Refika I. Pakunlu

Molecular Targeting of Drug Delivery Systems to Cancer

This review presents molecular targeting approaches in anticancer drug delivery systems (DDS) and identifies new developments in these systems. Targeting approaches include passive targeting (enhanced permeability and retention effect), targeting specific tumor conditions, topical delivery and active targeting, namely, targeting organs, cells, intracellular organelles and molecules, sandwich targeting, promoter targeting, indirect targeting and targeting by external stimuli. A novel advanced proapoptotic anticancer DDS that utilizes several molecular targets will be considered. Experimental data suggest that this DDS can simultaneously: (1) induce cell death, (2) prevent adverse effects on healthy tissues; (3) suppress and prevent multidrug resistance; and (4) inhibit cellular antiapoptotic defense.

Enhancement of the efficacy of chemotherapy for lung cancer by simultaneous suppression of multidrug resistance and antiapoptotic cellular defense: novel multicomponent delivery system.

The efficacy of chemotherapy of lung cancer is limited by the development of resistance in cancer cells during treatment. In most lung cancers, this resistance is associated with the overexpression of (a) multidrug resistance-associated protein (MRP) responsible for drug efflux from the cancer cells (pump resistance) and (b) BCL2 protein that activates antiapoptotic cellular defense (nonpump resistance). A novel liposomal proapoptotic anticancer drug delivery system was developed to enhance anticancer efficacy of the well-established drug doxorubicin (DOX). This multicomponent drug delivery system was tested on multidrug-sensitive and -resistant human small-cell lung cancer cells. The drug delivery system includes four components: (a) liposome as a carrier, (b) DOX as an inductor of apoptosis, (c) antisense oligonucleotides (ASOs) targeted to MRP1 mRNA as a suppressor of pump resistance, and (d) ASOs targeted to BCL2 mRNA as a suppressor of nonpump resistance. Intracellular internalization of ASOs and DOX; the influence of the proposed system on the expression of genes and proteins involved in the multidrug resistance, cytotoxicity, and apoptosis induction and antiapoptotic defense; and the activity of caspases were studied. It was found that the proposed liposomal delivery system successfully delivered ASOs and DOX to cell nuclei, inhibited MRP1 and BCL2 protein synthesis, and substantially increased the anticancer action of DOX by stimulating the caspase-dependent pathway of apoptosis in multidrug-resistant human lung cancer cells.

Simultaneous Modulation of Multidrug Resistance and Antiapoptotic Cellular Defense by MDR1 and BCL-2 Targeted Antisense Oligonucleotides Enhances the Anticancer Efficacy of Doxorubicin

AbstractPurpose. To enhance the anticancer efficacy of an established drug by the simultaneous suppression of pump and nonpump cellular resistance. Methods. Multidrug resistant human ovarian (A2780/AD) and breast (MCF-7/AD) cancer cells were used. Doxorubicin (DOX) and antisense oligonucleotides (ASO) targeted to MDR1 and BCL-2 mRNA were combined in a solution within one liposomal drug delivery system (LDDS) in different combination series. Ten series of experiments were performed. In each series cells were incubated with 12 to 45 concentrations of free DOX and different liposomal formulations over a period of 6 to 48 h. Cytotoxicity, apoptosis induction, caspases, MDR1, BCL-2, and APAF-1 genes, P-glycoprotein, and BCL-2 protein were studied. Results. The combination of DOX and ASO targeted to MDR1 and BCL-2 mRNA in one LDDS exhibited a dramatic increase in the anticancer action of DOX. As a result of the simultaneous suppression of pump and nonpump cellular resistance by the inhibition of P-glycoprotein and BCL-2 protein synthesis, a significant increase in the activation of caspases and apoptosis was observed. Conclusions. The simultaneous suppression of multidrug resistance and antiapoptotic cellular defense significantly enhanced the anticancer activity of DOX. Therefore, the proposed DDS combination may potentially be used in the treatment of multidrug-resistant ovarian and breast cancers.

New generation of liposomal drugs for cancer.

This review is focused on liposomes as a delivery system for anticancer agents and more specifically on the advantages of using liposomes as drug nanocarrier in cancer chemotherapy. The main advantages of liposomal drugs over the non-encapsulated drugs include: (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability to include several active ingredients in one complex liposomal drug delivery system (DDS). The review also includes our recent data on advanced liposomal anticancer drug delivery systems. As a conclusion we propose a novel liposomal DDS which includes inhibitors of pump resistance combined in one liposomal drug delivery system with an inhibitor of antiapoptotic cellular defense, an apoptosis inducer (a traditional anticancer drug) and a targeting moiety. The proposed drug delivery system utilizes a novel three tier approach, simultaneously targeting three molecular targets: (1) extracellular receptors or antigen expressed on the surface of plasma membrane of cancer cells in order to direct the whole system specifically to the tumor, preventing adverse side effects on healthy tissues; (2) drug efflux pumps in order to inhibit them and enhance drug retention by cancer cells, increasing intracellular drug accumulation and thereby limiting the need for prescribed high drug doses that cause adverse drug side effects; and (3) intracellular controlling mechanisms of apoptosis in order to suppress cellular antiapoptotic defense.

Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1α Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor

Purpose: To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1α (HIF1A). Experimental Design: The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis. Results: The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy. Conclusions: The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.