Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Nanocarrier-based interventions for the management of MDR/XDR-TB

Emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB over the past decade presents an unprecedented public health challenge to which countries of concern are responding far too slowly. Global Tuberculosis Report 2014 marks the 20th anniversary of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance, indicating the highest global level of drug-resistance ever recorded detection of 97?000 patients with MDR-TB resulting in 170?000 deaths in 2013. Treatment of MDR-TB is expensive, complex, prolonged (18–24 months) and associated with a higher incidence of adverse events. In this context, nanocarrier delivery systems (NDSs) efficiently encapsulating considerable amounts of second-line anti tubercular drugs (^sATDs), eliciting controlled, sustained and more profound effect to trounce the need to administer ^sATDs at high and frequent doses, would assist in improving patient compliance and avoid hepatotoxicity and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent ^sATDs. Besides, NDSs are also known to inhibit the P-glycoprotein efflux, reduce metabolism by gut cytochrome P-450 enzymes and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review first provides a holistic account on MDR-TB and discusses the molecular basis of Mycobacterium tuberculosis resistance to anti-tubercular drugs. It also provides an updated bird’s eye view on current treatment strategies and laboratory diagnostic test for MDR-TB. Furthermore, a relatively pithy view on patent studies on second-line chemotherapy using NDSs will be discussed.     

Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges

Introduction: Bearing in mind that many promising drug candidates have the problem of reaching their target site, the concept of advanced drug delivery can play a significant complementary role in shaping modern medicine. Among other nanoscale drug carriers, superparamagnetic iron oxide nanoparticles (SPIONs) have shown great potential in nanomedicine. The intrinsic properties of SPIONs, such as inherent magnetism, broad safety margin and the availability of methods for fabrication and surface engineering, pave the way for diverse biomedical applications. SPIONs can achieve the highest drug targeting efficiency among carriers, since an external magnetic field locally applied to the target organ enhances the accumulation of magnetic nanoparticles in the drug site of action. Moreover, theranostic multifunctional SPIONs make simultaneous delivery and imaging possible. In spite of these favorable qualities, there are some toxicological concerns, such as oxidative stress, unpredictable cellular responses and induction of signaling pathways, alteration in gene expression profiles and potential disturbance in iron homeostasis, that need to be carefully considered. Besides, the protein corona at the surface of the SPIONs may induce few shortcomings such as reduction of SPIONs targeting efficacy.

Areas covered: In this review, we will present recent developments of SPIONs as theranostic agents. The article will further address some barriers on drug delivery using SPIONs.

Expert opinion: One of the major success determinants in targeted in vivo drug delivery using SPIONs is the adequacy of magnetic gradient. This can be partially achieved by using superconducting magnets, local implantation of magnets and application of magnetic stents. Other issues that must be considered include the pharmacokinetics and in vivo fate of SPIONs, their biodegradability, biocompatibility, potential side effects and the crucial impact of protein corona on either drug release profile or mistargeting. Surface modification of SPIONs can open up the possibility of drug delivery to intracellular organelles, drug delivery across the blood–brain barrier, modifying metabolic diseases and a variety of other multimodal and/or theranostic applications.     

Recent advances in amphotericin B delivery strategies for the treatment of leishmaniases

ABSTRACT

Introduction: Among the drugs in clinical use for the treatment of leishmaniases, amphotericin B (AmB) is the most effective and has been the most extensively studied for the development of drug delivery strategies. Liposomal amphotericin B (AmBisome®) still represents the best therapeutic option for leishmaniases, however, its clinical efficacy depends on the patient immunological status and the endemic region. Moreover, the need for parenteral administration, its side effects and high cost significantly limit its use in developing countries.

Areas covered: This article provides insight into the novel drug delivery strategies that were investigated for AmB over the last 5 years and a final critical selection of emerging concepts and most promising approaches, based on the significance of preclinical antileishmanial and toxicity data.

Expert opinion: The feasibility of oral and topical delivery of AmB has been established in experimental models of leishmaniases. Highly effective AmB nanocarriers containing active targeting ligand and/or immunomodulatory component have also emerged. Translating these advances to the clinic still relies on the full demonstration of safety and efficacy in humans and on the viability and cost-effectiveness of large-scale industrial production.     

Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics

Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer’s disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer’s disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.     

