Current Drug Targets - Volume 12, Issue 8, 2011

Regardless of the extended use of anticancer agents even in multiple drug regimens, chemotherapy failure habitually occurs even in the most sensitive malignancies (i.e., breast cancer). This is mainly the consequence of: i) an extensive biodistribution and rapid plasma clearance which lead to ineffective drug concentrations into the tumor tissue; and, ii) multi-drug resistances exhibited by cancer cells. Drug delivery strategies have tried to revolutionize the fight against cancer by enhancing the concentration of chemotherapy agent into the tumor tissue, thus increasing the anticancer activity and minimizing the associated adverse systemic effects. With that aim, cytotoxic nanomedicines are engineered to control drug biodistribution and to overcome multi-drug resistance mechanisms. The most promising results are coming from passive drug targeting and active drug targeting strategies. Unfortunately, current nanotechnologies against cancer are principally limited by poor drug loading values, very fast drug release kinetics, and the complex simultaneous monitoring of the targeting efficiency. In line with these challenges, the objective of the present thematic issue of Current Drug Targets is to discuss the pharmaceutical and biomedical perspectives of nanomedicines against cancer. The most promising moves towards cancer treatment are exemplified in five selected contributions by well-known research groups. These review articles comprise insights into new concepts derived from nanotechnology, medicinal chemistry, physical chemistry, and advanced materials science with potential clinical applicability. The first contribution by Prof. Holgado and colleagues is an example of how biodegradable polymers could maximize drug delivery to tumors. This review article is particularly focussed on unique approaches of polymeric colloids in oral chemotherapy, drug delivery to brain tumors, and against multi-drug resistance cancer cells. In this way, the contributions by the research groups of Prof. Concheiro, and Prof. Qian highlight the very important applications of biodegradable copolymers in drug delivery to cancer, which can optimize the effectiveness/toxicity ratio of chemotherapy. These review articles further underline the possibilities rising from long-circulating amphiphilic copolymers in the delivery of genes, vaccines, and diagnostic agents....

Due to a very poor specificity, many chemotherapy agents generate a low antitumor effect and important severe side effects. Poly(D,L-lactide-co-glycolide) (PLGA)-based nanomedicines are under investigation to assure a very efficient anticancer activity in chemotherapy. In this work, we analyze the major applications of this FDA-approved biodegradable polymer in the formulation of nanomedicines against cancer. Despite conventional PLGA colloids could be only used to target tumors located into the mononuclear phagocyte system (MPS), special strategies are under intensive research to enhance the accumulation of anticancer drugs into any given tumor site. These are passive targeting (through the enhanced permeability and retention effect, so-called EPR effect), drug delivery through stimuli-sensitive colloids, and ligand-mediated targeting. We further discuss unique approaches of PLGA colloids in oral chemotherapy, drug delivery to brain tumors, and multi-drug resistance of cancer cells.

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR) effect, and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic® or Lutrol®) and the X-shaped poloxamines (Tetronic®), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.

Nanotechnology provides researchers with new tools for cancer treatment. Biodegradable polymeric nanoparticles, as an advanced drug delivery system, have promising applications in cancer treatment. Poly(ε- caprolactone)/poly(ethylene glycol) (PCL/PEG) copolymers are biodegradable and amphiphilic, and show potential application in drug delivery. In recent years, PCL/PEG copolymeric nanoparticles, as a potential nanoplatform for anticancer agent delivery, received increasing attention. This paper reviews PCL/PEG copolymer nanoparticles for anticancer agent delivery, including overcoming water insolubility of hydrophobic drug, targeting chemotherapeutic drug to tumor, and delivering genes, vaccines, and diagnostic agents.

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.

The main objective in the development of nanomedicine is to obtain delivery platforms for targeted delivery of drugs or imaging agents for improved therapeutic efficacy, reduced side effects and increased diagnostic sensitivity. A (nano)material class that has been recognized for its controllable properties on many levels is ordered mesoporous inorganic materials, typically in the form of amorphous silica (SiO2). Characteristics for this class of materials include mesoscopic order, tunable pore dimensions in the (macro)molecular size range, a high pore volume and surface area, the possibility for selective surface functionality as well as morphology control. The robust but biodegradable ceramic matrix moreover provides shelter for incorporated agents (drugs, proteins, imaging agents, photosensitizers) leaving the outer particle surface free for further modification. The unique features make these materials particularly amenable to modular design, whereby functional moieties and features may be interchanged or combined to produce multifunctional nanodelivery systems combining targeting, diagnostic, and therapeutic actions. This review covers the latest developments related to the use of mesoporous silica nanoparticles (MSNs) as nanocarriers in biomedical applications, with special focus on cancer therapy and diagnostics.

