Metallic nanoparticles: technology overview & drug delivery applications in oncology

Importance of the field: The targeted delivery of therapeutic agents to tumour cells is a challenge because most of the chemotherapeutic agents distribute to the whole body, which results in general toxicity and poor acceptance by patients and sometimes discontinuation of the treatment. Metallic nanoparticles have been used for a huge number of applications in various areas of medical treatment. Metallic nanoparticles are emerging as new carrier and contrast agents in cancer treatment. These metallic nanoparticles have been used for imaging of tumour cells by means of active and passive targeting. Recent advances have opened the way to site-specific targeting and drug delivery by these nanoparticles.

Areas covered in this review: This review summarizes the mechanisms of passive and active targeted drug delivery by metallic nanoparticles and their potential use in cancer theranostics.

What the reader will gain: The reader will gain information on the development of tumour cells, advantages of modern methods of cancer treatment over the traditional method, targeted delivery of anticancer agents using nanoparticles, influence of nanotechnology on the quality and expectancy of life, and challenges, implications and future prospects of metallic nanoparticles as probes in cancer treatment.

Take home message: The development of metallic nanoparticles is rapid and multidirectional, and the improved practical potential of metallic nanoparticle highlights their potency as new tools for future cancer therapeutics modalities.     

Targeting AAC-11 in cancer therapy

Importance of the field: Since its discovery in 1997, the antiapoptotic factor AAC-11 has rapidly gained attention due to its potential use in cancer therapy. Indeed, most cancer cells express elevated levels of AAC-11, which is now known to be involved in both tumor cells growth as well as sensitivity to chemotherapeutic drugs.

Areas covered in this review: In this review, we examine the most recent evidence about the role of AAC-11 in cancer biology and the therapeutic perspectives associated with its specific targeting. For that purpose, literature dealing with AAC-11 in the PubMed database was reviewed from 1997 up to date.

What the reader will gain: AAC-11 is an antiapoptotic gene that has the potential to be a target for anti-cancer therapy, and warrants further investigation. As its expression seems to predict unfavorable prognosis, at least in some cancers, it also may become a potent prognostic marker.

Take home message: Blocking AAC-11 function in cancer for therapeutic purposes might be of great interest. The recent report of efficient AAC-11 inhibiting peptides that sensitize tumor cells to chemotherapeutic drugs has raise the exciting notion that AAC-11 might be a druggable target and fueled the search for new therapeutic agents that could block AAC-11 function.     

Stimulation of Brain Nicotinic Acetylcholine Receptors (nAChR) and Inhibition of Brain Acetylcholinesterase (AChE) Activity

Introduction: The Fas/FasL system plays a significant role in tumorigenesis. Research has shown that its impairment in cancer cells may lead to apoptosis resistance and contribute to tumor progression. Thus, the development of effective therapies targeting the Fas/FasL system may play an important role in the fight against cancer.

Areas covered: In this review the recent literature on targeting the Fas/FasL system for therapeutic exploitation at different levels is reviewed. Promising pre-clinical approaches and various exceptions are highlighted. The potential of combined therapies is also explored, whereby tumor sensitivity to Fas-mediated apoptosis is restored, before an effective targeted therapy is employed.

Expert opinion: The success of the Fas/FasL system targeting for therapeutics will require a better understanding of the alterations conferring resistance, in order to use the most appropriate sensitizing chemotherapeutic or radiotherapeutic agents in combination with effective targeted therapies.     

Nanotechnology based platforms for survivin targeted drug discovery

Introduction: Development of an effective, safe and targeted drug delivery system to fight cancer and other diseases is a prime focus in the area of drug discovery. The emerging field of nanotechnology has revolutionised the way cancer therapy and diagnosis is achieved primarily due to the recent advances in material engineering and drug availability. Further, the recognition of the crucial role played by anti-apoptotic proteins such as survivin, has initiated the development of therapeutics that can target this protein as an attempt to develop alternative cancer therapies. However, a key challenge faced in drug development is the efficient delivery of survivin-targeted molecules to specific areas in the body.

