Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane

Singer, Jack W.; Shaffer, Scott A.; Baker, Brian; Bernareggi, A.; Stromatt, Scott; Nienstedt, Drew; Besman, Marc

doi:10.1097/00001813-200503000-00003

Cited by 135 publications

(78 citation statements)

References 16 publications

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“…A recent report confirmed that monoglutamyl-2′-TXL and diglutamyl-2′-TXL are the major intracellular metabolites of PG-TXL (2). Hydrolysis of these metabolites led to the release of free TXL.…”

Section: Introductionmentioning

confidence: 83%

A Novel Method for Imaging In Vivo Degradation of Poly(L-Glutamic Acid), a Biodegradable Drug Carrier

Melancon

Wang

et al. 2007

Pharm Res

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Purpose-To develop an L-PG-based imaging probe suitable for assessing the degradation of L-PG in vivo.Methods-Conjugates of L-PG and a near-infrared fluorescence (NIRF) dye, NIR813, were characterized with regard to quenching efficiency and degradability by cathepsin B (CB) and other proteases. The kinetics of L-PG-NIR813's degradation and its degradation in orthotopic human U87/ TGL glioma in nude mice after intravenous injection was assessed using NIRF optical imaging (n = 3).Results-The fluorescence signal from L-PG-NIR813 was efficiently quenched and activated at NIR813 loadings of 8-10%. Upon exposure to CB, the fluorescence intensity of L-PG-NIR813 increased 10-fold. L-PG-NIR813 was also degraded by another cysteine protease cathepsin L, but not by MMP-2, cathepsin E, cathepsin D, and plasmin. A selective CB inhibitor blocked the fluorescence activation. After intravenous injection, the degradation of L-PG-NIR813 was visualized primarily in the liver, which peaked at 4 h postinjection. Activation of L-PG-NIR813 but not D-PG-NIR813 was clearly seen in U87/TGL tumors. Conclusion-Our results indicate that L-PG-NIR813 may be used to monitor the in vivo degradation of L-PG-based polymeric drugs, and that this agent may prove useful in noninvasive imaging of protease activity, particularly that of cysteine proteases.

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Section: Introductionmentioning

confidence: 83%

A Novel Method for Imaging In Vivo Degradation of Poly(L-Glutamic Acid), a Biodegradable Drug Carrier

Melancon

Wang

et al. 2007

Pharm Res

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“…PG has been used for the delivery of several chemotherapeutic agents. One such conjugate, PG-TXL, has successfully advanced into clinical phase III studies (25). In the current study, 4HPR was conjugated to partially cross-linked PG composed of linear PG of low molecular weight (M n =13,000) by linking them together through hydrolytically labile ester bonds (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…PG is an attractive polymeric drug carrier owing to its biodegradability, biocompatibility, and ability to render waterinsoluble drugs water soluble when the drug molecules are covalently conjugated to the PG carrier (24,25). PG has been used for the delivery of several chemotherapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer

et al. 2007

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Abstract.To determine whether a polymer-drug conjugate might improve tumor cell kill compared to the corresponding unconjugated agent when used in combination with radiation, we examined the antitumor activity of a water-soluble conjugate of N-(4-hydroxyphenyl) retinamide (4HPR) and poly(L-glutamic acid), PG-4HPR, in lung cancer cells and xenografts. The antiproliferative activity of 4HPR and PG-4HPR in human lung cancer A549 cells was evaluated and the response of the cells to radiation measured by clonogenic assay. Response to irradiation was evaluated by measuring tumor growth delay in nude mice bearing intramuscularly inoculated A549 tumors. Histologic responses were assessed by examination of apoptosis (TUNEL assay) and cell proliferation (Ki67 staining). In vitro, 4HPR and PG-4HPR inhibited the proliferation of A549 cells, with IC 50 values of 25.8 μM and >50 μM, respectively, after 24 h of continuous exposure and 6.25 μM and 9.75 μM, respectively, after 120 h. Both agents increased radiosensitivity at an equivalent 4HPR concentration of 10 μM after 5 days of exposure, with enhancement factors of 1.40 and 1.43. In tumor xenografts, intravenous injection of 4HPR or PG-4HPR (30 mg eq. 4HPR/kg) enhanced radiosensitivity by 1.3 and 1.6, respectively, without apparent systemic toxicity. PG-4HPR augmented radiation-induced apoptosis and decreased cellular proliferation in vivo. The radiation response of A549 tumors was greater with PG-4HPR than with 4HPR, which may be attributed to increased delivery of 4HPR to the tumors and enhanced apoptotic response. These results suggest that a polymeric delivery system may be useful for modulating radiosensitivity. IntroductionIt has been shown that the addition of concurrent chemotherapy to radiotherapy (chemoradiotherapy) results in improved clinical outcome in terms of both locoregional control and overall survival in some groups of patients (1-3). However, chemoradiotherapy is often associated with severe, dose-limiting toxicities that limit its application. For example, Liao et al (4) found that the combination of twice-daily radiotherapy (XRT) and concurrent cisplatin/etoposide resulted in a favorable long-term outcome (26%, 5-year survival rate), but it also increased the incidence of more severe radiationinduced pneumonitis and esophagitis. Furthermore, most chemoradiotherapy regimens are platinum-based and there is evidence that the maximum tolerable toxicity has been reached with the dose intensities currently used in bolus cisplatin regimens. Therefore, new means are being explored to selectively target tumors with chemotherapeutic agents to reduce normal tissue toxicity and maximize antitumor efficacy.One approach to improve the efficacy of radiotherapy without increasing its side effects is to use molecularly targeted therapeutic agents such as epidermal growth factor receptor and vascular endothelial growth factor receptor inhibitors (1,5). The fact that the specificity of such agents will be high by design has given rise to the expectation that targeted drug...

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“…PGA-based formulations have been developed that have significantly enhanced the efficacy of agents, such as camptothecin and paclitaxel, not only by promoting tumour-specific cytotoxicity but also by improving their solubility in blood following systemic administration [1,10]. For instance, clinical studies on paclitaxel polyglumex, a PGA-paclitaxel conjugate, have demonstrated that this drug formulation is preferentially trapped in the tumour microenvironment allowing the tumour to be exposed to significantly higher chemotherapeutic concentrations than those in off-target tissues [7,9,11].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy

et al. 2016

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Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome-inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours.

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Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane

Cited by 135 publications

References 16 publications

A Novel Method for Imaging In Vivo Degradation of Poly(L-Glutamic Acid), a Biodegradable Drug Carrier

A Novel Method for Imaging In Vivo Degradation of Poly(L-Glutamic Acid), a Biodegradable Drug Carrier

Polymeric retinoid prodrug PG-4HPR enhances the radiation response of lung cancer

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy

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