Current Drug Metabolism (v.17, #8)

Meet Our Editorial Board Member by Baojian Wu (729-729).

Background: Tumor microenvironment is so complex that involves in many factors of tumor. Although enhanced permeability and retention effect is a main driving force of tumor targeted nanoparticles, the tumor microenvironment greatly affects the delivery efficiency of nanoparticles.
Methods: A careful search of the scientific database was performed to find the tumor microenvironment related papers. Then the papers were concluded and reviewed.
Results: In tumor, elevated interstitial fluid pressure, abnormal tumor vasculature, dense tumor extracellular matrix and elevated solid stress considerably hinder the extravasation and intratumor penetration of nanoparticles. Therefore, shaping the tumor microenvironment could improve nanoparticle delivery, including vascular normalization, vasculature promotion therapy, lymph normalization, reducing tumor stroma components, elevating blood pressure, elevating receptor expression, cell cycle arrest and priming by cytotoxic therapy.
Conclusion: Shaping the tumor microenvironment could considerably enhance the nanoparticles delivery.

Background: Glioblastoma multiforme, one of the most aggressive brain tumors, has a very poor clinical outcome. Despite the introduction of the alkylating reagent temozolomide (TMZ) to surgery and radiotherapy, the survival of patients could only be modestly increased up to less than 15 months. Therefore, innovative treatment strategies are urgently needed to improve survival of glioma patients.
Objective: Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a lot of attention due to their widespread diagnostic and therapeutic applications in neuro-oncology. In this review article we discuss the possible application of the SPIONs for the diagnostic and theraputic approaches in brain cancer. Additionally we report on recent pre-clinical and clinical developments on the generation of heat in the tumors through the application of SPIONs subjected to an alternating magnetic field (AMF).
Methods: A comprehensive review of the literature on the current status of using targeted SPIONs in brain tumor detection and therapy and also the potential hurdles to overcome was performed.
Results: Functionalized nanoparticles carrying tumor-specific agents, such as antibodies or proteins might further improve their tumor targeting capacity. Furthermore, multifunctional, theranostic SPIONs can be used for simultaneous in vivo tumor imaging and targeted drug deliery. Application of the ultrasound and external magnetic field technologies significantly improves accumulation of nanoparticles in brain tumors. Hyperthermic treatment using AMF has a therapeutic potential in management of brain tumors.
Conclusion: Superparamagnetic nanoparticle-based imaging, drug delivery and hyperthermic treatment can potentially be a powerful tool for precise diagnosis and treatment of brain tumors.

Delivery of Nanoparticles for Treatment of Brain Tumor by Chen Kang, Yuan Sun, Jing Zhu, Wen Li, Aili Zhang, Tairong Kuang, Jing Xie, Zhaogang Yang (745-754).
Background: Malignant brain tumor is a highly challenging disease for diagnosis, treatment, and management. Cytotoxicity, distribution and the ability to cross blood brain barrier are some of the most significant issues for the chemotherapy of brain tumors. Nanotechnology has been widely exploited in drug delivery with great potential in improving the drug efficiency and efficacy. The advent of nanotechnology would greatly facilitate the early detection and treatment of brain tumors. This review will be primarily focused on current nano drug delivery system for brain cancer therapy. Meanwhile, the existing impediments for therapeutic nanomedicines and critical analysis of the different delivery nanoparticles are also discussed.
Methods: We systematically evaluated the major factors that impact the current nanomedicines for brain tumor therapy. Meanwhile, various nanoparticle-based formulations for brain cancer detection and therapy are evaluated.
Results: 124 papers were included in this review. From the analysis of the nanomaterials, seven major nanomaterials have been discussed regarding the functionality and current therapeutic significance. The review also explains in detail about the different types of nanomaterials and their functionalities. This shows that each of these nanomaterials has specialized functions for the treatment of various kinds of brain cancer.
Conclusion: Nanomaterials provide a viable potential diagnosis mechanis. In the future, more research needs to be focused on developing a better diagnosis tool for detection of cancer on an urgent basis. Blood-brain barrier and cytotoxicity are some of the primary root causes for the impediment of treatment of cancer using nanoparticles. Therefore, different delivery systems should be exploited for the nanoparticles to surmount these issues.

