Intracellular Trafficking Considerations in the Development of Natural Ligand-Drug Molecular Conjugates for Cancer

Overexpressed receptors, characteristic of many cancers, have been targeted by various researchers to achieve a more specific treatment for cancer. A common approach is to use the natural ligand for the overexpressed receptor as a cancer-targeting agent which can deliver a chemically or genetically conjugated toxic molecule. However, it has been found that the therapeutic efficacy of such ligand-drug molecular conjugates can be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands. Therefore, a thorough understanding of the intracellular trafficking properties of these ligands can lead to novel design criteria for engineering ligands to be more effective drug carriers. This review presents a few commonly used ligand/receptor systems where intracellular trafficking considerations can potentially improve the therapeutic efficacy of the ligand-drug molecular conjugates

Prostate tumor attenuation in the nu/nu murine model due to anti-sarcosine antibodies in folate-targeted liposomes

Herein, we describe the preparation of liposomes with folate-targeting properties for the encapsulation of anti-sarcosine antibodies (antisarAbs@LIP) and sarcosine (sar@LIP). The competitive inhibitory effects of exogenously added folic acid supported the role of folate targeting in liposome internalization. We examined the effects of repeated administration on mice PC-3 xenografts. Sar@LIP treatment significantly increased tumor volume and weight compared to controls treated with empty liposomes. Moreover, antisarAbs@LIP administration exhibited a mild antitumor effect. We also identified differences in gene expression patterns post-treatment. Furthermore, Sar@LIP treatment resulted in decreased amounts of tumor zinc ions and total metallothioneins. Examination of the spatial distribution across the tumor sections revealed a sarcosine-related decline of the MT1X isoform within the marginal regions but an elevation after antisarAbs@LIP administration. Our exploratory results demonstrate the importance of sarcosine as an oncometabolite in PCa. Moreover, we have shown that sarcosine can be a potential target for anticancer strategies in management of PCa

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward

Antimitotic drugs in the treatment of cancer

Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.Medical Research Council of South Africa, the Research Committee of the Faculty of Health Sciences of the University of Pretoria, the Cancer association of South Africa and the National Research Foundation.http://link.springer.com/journal/280hb201

ExPLOITATION OF THE FOLATE RECEPTOR IN THE MANAGEMENT OF CANCER AND INFLAMMATORY DISEASE

Over the last 25+ years, the folate receptor (FR) has emerged as an attractive tumor biomarker with the potential to be exploited for therapeutic purposes. Increasing evidence suggests that this enclocytosing protein can functionally mediate the cellular uptake and retention of natural folates, certain antifolates, and folate-drug conjugates; the consequences of the latter two events could result in biological modulation, including (but not limited to) tumor-targeted cytotoxicity. Because its tissue expression profile appears to be somewhat limited to either tissues responsible for whole body retention of folates (e.g., kidney and placenta), or certain pathologic tissues (e.g., tumors or activated macrophages), the FR is believed to be a useful biological target for disease management. Indeed, recent years have been peppered with reports of novel FR-targeted therapies, and many have demonstrated impressive in vivo potency, particularly against tumor xenografts, without the undesirable toxicity that often accompanies nontargeted drug regimens. This chapter will provide essential details on the properties of the FR, including where it is expressed and how it has been successfully manipulated for therapeutic benefit. (C) 2008 Elsevier Inc

Abstract P2-16-24: Folate targeted SMDC’s: A possible new treatment alternative for folate receptor expressing TNBC patients

Abstract Triple negative breast cancer (TNBC) is a subtype characterized by lack of gene expression for the estrogen receptor, progesterone receptor and the Her2/neu protein. Hence, the lack of hormonal or Her2 targeted therapy options makes TNBC difficult to treat, resulting in a death rate which is disproportionately higher than for other breast cancer subtypes. Recently, the folate receptor (FR) was shown to be highly expressed in TNBC, and expression significantly correlated with the higher grades of malignancy as well as poor outcomes. These observations suggest that TNBC patients may benefit from treatment with an FR-targeted therapy. To address this question, an established FR-positive subcutaneous TNBC pre-clinical model (MDA-MB-231) was chosen to evaluate a panel of FR-targeted small molecule drug conjugates (SMDC) with high potencies and varying mechanisms of action. Thus, EC1456 (folate-tubulysin B; IC50 ∼ 1 nM) and EC1744 (a folate-DNA cross-linking agent; IC50 ∼0.1 nM) were dosed intravenously at 2 μmol/kg following a three times per week, two week schedule in tumor-bearing mice. Both FR-targeted agents were found to be highly active against the MDA-MB-231 tumors, with 80-100% cure rates. In all cases, the observed anti-tumor activity was not accompanied by any significant weight loss in the test animals. These findings suggest that folate-targeted SMDCs may be active against TNBC and that further preclinical studies are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-24.</jats:p