Folate-mediated delivery of macromolecular anticancer therapeutic agents

The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology.     

Folate-mediated delivery of macromolecular anticancer therapeutic agents

The receptor for folic acid constitutes a useful target for tumor-specific drug delivery, primarily because: (1) it is upregulated in many human cancers, including malignancies of the ovary, brain, kidney, breast, myeloid cells and lung, (2) access to the folate receptor in those normal tissues that express it can be severely limited due to its location on the apical (externally-facing) membrane of polarized epithelia, and (3) folate receptor density appears to increase as the stage/grade of the cancer worsens. Thus, cancers that are most difficult to treat by classical methods may be most easily targeted with folate-linked therapeutics. To exploit these peculiarities of folate receptor expression, folic acid has been linked to both low molecular weight drugs and macromolecular complexes as a means of targeting the attached molecules to malignant cells. Conjugation of folic acid to macromolecules has been shown to enhance their delivery to folate receptor-expressing cancer cells in vitro in almost all situations tested. Folate-mediated macromolecular targeting in vivo has, however, yielded only mixed results, largely because of problems with macromolecule penetration of solid tumors. Nevertheless, prominent examples do exist where folate targeting has significantly improved the outcome of a macromolecule-based therapy, leading to complete cures of established tumors in many cases. This review presents a brief mechanistic background of folate-targeted macromolecular therapeutics and then summarizes the successes and failures observed with each major application of the technology.     

Iron oxide nanoparticles for sustained delivery of anticancer agents

We have developed a novel water-dispersible oleic acid (OA)-Pluronic-coated iron oxide magnetic nanoparticle formulation that can be loaded easily with high doses of water-insoluble anticancer agents. Drug partitions into the OA shell surrounding iron oxide nanoparticles, and the Pluronic that anchors at the OA-water interface confers aqueous dispersity to the formulation. Neither the formulation components nor the drug loading affected the magnetic properties of the core iron oxide nanoparticles. Sustained release of the incorporated drug is observed over 2 weeks under in vitro conditions. The nanoparticles further demonstrated sustained intracellular drug retention relative to drug in solution and a dose-dependent antiproliferative effect in breast and prostate cancer cell lines. This nanoparticle formulation can be used as a universal drug carrier system for systemic administration of water-insoluble drugs while simultaneously allowing magnetic targeting and/or imaging.     

Recent progress in drug delivery systems for anticancer agents

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.     

Live bacteria as anticancer agents and tumor-selective protein delivery vectors

The development of novel cancer therapies that are selective for cancer cells with limited toxicity to normal tissues is a challenge for oncology researchers. Microorganisms, such as viruses with selectivity for tumor cells or tumor micro-environments, have been investigated as potential arsenals for decades. Genetically-modified, non-pathogenic bacteria have begun to emerge as potential antitumor agents, either to provide direct tumoricidal effects or to deliver tumoricidal molecules. Attenuated Salmonella, Clostridium and Bifidobacterium are capable of multiplying selectively in tumors and inhibiting their growth, representing a new approach for cancer treatment. Because of their selectivity for tumor tissues, these bacteria would also be ideal vectors for delivering therapeutic proteins to tumors. VNP20009, an attenuated strain of Salmonella typhimurium, and its derivative, TAPET-CD, which expresses an Escherichia coli cytosine deaminase (CD), are particularly promising, and are currently undergoing phase I clinical trials in cancer patients.     

Redox-responsive biocompatible nanocarriers based on novel heparosan polysaccharides for intracellular anticancer drug delivery

Heparosan is a natural precursor of heparin biosynthesis in mammals. It is stable in blood circulation but can be degraded in lysosomes, showing good biocompatibility and long circulation features. So heparosan can be designed as anticancer drug carriers to increase tumor selectivity and improve the therapeutic effect. A novel redox-sensitive heparosancystamine-vitamin E succinate(KSV) micelle system was constructed for intracellular delivery of doxorubicin(DOX). Simultaneously, the redox-insensitive heparosan-adipic acid dihydrazide-vitamin E succinate copolymer(KV) was synthesized as control. DOX-loaded micelles(DOX/KSV) with an average particle size of 90–120 nm had good serum stability and redox-triggered depolymerization. In vitro drug release test showed that DOX/KSV micelles presented obvious redox-triggered release behavior compared with DOX/KV. Cytotoxicity and cell uptake were investigated using MGC80-3 tumor cells and COS7 fibroblast-like cells. The cell survival rate of blank micelles was more than 90%, and the cytotoxicity of DOX/KSV in MGC80-3 cells was higher than in COS7 cells, indicating that the carrier has better biocompatibility and less toxicity side effect. The cytotoxicity of DOX/KSV against MGC80-3 cells was significantly greater than that of free DOX and DOX/KV. Furthermore, compared with DOX/KV in MGC80-3 cells, DOX/KSV micelles uptook more anticancer drugs and then released DOX faster into the cell nucleus. The micelles were endocytosed by multiple pathways, but clathrin-mediated endocytosis was the main pathway. Therefore, heparosan polysaccharide could be a potential option as anticancer carrier for enhancing efficacy and mitigating toxicity.     

PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect

As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a widely used polymer for fabricating 'nanoparticles' because of biocompatibility, long-standing track record in biomedical applications and well-documented utility for sustained drug release, and hence has been the centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors. These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect. Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues has been elucidated in this review with clarity.     

Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment

Context: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers.

Objective: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues.

Methods: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line.

Results: PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity.

Conclusions: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy.     

Alkaloid anticancer agents

Patent Summary

A process is claimed for the preparation of desethyldi-hydronavelbine. The process consists of a partial total synthesis of one of the dimeric components and allows for the synthesis of navelbine analogues. Navelbine has application in cancer chemotherapy, having broader antitumour activity and lower neurotoxicity than the known agents vinblastine and vincristine.

(+)-18′ S-4′-desethyl-4′-deshydroxy-7′-norviblastine was tested in vitro for antitumour activity in comparison with the 18′ (R)-epimer, vinblastine and navelbine. The IC50 values were determined in a 72 hour cytotoxicity assay and the respective values (μg/ml) were 0.0005, no activity, 0.0005 and 0.005, respectively. The total synthesis of desethyldihydronavelbine is described and the preparation of dihydrodesethylnavel-bine is also described. Altogether fifteen compounds are described, including their intermediates.     

Acetylenic anticancer agents

This review is a comprehensive survey of acetylenic anticancer agents obtained from living organisms. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. Although acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal chemistry, and/or pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 300 acetylenic metabolites isolated from living organisms.     

A new drug-delivery-system of anticancer agents: activated carbon particles adsorbing anticancer agents

A new drug delivery system comprizing activated carbon particles adsorbing anticancer agents has been developed in order to enhance anticancer efficacy on local lesions and to reduce systemic toxicity. The system is designed to release the adsorbed anticancer agent slowly at a designated concentration level at the local site, and to allow the agent to remain for a long time at the local site, with affinity for the lymphatic system and the surface of cancer cells. Through this process, anticancer efficacy is enhanced at the local lesion and systemic toxicity decreases. Because the size of the particles influences the distribution of the agent, size is selected according to both targeted organs, i.e. lymphatic metastases, carcinomatous peritonitis, and administration methods, i.e. intramural, intracavitary, intrabronchial, or intratumoral administration.     

New microtubule-inhibiting anticancer agents

Importance of this field: Microtubule-inhibiting drugs are among the most commonly prescribed agents in the combat against cancer, though the clinical use of these drugs is limited by acquired resistance, risk of hypersensitivity reactions and intolerable toxicity. With progress in our understanding of cytoskeleton structure and its related signaling pathways, a number of new microtubule-inhibiting agents with diversified structures and modes of action haveemerged.

What the reader will gain: This review mainly describes new microtubule-targeting anticancer agents that have been discovered (especially over the past 2 years), with emphasis on their diversity of structures and distinct modes ofaction.

Areas covered in this review: Data were obtained exclusively from public sources, including journals and scientific meeting abstracts, up to September 2009.

Take home message: A number of new agents have been discovered, and some have entered clinical trials. Even though most of these agents stabilize or destabilize tubulin via binding on the recognized tubulin binding sites, a few compounds bind to tubulin on undefined sites or interrupt microtubule in diverse ways. Moreover, some agents target microtubule indirectly such that they alter the post-translational modification of tubulin. Further investigation into their mechanism of action and evaluation of their anticancer efficacy will help to develop novel regimens that are superior to existingapproaches.     

Natural peroxy anticancer agents

Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of terrestrial and marine peroxides as an important source of leads for drug discovery.     