Areas covered: This review primarily focuses on the different strategies employing nanotechnology for targeting survivin expressed in human cancers. Different nanomaterials incorporating nucleic molecules or drugs targeted at survivin are discussed and the results obtained from studies are highlighted.

Expert opinion: There are extensive studies reporting different treatment regimens for cancer, however, they still result in systemic toxicity, reduced bioavailability and ineffective delivery. Novel approaches involve the use of biocompatible nanomaterials together with gene or drug molecules to target proteins such as survivin, which is overexpressed in cancerous cells. These nanoformulations allow the benefits of protecting easily degradable molecules, allow controlled release, and enhance targeted delivery and effectiveness. Hence, nanotherapy utilizing survivin targeting can be considered to play a key role in the development of personalized nanomedicine for cancer.     

Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platforms

Background: The treatment of solid tumours and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitiser (PS) to destroy target cells through a combination of visible light irradiation and molecular oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramolecular delivery platforms can improve PDT selectivity by exploiting cellular and physiological specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumour neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. In addition, polymeric prodrug delivery platforms triggered by the acidic nature of the tumour environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.     

Therapeutic targeting of B7-H1 in breast cancer

Introduction: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer.

Areas covered: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer.

Expert opinion: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

Targeting the anaphase promoting complex: common pathways for viral infection and cancer therapy

Introduction: The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase involved in regulation of the cell cycle through ubiquitination-dependent substrate proteolysis. Many viral proteins have been shown to interact with the APC/C, derailing cell cycle progression in order to facilitate their own replication. Induction of G₂/M arrest by viral APC/C inhibition can lead to apoptotic cell death. Some viral proteins cause cytotoxicity specifically in tumour cells, providing evidence that targeting the APC/C could be exploited to selectively eliminate cancer cells.

Areas covered: In this review, we provide a summary of studies from viral APC/C interactions over the last decade, as well as recent discoveries identifying the APC/C as a promising target in the context of cancer therapy.

Expert opinion: Current therapeutic strategies inducing mitotic arrest rely on activation of the spindle assembly checkpoint (SAC) for their function. Many cancer cells have a weakened SAC and escape apoptosis through mitotic slippage. Recent evidence has demonstrated that targeting the APC/C, particularly the co-activator Cdc20, might be a better alternative. Tumour cells display greater dependency on APC/C function than normal cells and oncogenic transformation can lead to increased mitotic stress, rendering cancer cells more vulnerable to APC/C inhibition.     

Targeting cancer with phosphodiesterase inhibitors

Importance of the field: For many cancers, there has been a shift from management with traditional, nonspecific cytotoxic chemotherapies to treatment with molecule-specific targeted therapies that are used either alone or in combination with traditional chemotherapy and radiation therapy. Accumulating data suggest that multi-targeted agents may produce greater benefits than those observed with single-targeted therapies, may have acceptable tolerability profiles, and may be active against a broader range of tumour types. Thus, regulation of cyclic nucleotide signalling is properly regarded as a composite of multiple component pathways involved in diverse aspects of tumour cell function. The impairment of cAMP and/or cGMP generation by overexpression of PDE isoforms that has been described in various cancer pathologies, and the effects of PDE inhibitors in tumour models in vitro and in vivo, may offer promising insight into future cancer treatments because of the numerous advantages of PDE inhibitors.

Areas covered in this review: In this review, we focus on the expression and regulation of cyclic nucleotide phosphodiesterases (PDEs) in tumour progression and provide evidence that PDE inhibitors may be effective agents for treating cancer; the review covers literature from the past several years.

