage by using suitable pH-dependent and antibody-mediated trafficking probe. Majority of the LNFs were also capable of existing in phago-lysosomal complex and able to effectively co-localise with the different cellular compartment of THP-1. The journey of the lipid carrier started through the formation of coated vesicle on differentiated macrophage surface, will further followed to idetify the efficient delivery of nano carrierat lysosomal and endosomal compartment in a sub cellular level of specific cell population. Comparative oral in vivo pharmacokinetic study revealed that nanostructured lipid carrier enhanced the pharmacokinetic profile compared to solid lipid nanoparticles and overall inclined the relative bioavailability by many folds. Cumulative results suggest that nanostructured lipid carrier could be an effective, alternative and promising lipid-mediated oral drug delivery approach than solid lipid nanoparticles.

Solid lipid matrix mediated nanoarchitectonics for improved oral bioavailability of drugs.

Introduction: Solid matrix mediated lipid nanoparticle formulations (LNFs) retain some of the best features of ideal drug carriers necessary for improving the oral absorption and bioavailability (BA) of both hydrophilic and hydrophobic drugs. LNFs with solid matrices may be typically categorized into three major types of formulations, viz., solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs) and lipid-drug conjugate nanoparticles (LDC-NPs). Solid matrix based LNFs are, potentially, the most appropriate delivery systems for poorly water soluble drugs in need of improved drug solubility, permeability, absorption, or increased oral BA. In addition, LNFs as matrices are able to encapsulate both hydrophobic and hydrophilic drugs in a single matrix based on their excellent ability to form cores and shells. Interestingly, LNFs also act as delivery devices to impart chemical stability to various orally administered drugs. Areas covered: Aim of the review is to forecast the presentation of pharmacokinetic characteristics of solid lipid matrix based nanocarriers which are typically biocompatible, biodegradable and non-toxic carrier systems for efficient oral delivery of various drugs. Efficient delivery is broadly mediated by the fact that lipophilic drugs are readily soluble in lipidic substrates that are capable of permeating across the gut epithelium following oral administration, subsequently delivering the moiety of interest more efficiently across the gut mucosal membrane. This enhances the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile. This article specifically focuses on the biopharmaceutical and pharmacokinetic aspects of such solid lipid matrix based nanoformulations and possible mechanisms for better drug absorption and improved BA following oral administration. It also briefly reviews methods to access the efficacy of LNFs for improving oral BA of drugs, regulatory aspects and some interesting lipid-derived commercial formulations, with a concluding remark. Expert opinion: LNFs enhance the overall BA of many drugs facing oral delivery challenges by improving their pharmacokinetic profile.

Dendrimer-Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I.

mRNA-mediated protein replacement represents a promising concept for the treatment of liver disorders. Children born with fumarylacetoacetate hydrolase (FAH) mutations suffer from Hepatorenal Tyrosinemia Type 1 (HT-1) resulting in renal dysfunction, liver failure, neurological impairments, and cancer. Protein replacement therapy using FAH mRNA offers tremendous potential to cure HT-1, but is currently hindered by the development of effective mRNA carriers that can function in diseased livers. Structure-guided, rational optimization of 5A2-SC8 mRNA-loaded dendrimer lipid nanoparticles (mDLNPs) increases delivery potency of FAH mRNA, resulting in functional FAH protein and sustained normalization of body weight and liver function in FAH-/- knockout mice. Optimization using luciferase mRNA produces DLNP carriers that are efficacious at mRNA doses as low as 0.05 mg kg-1 in vivo. mDLNPs transfect > 44% of all hepatocytes in the liver, yield high FAH protein levels (0.5 mg kg-1 mRNA), and are well tolerated in a knockout mouse model with compromised liver function. Genetically engineered FAH-/- mice treated with FAH mRNA mDLNPs have statistically equivalent levels of TBIL, ALT, and AST compared to wild type C57BL/6 mice and maintain normal weight throughout the month-long course of treatment. This study provides a framework for the rational optimization of LNPs to improve delivery of mRNA broadly and introduces a specific and viable DLNP carrier with translational potential to treat genetic diseases of the liver.

Formulations, Pharmacodynamic and Clinical Studies of Nanoparticles for Lung Cancer Therapy - An Overview.

BACKGROUND: Nanoparticles play an important role in the area of drug delivery and have been applied in lung cancer treatments for the purpose of controlled release and cancer cell targeting. METHOD: A review covering various nanoparticle formulations for lung cancer therapy is presented. The pharmacodynamic models for evaluating anti-lung cancer drugs are summarized upon drug administration routes. Moreover, the current clinical applications of nano-drugs for lung cancer treatments are also reviewed, including the administration routes, dose forms and clinical trials. RESULTS: The preparation methods of anti-lung cancer nanoparticles varied from different formulations. Owing to the improvement of their bioavailability, stability and residency at lung, the anti-lung cancer drugs encapsulated by nanoparticles showed better therapeutic effects than the naked drug. Likewise, characterization including pharmacology, physical and chemical properties should be taken into consideration. More importantly, different pharmacological animal models should be correctly selected for the pharmacodynamics assessment. Finally, the investigation of anti-lung cancer nanoparticles in clinical trials provided experience on further related research. CONCLUSION: Nanoparticle delivery system for lung cancer therapy is still in its early stage and expecting numerous challenges.

Comparative study of oral lipid nanoparticle formulations (LNFs) for chemical stabilization of antitubercular drugs: physicochemical and cellular evaluation.

Rifampicin (RIF) and Isoniazid (INH) are two major first-line antitubercular drugs (ATDs) that are typically administered orally, in combination. However, INH-catalysed degradation of RIF under acidic pH environment of the stomach is a major concern related to its oral delivery, and is dramatically accelerated upon further exposure to and interaction with INH. This interaction, in turn, triggers a direct decline in the available RIF dose below the sub-therapeutic level, thereby diminishing its therapeutic efficacy. We hypothesized that encapsulation of both these important ATDs into lipid nanoparticle formulations (LNFs) may help mitigate the acid hydrolysis of RIF, its subsequent interaction with INH and its eventual INH-mediated accelerated chemical degradation in the gastric environment. We further hypothesized that these LNFs would be capable of enhanced uptake and localization into intra-cellular compartments of lung macrophages, thereby potentially targeting the Tb pathogen in its in vivo niche. For this purpose, we evaluated two promising LNFs, viz., solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for encapsulating these ATDs. Here, we report on the design, development and comparative evaluation of SLN and NLC-based lipid formulations of both INH and RIF. Our strategy of nanoencapsulation substantially prolonged encapsulated RIF release and improved its chemical stability in presence of INH in a simulated gastric acidic environment. In vitro cell culture studies showed a well-quantifiable uptake of LNFs in a human alveolar macrophage cell line. Overall, these evaluations provided promising results for establishing the potential of both formulations for TB therapy.

Preparation of quantum dot/drug nanoparticle formulations for traceable targeted delivery and therapy.

Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future.