Ras-related small GTP-binding proteins (also commonly referred to as small GTPases) comprise a large group of highly conserved signaling proteins with more than 100 mammalian family members. Many of these proteins are components of signaling pathways that link extracellular signals via transmembrane receptors to cytoplasmic or nuclear responses. Based on structure, sequence and function, the Ras superfamily can be categorized into distinct families -Ras, ARF, Rho, Rab, Ran, Rheb, Rap, Rit and Rad, each of which may be further divided into subfamilies. They function as molecular switches cycling between their active, GTP-bound, and inactive, GDP-bound, conformations [1]. Named for their ability to bind and hydrolyze GTP, it is now known that the intrinsic GTPase activity of many of these molecules is low to negligible [2]. Molecules that regulate nucleotide cycling on these proteins include GTPase activating proteins (GAPs), which promote hydrolysis of bound GTP and thus favor the inactive state, and GTP exchange factors (GEFs) which facilitate the exchange of bound GDP for GTP and thereby, GTPase activation. These Ras-like signaling proteins are essential for multiple cellular processes such as cell proliferation, dynamics of the cytoskeleton, membrane trafficking, and nucleo-cytoplasmic transport. They are involved in many physiological processes, including establishment and maintenance of polarity, adhesion, migration, cell division, cell differentiation and tissue regeneration. Given their pivotal role in so many critical developmentally regulated processes, small GTPases are involved in a wide spectrum of pathological human conditions, such as tumor growth and metastasis in cancer progression, inflammation and vascular diseases, mental retardation, and infections. This mini-issue covers diverse aspects of the cell biology and the biochemical regulation the small GTP binding proteins as well as their individual and collective cell biological functions in health and disease. Specific topics addressed include the roles and regulators of Rho and Rab families of small GTPases in cancer progression, as well as how signal transduction mediated by these same proteins can impinge on neurodegenerative disease. Rheb-regulated signaling, including its potential to provide novel anti-cancer therapeutics, is also reviewed.

The Rab family of GTPases contains over 60 genes in the human genome and contributes to regulation of intracellular membrane trafficking along endocytic and exocytic pathways as well as specialized pathways in specific cell types. It has become increasingly clear that disruption of the intracellular membrane trafficking system at different stages can cause various diseases. In the past decade, altered expression levels and mutations of Rab GTPases have been associated with diseases such as cancer, Alzheimer's disease, and various genetic disorders. This review discusses the specific Rab GTPases and their involvement in the diseases.

Rho GTPases (Ras homologous family) comprise the largest subfamily cluster of the Ras-homology superfamily. Rho GTPases exist in inactive GDP and active GTP forms. The active forms of the Rho family members bind with numerous effector proteins that are crucial for various biological processes. Accumulating evidence exemplifies the importance of Rho effector proteins in various steps of cancer progression. Here, we highlight the actions of various effectors of Rho members in cancer invasion and metastasis.

The establishment of neural connectivity implicates tight regulation of the intracellular signaling pathways mediated by axon guidance molecules. The Rho family of small GTPases, in particular Rho, Rac, and Cdc42, are important regulators of the cytoskeleton in neuronal cells acting, downstream of most, if not all, guidance cue receptors. Furthermore, recent studies using in vivo knockout mouse models provide new evidence of the primary role played by Rho GTPase signaling during the development of the nervous system. Here, we review our recent understanding of Rho GTPase signaling in response to classical axon guidance cues in mammalian cells. We also describe how in vivo knockout mouse models have been useful to implicate Rho GTPase signaling during the formation of the nervous system. Finally, we present several lines of evidence showing the involvement of Rho GTPase signaling in the development and progression of neurodegenerative diseases.

Several mechanisms function in the endocytic regulation of the Wnt/β-catenin signaling pathway to promote or interrupt the progression of critical cellular processes during embryonic development or disease progression. Endocytosis was initially associated with the formation of a morphogen gradient of Wnt/β-catenin signaling, but current studies have documented its role in defining signal intensity and propagation. Although the exact parameters that define and dictate the internalization of Wnt receptors and co-receptors via clathrin- or caveolae-mediated endocytosis remain unclear, new studies indicate that the trafficking of the signaling pool of the dual-function protein β-catenin from sites of cell-cell contacts serve as a mechanism to finely tune the outcome of the Wnt/β-catenin signaling. This review discusses the endocytic regulation of Wnt/ β-catenin signaling that occurs at the cell surface as well as within the cell.

mTOR exists in two distinct complexes. mTOR complex 1 (mTORC1) is potently inhibited by the immunosupressive macrolide rapamycin; whereas, mTORC2 is insensitive to this drug. These mTOR complexes play an integral role in the regulation of many cellular processes including protein synthesis, autophagy, lipid synthesis, mitochondrial metabolism/biogenesis, and cell cycle. Both mTOR complexes are important for maintaining cellular homeostasis and the growth of many types of cancer. Rapamycin and rapalogs have been effective in treating only a small number of these cancers, and other methods are being developed in order to address the short-comings of these drugs. The most direct of these approaches include ATP-competitive inhibitors of the mTOR kinase or dual inhibitors of both mTOR and PI3 kinase. However, other methods of inhibiting mTORC1 may prove clinically useful as well. These include amino acid depletion using asparaginase and inhibition of the Rheb GTPases with farnesyl transferase inhibitors or statins. Most excitingly, mTORC1 activation has been shown to cause and sensitize cells to DNA damage and ER stress. Many of the drugs currently used in the clinic for the treatment of cancer cause these types of stress, and existing drugs may be tailored to treat tumors with high mTORC1 activity.