Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms.

The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs.

CPZEN-45 is a novel compound with activity against drug-susceptible and drug-resistant tuberculosis (TB). The present study was undertaken to determine the best dose and dosing regimen of inhalable CPZEN-45 powders to use in efficacy studies with TB-infected guinea pigs. The disposition of CPZEN-45 after intravenous, subcutaneous (SC), and direct pulmonary administration (INS) was first determined to obtain their basal pharmacokinetic (PK) parameters.

Designing Aerosol Therapies Based on the Integrated Evaluation of In Vitro, In Vivo, and In Silico Data.

Despite the advantages of the pulmonary route of administration and inhalable dosage forms, other routes of administration and dosage forms are often considered first to treat lung diseases. This occurs, in part, due to the perceived limitations of inhaled therapies resulting from the improper design and interpretation of their in vitro and in vivo evaluation. The present study outlines the elements that should be considered in the design, performance, and interpretation of the results of the preclinical evaluation of novel inhaled therapies.

Understanding of Ovarian Cancer Cell-Derived Exosome Tropism for Future Therapeutic Applications.

Exosomes, a subtype of extracellular vesicles, ranging from 50 to 200 nm in diameter, and mediate cell-to-cell communication in normal biological and pathological processes. Exosomes derived from tumors have multiple functions in cancer progression, resistance, and metastasis through cancer exosome-derived tropism. However, there is no quantitative information on cancer exosome-derived tropism.

Efficacy of Combined Rifampicin Formulations Delivered by the Pulmonary Route to Treat Tuberculosis in the Guinea Pig Model.

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane.

Vaginal Suppositories Containing SHetA2 to Treat Cervical Dysplasia: Pharmacokinetics of Daily Doses and Preliminary Safety Profile.

SHetA2 is a new drug with potential to treat cervical dysplasia, but only 0.02% of the dose is absorbed into the cervix after oral administration. By contrast, 23.

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice.

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity.

Development and validation of a reverse phase HPLC method for SHetA2, a novel anti-cancer drug, in mouse biological samples.

SHetA2 is a flexible heteroarotinoid that has the potential to prevent and treat lung, ovarian and cervical cancer without significant toxicity. A simple and reliable high performance liquid chromatographic (HPLC) method was developed to determine SHetA2 concentrations in the lungs, reproductive organs and plasma of mice. SHetA2 was extracted from these biological matrices by solid phase and liquid-liquid extraction in the presence of 4% HPO and acetonitrile followed by filtration through a Captiva filtration plate.

Cryogenic Fabrication of Dry Powders to Enhance the Solubility of a Promising Anticancer Drug, SHetA2, for Oral Administration.

SHetA2 is a novel anticancer drug with poor aqueous solubility. In formal toxicological studies, Kolliphor HS 15 was used as a solubilizing agent to increase the oral bioavailability of SHetA2. The purpose of this study was to formulate SHetA2 and Kolliphor HS 15 as solid powders to facilitate their filling in hard gelatin capsules for clinical trials.

Pharmacokinetics and Pharmacodynamics of Escalating Doses of SHetA2 After Vaginal Administration to Mice.

SHetA2 is a novel compound with strong potential to treat cervical dysplasia, but its low aqueous solubility limits its oral bioavailability. A vaginal suppository achieved SHetA2 cervix concentrations that were severalfold above the predicted therapeutic levels. Thus, we aimed at determining the minimum dose that would achieve SHetA2 therapeutic levels while reducing cyclin D1 levels, the pharmacodynamic end point.

Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs.

For many years, administration of drugs by inhalation has been the mainstay treatment for obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease. Antibiotics and other drugs have been administered for decades as aerosols to treat other pulmonary disease in a clinical setting, but it was until the early 1980's that colistin was formally marketed as a solution for nebulization in Europe (Colomycin, Pharmax, Bexley). The solubility of other drugs and the size of the dose required to achieve therapeutic concentrations at the site of action, made treatment times long and difficult to be performed at home.

Influence of the estrus cycle of the mouse on the disposition of SHetA2 after vaginal administration.

SHetA2 is a novel compound with the potential to treat cervical dysplasia, but has poor water solubility. A vaginal suppository formulation was able to achieve therapeutic concentrations in the cervix of mice, but these concentrations were variable. Histological analysis indicated that mice in the same group were in different stages of their estrous cycle, which is known to induce anatomical changes in their gynecological tissues.