What the reader will gain: PDEs have been studied in a variety of tumours; data have suggested that the levels of PDE activity are elevated and, therefore, the ratio of cGMP to cAMP is affected. In addition, PDE inhibitors may be potential targets for tumour cell growth inhibition and induction of apoptosis. This review explores the prospects of targeting PDEs with therapeutic agents for cancer, as well as the shortcomings of this approach such as dose-limiting side effects, toxicity/efficacy ratio and selectivity towards tumour tissue. In addition, it includes opinions and suggestion for developing PDE inhibition for cancer treatment from initial concept to potential therapeutic application and final relevance in clinical use.

Take home message: Impaired cAMP and/or cGMP generation upon overexpression of PDE isoforms has been described in various cancer pathologies. Inhibition of selective PDE isoforms, which raises the levels of intracellular cAMP and/or cGMP, induces apoptosis and cell cycle arrest in a broad spectrum of tumour cells and regulates the tumour microenvironment. Therefore, the development and clinical application of inhibitors specific for individual PDE isoenzymes may selectively restore normal intracellular signalling, providing antitumour therapy with reduced adverse effects.     

Receptor-mediated tumor targeting based on peptide hormones

Importance of the field: Tumor targeting with peptides is based on the discovery that receptors for many regulatory peptides are overexpressed in tumor cells, compared with their expression in normal tissues. Consequently, these peptides and their analogues can be used as carriers/targeting moieties for the preparation of diagnostic and therapeutic agents that have increased selectivity and decreased peripheral toxicity.

Areas covered in this review: Here an overview is given of the most relevant gonadotropin-releasing hormone (GnRH) and somatostatin derivatives, as well as of their applications in cancer diagnosis and therapy. For this purpose, recently published data in these areas (mostly articles published from 2000 to 2009) were reviewed.

What the reader will gain: In contrast to other regulatory peptides that stimulate the tumor growth, GnRH and somatostatin derivatives have inhibitory effect; therefore, they were used primarily for the preparation of various conjugates to be used in targeted chemotherapy, targeted radiotherapy, photodynamic therapy, boron neutron capture therapy and cancer diagnosis. Some of these conjugates have already found clinical applications, whereas others are now in preclinical and clinical trials.

Take home message: Tumor targeting with hormone peptides provides a basis for the development of new diagnostic and therapeutic approaches for cancer.     

Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications

Importance of the field: Metal oxide nanoparticles, including zinc oxide, are versatile platforms for biomedical applications and therapeutic intervention. There is an urgent need to develop new classes of anticancer agents, and recent studies demonstrate that ZnO nanomaterials hold considerable promise.

Areas covered in this review: This review analyzes the biomedical applications of metal oxide and ZnO nanomaterials under development at the experimental, preclinical and clinical levels. A discussion regarding the advantages, approaches and limitations surrounding the use of metal oxide nanoparticles for cancer applications and drug delivery is presented. The scope of this article is focused on ZnO, and other metal oxide nanomaterial systems, and their proposed mechanisms of cytotoxic action, as well as current approaches to improve their targeting and cytotoxicity against cancer cells.

What the reader will gain: This review aims to give an overview of ZnO nanomaterials in biomedical applications.

Take home message: Through a better understanding of the mechanisms of action and cellular consequences resulting from nanoparticles interactions with cells, the inherent toxicity and selectivity of ZnO nanoparticles against cancer may be improved further to make them attractive new anticancer agents.     

Targeting silibinin in the antiproliferative pathway

Importance of the field: Due to the failure and severe toxicity of cancer chemotherapy, silibinin, a natural flavonoid from the seeds of milk thistle, has recently received more attention for its potential anticancer and nontoxic roles in animals and humans. Silibinin has clearly demonstrated inhibition of multiple cancer cell signaling pathways, including growth inhibition, inhibition of angiogenesis, chemosensitization, and inhibition of invasion and metastasis. Cumulative evidence implicates that silibinin is a potential agent for cancer chemoprevention and chemotherapy.

