Targeting Therapeutic and Imaging Agents to Folate Receptor Positive Tumors

Reddy, Joseph A.; Allagadda, V. M.; Leamon, Christopher P.

doi:10.2174/1389201053642376

Cited by 111 publications

(76 citation statements)

References 79 publications

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“…Folate targeting of liposomal drug carriers has been shown in a number of studies but has yet to be optimized for effective therapeutic applications (5,22,23). Here, we have investigated the uptake of folate targeted liposomal carriers in the J6456 lymphoma tumor model up-regulated for the folate receptor.…”

Section: Discussionmentioning

confidence: 99%

Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors

Shmeeda

Mak²,

Tzemach³

et al. 2006

Molecular Cancer Therapeutics

123

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The folate receptor is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anticancer agents to folate receptorexpressing tumors. This study examines folate-lipid conjugates as a means of enhancing the tumor selectivity of liposome-encapsulated drugs in a mouse lymphoma model. Folate-derivatized polyethylene glycol (PEG 3350 )-distearoyl-phosphatidylethanolamine was post-loaded at various concentrations into the following preparations: radiolabeled PEGylated liposomes, PEGylated liposomes labeled in the aqueous compartment with dextran fluorescein, and PEGylated liposomal doxorubicin (PLD, Doxil). We incubated folate-targeted radiolabeled or fluorescent liposomes with mouse J6456 lymphoma cells up-regulated for their folate receptors (J6456-FR) to determine the optimal ligand concentration required in the lipid bilayer for liposomal cell association, and to examine whether folate-targeted liposomes are internalized by J6456-FR cells in suspension. Liposomal association with cells was quantified based on radioactivity and fluorescence-activated cell sorting analysis, and internalization was assessed by confocal fluorescence microscopy. We found an optimal ligand molar concentration of f0.5% using our ligand. A substantial lipid dosedependent increase in cell-associated fluorescence was found in folate-targeted liposomes compared with nontargeted liposomes. Confocal depth scanning showed that a substantial amount of the folate-targeted liposomes are internalized by J6456-FR cells. Binding and uptake of folate-targeted PLD by J6456-FR cells were also observed in vivo after i.p. injection of folatetargeted PLD in mice bearing ascitic J6456-FR tumors. The drug levels in ascitic tumor cells were increased by 17-fold, whereas those in plasma were decreased by 14-fold when folate-targeted PLD were compared with nontargeted PLD in the i.p. model. Folate-targeted liposomes represent an attractive approach for the intracellular delivery of drugs to folate receptor -expressing lymphoma cells and seem to be a promising tool for in vivo intracavitary drug targeting. [Mol Cancer Ther 2006;5(4):818 -24]

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Section: Discussionmentioning

confidence: 99%

Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors

Shmeeda

Mak²,

Tzemach³

et al. 2006

Molecular Cancer Therapeutics

123

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“…The FR is functionally expressed in high quantities by many primary and metastatic cancers (2)(3)(4)(5)(6)(7)(8). As a result, "folate targeting" has been successfully applied toward the delivery of a wide variety of therapeutic-and imaging-based agents to tumors that express the FR protein (9)(10)(11)(12). Compared with their nontargeted counterparts, folic acid-bearing drugs and delivery systems have repeatedly shown greater cancer cell specificity and selectivity in numerous preclinical studies (13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

Reddy

Dorton

Bloomfield

et al. 2014

Clinical Cancer Research

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Purpose: When evaluated in patients with ovarian and other cancer, vintafolide (EC145), a potent folatetargeted vinca alkaloid conjugate, displayed a toxicity profile that seemed to be nonoverlapping with many standard-of-care cancer therapeutics. It was, therefore, hypothesized that combining vintafolide with certain approved anticancer drugs may afford greater therapeutic efficacy compared with single-agent therapy. To explore this concept, vintafolide was evaluated in combination with pegylated liposomal doxorubicin (PLD; DOXIL), cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, and irinotecan against folate receptor (FR)-positive models.Experimental Design: FR-expressing KB, M109, IGROV, and L1210 cells were first exposed to graded concentrations of vintafolide, either alone or in combination with doxorubicin (active ingredient in PLD), and isobologram plots and combination index values generated. The vintafolide combinations were also studied in mice bearing various FR-expressing tumors.Results: Vintafolide displayed strong synergistic activity against KB cells when combined with doxorubicin, and no less-than-additive effects resulted when tested against M109, IGROV, and L1210 cells. In contrast, when either desacetylvinblastine hydrazide (DAVLBH; the vinca alkaloid moiety in vintafolide) or vindesine (the vinca alkaloid most structurally similar to DAVLBH) were tested in combination with doxorubicin, less-than-additive antitumor effects were observed. In vivo, all vintafolide drug combinations produced far greater antitumor effect (complete responses and cures) compared with the single agents alone, without significant increase in overall toxicity. Importantly, these benefits were not observed with combinations of PLD and DAVLBH or vindesine.Conclusions: On the basis of these encouraging preclinical results, clinical studies to evaluate vintafolide drug combination therapies are now under way.

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“…FRα is an attractive candidate for targeted biologic therapy of ovarian cancer [6,7]. It is reported to be expressed in the majority of non-mucinous epithelial ovarian tumors at levels 10-to 100-fold higher than its normal expression in the kidney and on lung and breast epithelial cells [8].…”

Section: Introductionmentioning

confidence: 99%

Folate receptor alpha as a tumor target in epithelial ovarian cancer

Kalli¹,

Oberg²,

Keeney³

et al. 2008

Gynecologic Oncology

385

271

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Objectives-Folate receptor α (FRα) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FRα expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease.Methods-FRα expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FRα staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death.Results-FRα expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FRα status detected at diagnosis. Metastatic foci were similar to primary tumors in FRα staining. FRα status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses.Conclusion-FRα expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FRα expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer.

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Targeting Therapeutic and Imaging Agents to Folate Receptor Positive Tumors

Cited by 111 publications

References 79 publications

Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors

Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with up-regulated folate receptors

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

Folate receptor alpha as a tumor target in epithelial ovarian cancer

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