Design of a multivalent galactoside ligand for selective targeting of HPMA copolymer–doxorubicin conjugates to human colon cancer cells

David, Ayelet; Kopečková, Pavla; Minko, Tamara; Rubinstein, Abraham; Kopeček, Jindřich

doi:10.1016/j.ejca.2003.07.001

Cited by 97 publications

(59 citation statements)

References 34 publications

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“…After 3-4 weeks, all female mice had healthy viable offspring. The number of offspring per mouse (4)(5)(6)(7)(8) and their viability, weight change, and behavior during the following 4 weeks were not different from the offspring of the control mice (Table 1). Taken together, these data indicate that targeted conjugates of PEG polymer and anticancer drug CPT do not breach the pituitary and blood-brain barriers from the systemic circulation (Fig.…”

Section: Induction Of Cell Death Signalmentioning

confidence: 90%

Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide

Dharap

Wang

Chandna

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

318

297

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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...

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Section: Induction Of Cell Death Signalmentioning

confidence: 90%

Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide

Dharap

Wang

Chandna

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

318

297

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“…Previous work has demonstrated that two functionally unrelated GPCRs, i.e., MC4R and CCK2R, or MC4R and the δ-opioid receptor (δ-OR), can be noncovalently cross-linked by their corresponding heterobivalent ligands with high avidity (12,17,19). Multivalency can increase binding avidity, but not necessarily increase targeting specificity (32,33). By following the previous in vitro findings, the current work studied the parameters including linker length and flexibility, surface receptor expression level per cell, ratio of receptor expression level, receptor-ligand affinity, and ligand concentration on which this targeting specificity depends.…”

Section: Discussionmentioning

confidence: 99%

Heterobivalent ligands target cell-surface receptor combinations in vivo

Josan

Vagner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A challenge in tumor targeting is to deliver payloads to cancers while sparing normal tissues. A limited number of antibodies appear to meet this challenge as therapeutics themselves or as drug-antibody conjugates. However, antibodies suffer from their large size, which can lead to unfavorable pharmacokinetics for some therapeutic payloads, and that they are targeted against only a single epitope, which can reduce their selectivity and specificity. Here, we propose an alternative targeting approach based on patterns of cell surface proteins to rationally develop small, synthetic heteromultivalent ligands (htMVLs) that target multiple receptors simultaneously. To gain insight into the multivalent ligand strategy in vivo, we have generated synthetic htMVLs that contain melanocortin (MSH) and cholecystokinin (CCK) pharmacophores that are connected via a fluorescent labeled, rationally designed synthetic linker. These ligands were tested in an experimental animal model containing tumors that expressed only one (control) or both (target) MSH and CCK receptors. After systemic injection of the htMVL in tumor-bearing mice, label was highly retained in tumors that expressed both, compared with one, target receptors. Selectivity was quantified by using ex vivo measurement of Europium-labeled htMVL, which had up to 12-fold higher specificity for dual compared with single receptor expressing cells. This proof-of-principle study provides in vivo evidence that small, rationally designed bivalent htMVLs can be used to selectively target cells that express both, compared with single complimentary cell surface targets. These data open the possibility that specific combinations of targets on tumors can be identified and selectively targeted using htMVLs.receptor targeting | multivalency | cross-linking | gene expression profiling

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“…While it is well acknowledged that, on the macroscale, these multivalent interactions strongly influence ligand-receptor binding kinetics and the biological responses they govern, the microscale patterning of ligands on substrates can also have a profound effect on multivalent kinetics and are able to further modulate biological signaling [4] . In particular, ligand-receptor clusters can dramatically increase interactions between cell and substrate; not only the valency, but spatial factors such as branching mode and the localized clustering of groups are important [5][6][7] in influencing binding and downstream signaling processes [8,9] . Still, despite the prevalence of patterned ligand presentation in cell biology and its demonstrated significance on 2D tissue engineering formats [10,11] , it remains largely unappreciated by those who design nanoparticle synthetic systems intended to interact with cells.…”

mentioning

confidence: 99%

Ligand‐Clustered “Patchy” Nanoparticles for Modulated Cellular Uptake and In Vivo Tumor Targeting

et al. 2010

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Despite the evident success of using a multivalent approach to increase efficacy of targeted delivery, a clear understanding of how multiple ligands behave collectively to influence the uptake of nanoparticle cell-targeting agents has not been reached. Although when present in large quantity, multivalent ligands can increase binding avidities to cells, it is also conceivable, that the manner in which these ligands are presented to the cell may have a significant effect on uptake. Here we examine this parameter using a linear dendritic polymer construct that enabled us to pattern the surfaces of nanoparticles with variable sized ligand clusters in different spatial arrangements. We demonstrate for the first time the clear impact of folate presentation on intracellular uptake both in vitro and in vivo. The findings presented here suggest that the nature of ligand presentation on a nanoparticle surface may play an important role in drug targeting; the results suggest potential impact for other targeting moieties and provide a framework for further refinement of future multivalent targeting strategies.Many biological systems interact through multiple simultaneous interactions [1][2][3] . While it is well acknowledged that, on the macroscale, these multivalent interactions strongly influence ligand-receptor binding kinetics and the biological responses they govern, the microscale patterning of ligands on substrates can also have a profound effect on multivalent kinetics and are able to further modulate biological signaling [4] . In particular, ligand-receptor clusters can dramatically increase interactions between cell and substrate; not only the valency, but spatial factors such as branching mode and the localized clustering of groups are important [5][6][7] in influencing binding and downstream signaling processes [8,9] . Still, despite the prevalence of patterned ligand presentation in cell biology and its demonstrated significance on 2D tissue engineering formats [10,11] , it remains largely unappreciated by those who design nanoparticle synthetic systems intended to interact with cells.Traditionally, ligands have been attached in moderate to large quantities to liposomes, inorganic nanoparticles and linear-linear block copolymer micelles [12,13] ; however, typically they are presented in a randomly distributed fashion across the nanoparticle surface from a linear tether, typically polyethylene glycol (PEG), in a structure that does not enable manipulation of ligands in specific groupings with control of cluster group size and spacing.We hypothesized that precise control over the elements promoting and controlling multivalent presentation on targeted therapeutic carriers could enhance the efficacy and specificity of targeted delivery. To test this hypothesis, scaffolds that are able to localize a variable number of ligands within confined regions are required; this requirement cannot be satisfied by traditional material systems used in targeted delivery [14] such as linear-linear block polymers and PEG-fu...

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Design of a multivalent galactoside ligand for selective targeting of HPMA copolymer–doxorubicin conjugates to human colon cancer cells

Cited by 97 publications

References 34 publications

Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide

Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide

Heterobivalent ligands target cell-surface receptor combinations in vivo

Ligand‐Clustered “Patchy” Nanoparticles for Modulated Cellular Uptake and In Vivo Tumor Targeting

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