Areas covered in this review: Our aim is to discuss the recent progress of silibinin in regulating multiple anticancer proliferative signaling pathways; the review covers literature mainly from the past 3 – 5 years.

What the reader will gain: One of the strategies for tumor therapy is eradication of cancer cells through targeting specific cell-proliferative pathways. This review highlights the current knowledge of silibinin in regulating multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways.

Take home message: The molecular mechanisms of silibinin-mediated antiproliferative effects are mainly via receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways in various cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a new approach for improving chemopreventive and chemotherapeutic effects.     

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

Importance of the field: Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).

Areas covered in this review: This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.

What the reader will gain: This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.

Take home message: For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth^®) liposomes.     

Biodegradable polymers for targeted delivery of anti-cancer drugs

ABSTRACT

Introduction: Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy.

Areas covered: This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered.

Expert opinion: Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.     

Aurora kinase inhibitor patents and agents in clinical testing: an update (2009 – 10)

Introduction: Mitosis is a key step in the cell cycle and is controlled by several cell cycle regulators, including aurora kinases. Aurora family members A, B and C are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis. Overexpression/amplification of aurora kinases has been implicated in oncogenic transformation, including the development of chromosomal instability in cancer cells. Hence, the use of aurora kinase small molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers.

Area covered: This review provides an update on aurora kinase inhibitors based on developments from 2009 to 2010. The medicinal chemistry aspects of aurora kinase inhibitors, with a particular emphasis on the patent literature, are reviewed. Databases such as PubMed, SCOPUS, Scifinder and www.clinicaltrials.gov database were used to search for literature in the preparation of this review.

Expert opinion: Around a dozen aurora kinase inhibitors are currently undergoing various Phase I – II evaluations for different human cancers. Instead of being applied as a monotherapy, combinations of aurora kinase inhibitors and existing chemotherapeutic compounds seem to give better therapeutic outcomes and are, therefore, a promising future cancer therapy.     

Nanoparticles for imaging and treatment of metastatic breast cancer

Introduction: Metastatic breast cancer is one of the most devastating cancers that have no cure. Many therapeutic and diagnostic strategies have been extensively studied in the past decade. Among these strategies, cancer nanotechnology has emerged as a promising strategy in preclinical studies by enabling early identification of primary tumors and metastases, and by effective killing of cancer cells.

Areas covered: This review covers the recent progress made in targeting and imaging of metastatic breast cancer with nanoparticles, and treatment using nanoparticle-enabled chemo-, gene, photothermal- and radio-therapies. This review also discusses recent developments of nanoparticle-enabled stem cell therapy and immunotherapy.

Expert opinion: Nanotechnology is expected to play important roles in modern therapy for cancers, including metastatic breast cancer. Nanoparticles are able to target and visualize metastasis in various organs, and deliver therapeutic agents. Through targeting cancer stem cells, nanoparticles are able to treat resistant tumors with minimal toxicity to healthy tissues/organs. Nanoparticles are also able to activate immune cells to eliminate tumors. Owing to their multifunctional, controllable and trackable features, nanotechnology-based imaging and therapy could be a highly potent approach for future cancer research and treatment.     

Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer

Introduction: High-motility group box (HMGB)-1 is the focus of recent cancer research. HMGB1 plays a critical role in cancer development, progression, and metastasis by activation of cancer cells, enhancement of tumor angiogenesis, and suppression of host anti-cancer immunity. HMGB1 is a relevant target for cancer treatment.

Areas covered: This review aims to overview the biological feature and diverses role in cancer of HMGB1. HMGB1 is a non-histone chromosomal protein, a secretory protein binding to the receptor for advanced glycation end products in cancer cells and monocyte-lineage immune cells, and a DNA presenting chaperon for toll-like receptors. HMGB1 enhances proliferation, motility, invasion and survival of cancer cells. In contrast, HMGB1 induces apoptosis in monocyte-lineage immune cells and inhibits tumor-infiltrating macrophages and dendritic cells, lymph node sinus macrophages and liver Kupffer cells to attenuate anti-cancer immune responses and anti-metastatic organ defense. Then the novel techniques for inhibiting HMGB1 are reviewed.