Current Status and Future Directions of Nanoparticulate Strategy for Cancer Immunotherapy by Xu Zhou, Renhe Liu, Shuo Qin, Ruilian Yu, Yao Fu (755-762).
Background: Rapid advancement over the past few decades in cancer immunotherapy provides life-saving options for cancer patients. However, commonly used strategies including small molecules and various biomacromolecule-based therapeutics suffer from serious off-target toxicity and a lack of stability in the circulation.
Objective: To overcome these problems, various nanoparticulate delivery systems have been developed to achieve controlled and sustained drug release, improved stability and pharmacokinetic profiles, and tumor specificity to reduce off-target adverse effects.
Method: We reviewed representative studies on multiple nanoparticulate platform systems for delivering therapeutics in cancer immunotherapy, and discussed the advances and perspectives for the future development of novel therapeutics in cancer immunotherapy.
Results and Perspectives: Nanoparticles for the controlled delivery of immune modulating agents represents a viable approach in cancer immunotherapy. Besides seeking novel carrier systems or new materials, efforts need to be contributed to delineating the impact of intrinsic properties of nanoparticles such as material composition, morphology, size distribution, charge, and stiffness in manipulating immune responses in cancer therapy.

Actively Targeted Nanoparticles for Drug Delivery to Tumor by Ye Bi, Fei Hao, Guodong Yan, Lesheng Teng, Robert J. Lee, Jing Xie (763-782).
Background: Nanomedicine is an emerging therapeutic modality. Nanoparticles (NPs) are potential vehicles for delivery of anticancer therapeutics. NPs can be designed to facilitate tumor drug delivery both by passive and active targeting mechanisms. Passive targeting of NPs to tumors can be achieved through the enhanced permeability and retention (EPR) effect. Meanwhile, actively targeted NPs can be designed based on two different targeting mechanisms, ligand-directed targeting to the tumor cells and tumor microenvironment (TME)-directed targeting.
Methods: We searched for and reviewed recently published literature on actively targeted NPs. Progress in this field was summarized in several focus areas, including methods for targeting of tumor cells and for targeting TME. Advantages and limitations of each approach were discussed.
Results: This article covers data from 240 recent publications and provided numerous examples of ligand-directed NPs targeting tumor cell-selective surface receptors. Targeting ligands discussed include proteins such as transferrin and antibodies, as well as low molecular weight agents, such as peptides, aptamers, carbohydrates, and folate. In addition, extensive discussions of TME targeting NPs, designed to release drug in response to TME-specific stimuli, such as low pH, tumor-selective enzymes, and unique characteristics of tumor neovasculature, are also included in this review. In general, many novel actively targeting strategies have been developed and encouraging data have been reported in numerous settings, both in vitro and in animal studies.
Conclusion: Active targeting of NPs has experienced rapid growth as a field of research and is continuously expanding. There are now some early examples of efforts on clinical translation and reported clinical trials on these NPs. Future development of actively targeted NPs depends on better understanding of the many factors affecting the behavior of NPs in vivo and likely involves combining the approaches of targeting the tumor cells and of targeting components of the TME.

Influence of Tumor Microenvironment on the Distribution and Elimination of Nano-formulations by Birendra Chaurasiya, Arpan Mahanty, Debmalya Roy, Yan Shen, Jiasheng Tu, Chunmeng Sun (783-798).
Objective: To give an in-depth overview about the tumor and its surrounding microenvironment influencing distribution and elimination of nanoformulations.
Mehtods: This up-to-date review will summarize the microenvironmental components and their influence on the various factors related to nanoformulations and tumor which affect the penetration, distribution, regulation and clearance of nanoformulations from the tumor cells. Results of recent advances in miroenvironmental tuning with nanoformulations will be evaluated mechanistically. In addition, those natures of tumors involving enhanced cancer therapy will be discussed. Finally, strategies of nanoparticulate design and decoration to achieve efficient drug delivery are presented.
Results: Development of tumor is facilitated by its surrounding microenvironment and is regulated by different extra and intracellular components. Drug-loaded nanoformulations are mainly administered via oral and parenteral routes which reach tumor cells via different mechanisms. Chemotherapeutics get diffused from circulation into the surrounding microenvironment which latter get internalized into the cellular interstial area by passive diffusion mechanism due to virtue of size, charge, and pegylation effects, or by ligands and receptor mediated, or through enhanced permeability and retention effects through leaky apertures. Due to mildly acidic environment and hypoxic interstial environment, the influx of nanoformulations is hindered. The metabolites of the nanoformulations get diffused out from the tumor cells as a results of high interstial fluid pressure and get cleared either via liver or via renal execration.
Conclusion: Well-understanding tumoral microenvironments which significantly affect distribution and elimination of nanoformulations is essential for engineering delivery systems with superior anti-tumoral effect.