Lanthanides as anticancer agents

The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metals and metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. A lot of metal-based drugs are widely used in the treatment of cancer. The clinical success of cisplatin and other platinum complexes is limited by significant side effects acquired or intrinsic resistance. Therefore, much attention has focused on designing new coordination compounds with improved pharmacological properties and a broader range of antitumor activity. Strategies for developing new anticancer agents include the incorporation of carrier groups that can target tumor cells with high specificity. Also of interest is to develop complexes that bind to DNA in a fundamentally different manner than cisplatin, in an attempt to overcome the resistance pathways that have evolved to eliminate the drug. This review focuses on recent advances in developing lanthanide anticancer agents with an emphasis on lanthanide coordination complexes. These complexes may provide a broader spectrum of antitumor activity. They were compared with classical platinum anticancer drugs. Lanthanides are also of interest because of their therapeutic radioisotopes. The dominant pharmacological applications of lanthanides are as agents in radioimmunotherapy and photodynamic therapy.     

Azine-carboxamides as anticancer agents

Despite disappointing results with the Raf inhibitor ZM 336372, AstraZeneca claims new B-Raf kinase inhibitors with the same m-phenylenediamine core structure. The new bisamides have two distinct linker groups attached. One is a substituted aromatic carboxylic acid group that constitutes the lipophilic part of the molecule, and the other is usually a pyrimidine carboxylic acid. The new molecules are part of a series of m-phenylenediamine bisamides. The compounds are expected to have anticancer activity due to their B-Raf inhibitory activity. B-Raf is mutated in a number of cancers into a constitutively active enzyme.     

Recent anticancer cytotoxic agents

In spite of the impressive progress in diagnosis, surgery and therapy that occurred since the Sixties, the overall cancer mortality is still high and the medical need is largely unmet. A number of innovative strategies, aimed to target malignant abnormalities of tumor cells are in development and begin to give important results. In alternative, angiogenesis inhibition has been addressed with the aim to limit the tumor ability to grow and metastasize. However, it will likely take some years to fully define the therapeutic role of different innovative drugs. Therefore, cytotoxic drugs will continue to represent a chief part of the therapy in the forthcoming years, possibly in combination with innovative agents addressing molecular targets. Most important traditional chemotherapeutic drugs or investigational anticancer agents were derived from natural sources also through synthetic structural modifications. In the Nineties, taxanes and camptothecins represented important success stories of this approach, while among DNA interacting agents anthracyclines continued to represent a structural platform for discovering new drugs and DNA minor groove binders represented a new field of investigation. Combinatorial chemistry combined with high-throughput screening programs are an important source of totally synthetic new agents, however, it should not be disregarded the fact that nature already performed combinatorial chemistry and leads selection through the ages. New natural or semisynthetic agents acting as tubulin stabilizers or DNA interactive agents of various mechanisms of action are presently investigated and will probably continue to give important contribution to cancer therapy in the near future. In this review, the medicinal chemistry and the development status of these anticancer cytotoxic agents are focused and discussed.     

Synthesis and characterization of RGD-fatty acid amphiphilic micelles as targeted delivery carriers for anticancer agents

Novel amphiphilic conjugates consisting of an Arg-Gly-Asp (RGD) peptide binding motif and aliphatic fatty acids of varying chain length (C10-C18) were synthesized and evaluated for their ability to form micelles and bind specifically to alphaVbeta3 integrin over-expressing tumor cells. The aphilphiles were characterized by IR, proton NMR and mass spectrometry. The size and zeta potential of the resultant micelles were ranged from 178 to 450 nm and - 13.5 to 39.6 mV, respectively. The critical micellar concentration (CMC), drug loading efficiency and tumor cell binding of these amphiphiles were determined. The CMC values, determined by pyrene fluorescent probe method, ranged from 0.02 to 0.12 mM for C14-RGD, C16-RGD and C18-RGD. The C18-RGD micelles with lowest CMC were found to increase the solubility of taxol, a model anticancer drug, by 87%. C18-RGD amphiphiles also exhibited significantly higher (12.1 +/- 1.14%, P < 0.05) binding to alphaVbeta3 integrin over-expressing human breast cancer cells (HTB-129) when compared to normal human epidermal keratinocyte (NHEK) cells (6.68 +/- 0.34). The results from this study demonstrated the feasibility of designing RGD-fatty acid amphiphiles as micellar drug delivery carriers to target to cancer cells.