Expert opinion: Various techniques targeting HMGB1 are subjected to trial. HMGB1 targeting is a potential therapeutic techniqueagainst cancer development, progression, and especially metastasis. Technical breakthroughs in application of HMGB1 targeting to human diseases are now urgently required.     

Overcoming multidrug resistance with nanomedicines

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Areas covered: Herein, we focused on an implementation of nanoscale drug delivery strategies (nanomedicines) to treat tumors that resist MDR. Specifically, we briefly discuss the MDR phenomenon and provide structural and functional characterization of key proteins that account for MDR. We next describe the strategies to target tumors using nanoparticles and provide a mechanistic overview of how changes in the influx:efflux ratio result in overcoming MDR.

Expert opinion: Various strategies have been applied in preclinical and clinical settings to overcome cancer MDR. Among them are the use of chemosensitizers that aim to sensitize the cancer cells to chemotherapeutic treatment and the use of nanomedicines as delivery vehicles that can increase the influx of drugs into cancer cells. These strategies can enhance the therapeutic response in resistant tumors by bypassing efflux pumps or by increasing the nominal amounts of therapeutic payloads into the cancer cells at a given time point.     

Targeted nanotheranostics for personalized cancer therapy

Introduction: The development of nanomedicine, during the last 10 years have given rise to novel delivery systems among which multifunctional platforms called nanotheranostics that are designed to simultaneously diagnose and cure cancer. These systems can be built using the large panel of biocompatible and biodegradable materials. The recent advances of imaging modalities even enable targeted nanotheranostics to probe molecular structures on specific cells opening the doors to personalized cancer therapy.

Areas covered: This review presents the different requirements nanotheranostics should fulfill to achieve an optimized anticancer therapy. It focuses on two imaging modalities: MRI and ultrasonography used to visualize drug delivery, release, and efficacy. The advantages and limitations of these two methods are considered. The review will enable the readers to virtually tune a nanotheranostic system according to the nature of the targeting tissue and the availability of imaging modality.

Expert opinion: Despite great perspectives, described for nanotheranostic systems in personalized cancer therapy, the imaging techniques still face technological issues, such as high sensitivity and good spatial and temporal resolutions. Active targeting should consider better specificity and low immunogenicity of the ligand selected, to be more efficient.     

P53-Derived peptides conjugation to PEI: an approach to producing versatile and highly efficient targeted gene delivery carriers into cancer cells

ABSTRACT

Objectives: Targeted delivery of cytotoxic drugs or therapeutic antisense RNAs into specific cells is a major bottleneck in cancer therapy. To overcome this problem and improve the specificity for cancer cells, we describe a new-targeted delivery system using p53-derived peptides, namely PNC 27 and PNC 28. These peptides target HDM-2 on the surface of cancer cells. HDM-2 is overexpressed on the surface of cancerous cells, but not present on the untransformed cells.

Methods: To determine HDM-2-expressing cells, we used immunocytochemistry and flow cytometry analysis on nine cell lines including MCF-7 and NIH-3t3. Conjugation of peptides to vectors was confirmed using reverse-phase high-pressure liquid chromatography (RP-HPLC). Physicochemical properties of vector/DNA complexes including particle size, surface charge and DNA condensation ability were determined. In transfection studies, three plasmids were used including luciferase, pEGFP and shRNA plasmid against Bcl-XL mRNA. The level of Bcl-XL expression was determined by real-time PCR and western blot techniques.

Results: The results of gene delivery and shRNA-based gene silencing studies indicated that conjugation of PNC peptides could enhance gene delivery efficiently with high-targeted activity exclusively into cancer cells.

Conclusion: Our results strongly indicated that this targeting system could be utilized as an efficient targeting method for most cancer cells.