Targeting anti-HIV drugs to the CNS

The development of antiretroviral drugs over the past couple of decades has been commendable owing to the identification of several new targets within the overall HIV replication cycle. However, complete control over HIV/AIDS is yet to be achieved. This is because the current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. This occurs because most anti-HIV drugs do not accumulate in certain cellular and anatomical reservoirs including the CNS. Insufficient delivery of anti-HIV drugs to the CNS is attributed to their low permeability across the BBB. Hence, low and sustained viral replication within the CNS continues even during prolonged antiretroviral drug therapy. Therefore, developing novel approaches that are targeted at enhancing the CNS delivery of anti-HIV drugs are required. In this review, we discuss the potential of nanocarriers and the role of cell-penetrating peptides in enhancing drug delivery to the CNS. Such drug delivery approaches could also lead to higher drug delivery to other cellular and anatomical reservoirs where the virus harbors than with conventional treatment, thus providing an effective therapy to eliminate the virus completely from the body.     

Exploiting Fluorescence Lifetime Plasticity in FLIM: Target Molecule Localization in Cells and Tissues

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Advancement in carbon nanotubes: basics, biomedical applications and toxicity

Objectives Carbon nanotubes (CNTs) have attracted much attention by researchers worldwide in recent years for their small dimensions and unique architecture, and for having immense potential in nanomedicine as biocompatible and supportive substrates, as a novel tool for the delivery of therapeutic molecules including peptides, RNA and DNA, and also as sensors, actuators and composites. Key findings CNTs have been employed in the development of molecular electronic, composite materials and others due to their unique atomic structure, high surface area‐to‐volume ratio and excellent electronic, mechanical and thermal properties. Recently they have been exploited as novel nanocarriers in drug delivery systems and biomedical applications. Their larger inner volume as compared with the dimensions of the tube and easy immobilization of their outer surface with biocompatible materials make CNTs a superior nanomaterial for drug delivery. Literature reveals that CNTs are versatile carriers for controlled and targeted drug delivery, especially for cancer cells, because of their cell membrane penetrability. Summary This review enlightens the biomedical application of CNTs with special emphasis on utilization in controlled and targeted drug delivery, as a diagnostics tool and other possible uses in therapeutic systems. The review also focuses on the toxicity aspects of CNTs, and revealed that genotoxic potential, mutagenic and carcinogenic effects of different types of CNTs must be explored and overcome by formulating safe biomaterial for drug delivery. The review also describes the regulatory aspects and clinical and market status of CNTs.     

hTe exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. hTe current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in provid-ing signiifcant beneifts to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). hTe BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nan-otherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer signiifcant ad vantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are brielfy discussed. hTe drug transport mechanisms at the BBB are outlined. hTe approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic ap-proaches for their enhanced clinical application in brain-tumor therapy are discussed.     

Delivery of Superparamagnetic Polymeric Micelles Loaded With Quercetin to Hepatocellular Carcinoma Cells

The aim of this study is to develop co-encapsulation of quercetin (QCT) and superparamagnetic iron oxide nanoparticles (SPIONs) into methoxy-poly(ethylene glycol)-b-oligo(?-caprolactone), mPEG750-b-OCL-Bz micelles (QCT-SPION-loaded micelles) for inhibition of hepatitis B virus-transfected hepatocellular carcinoma (HepG2.2.15) cell growth. QCT-SPION-loaded micelles were prepared using film hydration method. They were spherical in shape with an average size of 22-55 nm. The best QCT-SPION-loaded micelles showed entrapment efficiency and loading capacity of QCT at 70% and 3.5%, respectively, and of SPIONs at 15% and 0.8%, respectively. Transverse (T₂) relaxivity of SPIONs was 137 mM^?1s^?1. SPION clusters present inside the core of QCT-SPION-loaded micelles increased T₂ relaxivity value (246 mM^?1s^?1) indicating the good magnetic resonance imaging sensitivity of QCT-SPION-loaded micelles in comparison with SPIONs. QCT-SPION-loaded micelles could be taken up by HepG2.2.15 cells and showed higher cytotoxicity than QCT. Furthermore, these cells were arrested by QCT-SPION-loaded micelles at the G0/G1 phase of cell cycle. QCT-SPION-loaded micelles accumulated in the vicinity of Neodymium Iron Boron (NdFeB) magnetic disc, resulting in the potent inhibition of cancer cell growth at the strong magnetic field strength. In conclusion, mPEG750-b-OCL-Bz micelles are a promising multi-functional vehicle for co-delivery of QCT and SPIONs for disease monitoring and therapies of hepatocellular carcinoma.