The central problem in cancer chemotherapy is the severe toxic side effects of anticancer drugs on healthy tissues. Invariably the side effects impose dose reduction, treatment delay, or discontinuance of therapy. To limit the adverse side effects of cancer chemotherapy on healthy organs, we proposed a drug delivery system (DDS) with specific targeting ligands for cancer cells. The proposed DDS minimizes the uptake of the drug by normal cells and enhances the influx and retention of the drug in cancer cells. This delivery system includes three main components: (i) an apoptosis-inducing agent (anticancer drug), (ii) a targeting moiety-penetration enhancer, and (iii) a carrier. We describe one of the variants of such a system, which utilizes camptothecin as an apoptosis-inducing agent and poly(ethylene glycol) as a carrier. Luteinizing hormone-releasing hormone ( adverse side effects ͉ apoptosis ͉ cancer ͉ targeted drug delivery T he efficacy of cancer chemotherapy is limited by severe adverse side effects induced by anticancer drugs (1-4). The cytotoxic effect on healthy organs can be significantly diminished by employing special drug delivery systems (DDS) targeted specifically to cancer cells (5, 6). Targeting is especially important in circumstances where a localized tumor is removed surgically, and chemotherapy is prescribed as a follow-up preventive against potential metastases.Cancer targeting is usually achieved by adding to the DDS a ligand moiety specifically directed to certain types of binding sites on cancer cells. Several different targeting moieties were examined, including sugars (7-11), lectins (12-14), receptor ligands (5, 15-18), and antibodies (19-23) and their fragments (24). Recently, we found that the receptors for luteinizing hormone-releasing hormone (LHRH) are overexpressed in breast, ovarian, and prostate cancer cells (5,15,25). LHRH receptors (LHRHRs) are not expressed detectably in most visceral organs. We have taken advantage of this differential receptor expression and used a modified LHRH peptide as a targeting moiety on DDS to enhance drug uptake by the mentioned cancer cells and reduce the relative availability of the toxic drug to normal cells. We constructed and evaluated in vitro targeted DDS, which included (i) poly(ethylene glycol) (PEG) polymer as a carrier; (ii) camptothecin (CPT) as an anticancer drug; and (iii) modified LHRH peptide as a targeting moiety (5,15). In vitro evaluations confirmed the high anticancer activity of such conjugates against human ovarian, breast, and prostate cancer cells (15). Further, it was demonstrated that the cytotoxicity of the LHRH-targeted conjugates in human cancer cells was competitively inhibited by free LHRH peptide (25). The present investigations were aimed at evaluating the antitumor activity and apoptosis-induction capacity of the conjugates in experiments on mice bearing xenografts of human ovarian carcinoma. Tumor and organ distribution profiles of the targeted and nontargeted conjugates were also determined in these mice for cau...

To compare the influence of different characteristics of nanocarriers on the efficacy of chemotherapy and imaging, we designed, characterized, and evaluated three widely used nanocarriers: linear polymer, dendrimer and liposome in vitro and in vivo. These nanocarriers delivered the same anticancer drug (paclitaxel) and/or imaging agent (Cy5.5). A synthetic analog of LHRH peptide targeted to receptors overexpressed on the membrane of cancer cells was attached to the nanocarriers as a tumor targeting moiety. Significant differences were found between various studied non-targeted carriers in their cellular internalization, cytotoxicity, tumor and organ distribution and anticancer efficacy. LHRH peptide substantially enhanced intratumoral accumulation and anticancer efficacy of all delivery systems and minimized their adverse side effects. For the first time, the present study revealed that the targeting of nanocarriers to tumorspecific receptors minimizes the influence of the architecture, composition, size and molecular mass of nanocarriers on the efficacy of imaging and cancer treatment.

The relative difference in polymeric architectures of dendrimer and linear bis(poly(ethylene glycol)) (PEG) polymer in conjugation with paclitaxel has been described. Paclitaxel, a poorly soluble anticancer drug, was covalently conjugated with PAMAM G4 hydroxyl-terminated dendrimer and bis(PEG) polymer for the potential enhancement of drug solubility and cytotoxicity. Both conjugates were characterized by 1NMR, HPLC, and MALDI/TOF. In addition, molecular conformations of dendrimer, bis(PEG), paclitaxel, and its polymeric conjugates were studied by molecular modeling. Hydrolysis of the ester bond in the conjugate was analyzed by HPLC using esterase hydrolyzing enzyme. In vitro cytotoxicity of dendrimer, bis(PEG), paclitaxel, and polymeric conjugates containing paclitaxel was evaluated using A2780 human ovarian carcinoma cells. Cytotoxicity increased by 10-fold with PAMAM dendrimer-succinic acid-paclitaxel conjugate when compared with free nonconjugated drug. Data obtained indicate that the nanosized dendritic polymer conjugates can be used with good success as anticancer drug carriers.

We designed, synthesized, and evaluated in vitro and in vivo a novel targeted anticancer polymeric prodrug containing multiple copies of tumor targeting moiety [synthetic luteinizing hormone-releasing hormone (LHRH) peptide, analog of LHRH] and anticancer drug (camptothecin). One, two, or three molecules of the targeting peptide and anticancer drug were covalently conjugated with bis(2-carboxyethyl) polyethylene glycol polymer using citric acid as a multivalent spacer. We showed that LHRH peptide was bound to extracellular receptors and localized in plasma membrane of cancer cells. The designed tumortargeted prodrug increased the solubility of anticancer drug and offered cytoplasmic and/or nuclear delivery of drug to cancer cells expressing LHRH receptors. The multicomponent prodrug containing three copies of the targeting peptide and drug was almost 100 times more cytotoxic and substantially had enhanced antitumor activity compared with the analogous nontargeted prodrug and prodrugs containing one or two copies of active components.Many anticancer drugs used in chemotherapy require modifications to increase solubility, decrease adverse side effects, limit nonspecific activity, increase circulation time, modify biodistribution, and so on. Various drug delivery systems (DDS) have been developed to provide these modifications

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