The Role of Drug Transporters in the Pharmacokinetics of Antibiotics by Wen Jin Hua, Wei Xiao Hua, Zhou Jian, Peng Hong Wei, Lu Yan Ni, Li Yu Hua, Cao Duan Wen, Zhou Ying, Cao Li (799-805).
Background: Various transporters, including efflux transporters and uptake transporters, play an important role in the pharmacokinetics of drugs. Currently, studies suggest that several antibiotics also serve as substrates for transporters. In addition, these antibiotics are usually combined with other drugs to treat diseases, more effectively. Therefore, it is necessary to focus on the role of transporters in pharmacokinetics and drug-drug interactions of antibiotics.
Methods: This review summarizes the findings of recent studies as well as information retrieved from several databases (until June 2015): ISI Web of KnowledgeSM (ISI WoK), SciFinder (Caplus, Medline, Registry, Casreact, Chrmlist, and Chemcasts) and PubMed (indexed for Medline).
Results: The present review provides useful information for the study of transporters in the pharmacokinetics and drug-drug interactions of antibiotics, and should assist researchers investigating these topics.
Conclusion: The drug transporters mediate intestinal absorption, hepatic uptake, and kidney or biliary excretion. It is necessary to focus on drug-drug interactions when these antibiotics are combined with other chemical substances that are also the substrates for transporters.

Background: P-glycoprotein (P-gp), a well known ATP dependent efflux membrane transporter, has been attracting considerable interests of medical researchers due to its efflux pump effect being a primary cause of multidrug resistance (MDR) and poor bioavailability (BA) of anticancer agents. How to resolve the aforesaid problems has become the research hot-points in the medical and pharmaceutical fields. The past three decades have witnessed rapid development of the P-gp inhibition-based strategies used for modulating pharmacokinetics (PK) and thus overcoming MDR and improving BA of anticancer drugs.
Methods: An electronic search of PubMed database from inception to April, 2016 was conducted. Additionally, we searched the reference lists of included studies and carried out a citation search for the included studies via Web of Science to find other potentially relevant studies.
Results and Conclusion: Lots of the studies of the P-gp inhibition-based strategies are under preclinical phase and the obtained results are exciting and may represent great promise in the clinical application potential. In order to provide useful information for the development of novel strategies for improving BA of anticancer drugs, this article aims to review the research progress in the P-gp inhibition-based strategies that has been acquired over the last three decades, with focus on the P-gp inhibitors, herbal constituents and pharmaceutical excipients as well as novel P-gp-linked drug delivery systems (DDSs). Additionally, the fundamental knowledge on P-gp also is briefly discussed.

Salusins in Hypertension and Related Cardiovascular Diseases by Urszula Kolakowska, Witold Olanski, Anna Wasilewska (827-833).
The salusins are bioactive peptides with hemodynamic effects. They play a role in hypertension, atherogenesis and cardiovascular diseases. In this review we focus on new actions, which are related to the regulation of blood pressure.
Decrease in salusin-̛ and the increase in salusin-̜ concentrations are known to contribute to the development of the metabolic syndrome and atherosclerosis.
Microinjections of salusin-̜ in the paraventricular nucleus (PVN) increases the plasma argininevasopressin (AVP) and norepinephrine levels, which contribute to hypertension. It also increases the AVP release from the rostral ventrolateral medulla (RVLM) via the projection from PVN to RVLM. Increased activity of the RVLM neurons is transmitted to the intermediolateral nucleus (IML) cell column of the spinal cord, where peripheral sympathetic nerves to the heart, arterioles and kidneys are activated, thus increasing blood pressure. Microinjection of salusin-̜ into the RVLM increased renal sympathetic nerve activity, median arterial pressure (MAP) and heart rate (HR). There was no significant effect on the AVP level in the RVLM and plasma.
Microinjection of salusin-̜ in the nucleus tractus solitarii (NTS) produces a dose dependent hypotension and bradycardia. Intravenous injection of salusin-̜ significant increased MAP, but did not have a meaningful outcome on HR. Nevertheless, intravenous injection of a very high dose of salusin-̜ caused instantaneous decrease in both MAP and HR. Salusin-̜ overexpression provoked severe and prolonged hypertension accompanied by tachycardia in rats.
It is clear that more research needs to be done to evaluate the function of salusin-̜ in the mechanism of essential hypertension, atherosclerosis, and the metabolic syndrome.