Development of a dietary formulation of the SHetA2 chemoprevention drug for mice.

Development of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity.

SHetA2 Dry Powder Aerosols for Tuberculosis: Formulation, Design, and Optimization Using Quality by Design.

Tuberculosis (TB) is a life threatening pulmonary infection caused by Mycobacterium tuberculosis (MTB). Current treatments are complex, lengthy, and associated with severe side effects that decrease patient compliance and increase the probability of the emergence of drug resistant strains. Thus, more effective drugs with little to no side effects are needed to diversify the armamentarium against the global TB epidemic.

Optimization of a Vaginal Suppository Formulation to Deliver SHetA2 as a Novel Treatment for Cervical Dysplasia.

Cervical dysplasia induced by the human papilloma virus unpredictably progresses to cervical cancer. Therapeutic options are invasive and affect the patient's quality of life. SHetA2 has demonstrated therapeutic efficacy against human and murine human papilloma virus-induced tumors, but its oral bioavailability is <1%.

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs.

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber.

Inhaled Formulation Design for the Treatment of Lung Infections.

Lung infections may be bacterial, viral or fungal and they are typically treated with oral or parenteral antibiotics. Inhaled dry powder formulations offer unique opportunities for treating lung infections with enhanced effectiveness and stability. Since drug delivery to the lungs requires chronic and repeated administration of larger amounts of therapeutics, dry powder formulations are attractive alternatives to deliver drugs directly to the lungs as they are not limited by solubility issues and they are regarded as being more stable than liquid dosage forms.

Pharmacokinetics of Inhaled Rifampicin Porous Particles for Tuberculosis Treatment: Insight into Rifampicin Absorption from the Lungs of Guinea Pigs.

Tuberculosis (TB) is a life-threatening infection that requires a lengthy treatment process that is often associated with adverse effects. Pulmonary delivery of anti-TB drugs has the potential to increase efficacy of treatment by increasing drug concentrations at the lungs, the primary site of infection. The aim of the present study is to evaluate the disposition of rifampicin (RIF) after its pulmonary administration as porous particles (PPs) to guinea pigs and contrast it to that after oral administration.

Inhalation drug delivery devices: technology update.

The pulmonary route of administration has proven to be effective in local and systemic delivery of miscellaneous drugs and biopharmaceuticals to treat pulmonary and non-pulmonary diseases. A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler device, and the patient. However, the biggest single problem that accounts for the lack of desired effect or adverse outcomes is the incorrect use of the device due to lack of training in how to use the device or how to coordinate actuation and aerosol inhalation.

Mechanisms of absorption and elimination of drugs administered by inhalation.

Pulmonary drug delivery is an effective route for local or systemic drug administration. However, compared with other routes of administration, there is a scarcity of information on how drugs are absorbed from the lung. The different cell composition lining the airways and alveoli makes this task extremely complicated.

Pharmaceutical aerosols for the treatment and prevention of tuberculosis.

Historically, pharmaceutical aerosols have been employed for the treatment of obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease, but in the past decades their use has been expanded to treat lung infections associated with cystic fibrosis and other respiratory diseases. Tuberculosis (TB) is acquired after inhalation of aerosol droplets containing the bacilli from the cough of infected individuals. Even though TB affects other organs, the lungs are the primary site of infection, which makes the pulmonary route an ideal alternative route to administer vaccines or drug treatments.

Isoxyl assays in plasma.

Isoxyl is an effective drug to treat multi-drug resistant (MDR) tuberculosis but was abandoned due to failure in some clinical outcomes. The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatographic (HPLC) method for determination of isoxyl concentrations in plasma, a prerequisite for understanding poor in vivo behavior of the drug. In the method, isoxyl was extracted from guinea pig plasma with acetonitrile and quantified by a Hewlett Packard 1100 series HPLC coupled with a Spherisorb 5 μm ODS2 (2 × 100 mm) column and UV detection at 270 nm.

Pulmonary immunization of guinea pigs with diphtheria CRM-197 antigen as nanoparticle aggregate dry powders enhance local and systemic immune responses.

This study establishes the immune response elicited in guinea pigs after pulmonary and parenteral immunizations with diphtheria CRM-197 antigen (CrmAg). Several spray-dried powders of formalin-treated/untreated CrmAg nanoaggregates with L-leucine were delivered to the lungs of guinea pigs. A control group consisting of alum with adsorbed CrmAg in saline was administered by intramuscular injection.