Biodistribution of paclitaxel and poly( l -glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor

Li, Chun; Newman, Robert A.; Wu, Qing; Shi, Ke; Chen, Wei; Hutto, Toni; Kan, Zuxing; Brannan, Melvin D.; Charnsangavej, Chusilp; Wallace, Sidney

doi:10.1007/s002800000168

Cited by 112 publications

(102 citation statements)

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“…DOCT accumulation was observed in reticulo endothelial system (RES) organs (liver and spleen), kidneys and in highly perfused organs such as the lungs and heart. 25,57 No significant difference in the pattern of distribution between targeted and nontargeted Nps was observed. These nanoformulations could be validated in a suitable cancer model to obtain a clear understanding of their fate.…”

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confidence: 95%

In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Sreeranganathan

Uthaman

Sarmento

et al. 2017

IJN

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Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide–N-Hydoxysuccinimide (EDC–NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28–based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors.

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confidence: 95%

In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Sreeranganathan

Uthaman

Sarmento

et al. 2017

IJN

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“…To take advantage of the EPR effect, macromolecules have to remain in circulation for at least 6 h (Matsumura and Maeda, 1986). The prolonged circulation time of PPX facilitates tumour accumulation through the EPR effect, as has been demonstrated in animal models (Li et al, 2000). The release of paclitaxel from the polymeric backbone is dependent on lysosomal proteases, particularly cathepsin B (Shaffer et al, 2007).…”

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confidence: 86%

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

et al. 2008

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Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m À2 PPX or 75 mg m À2 docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio ¼ 1.09, P ¼ 0.257), 1-year survival (PPX ¼ 25%, docetaxel ¼ 29%, P ¼ 0.134), and time to progression (PPX ¼ 2 months, docetaxel ¼ 2.6 months, P ¼ 0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (Po0.001) and febrile neutropenia (P ¼ 0.006). Grade 3 or 4 neuropathy (Po0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, Po0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m À2 resulted in increased neurotoxicity compared with docetaxel. (Jemal et al, 2007). For patients who present with advanced-stage disease (IIIb or IV), platinum-based multi-agent chemotherapy modestly improves survival compared with best supportive care or singleagent therapy (Pfister et al, 2004). However, nearly all patients relapse, and only 10 -20% survive 2 years. Three agents are currently approved for second-line therapy in advanced nonsmall-cell lung cancer (NSCLC). Docetaxel and erlotinib were approved on the basis of improved survival compared with best supportive care (Shepherd et al, 2000(Shepherd et al, , 2005. Pemetrexed received approval as second-line therapy due to its similarity in survival and response rates with lower toxicity than that of docetaxel, although statistical noninferiority was not achieved (Hanna et al, 2004). Despite response rates of approximately 10%, second-line treatment improves survival by approximately 2 months compared with best supportive care.Owing to the palliative nature of second-line therapy in NSCLC and its relatively modest effect on survival, minimising the toxicity of therapy is an important consideration. Additional effective therapies that achieve that goal are needed.Paclitaxel poliglumex (PPX) is a macromolecular polymer -drug conjugate that links paclitaxel to a biodegradable polymeric backbone consisting of L-glutamic acid residues. Because the conjugation site is through the 2 0 hydroxyl of paclitaxel, a site crucial for tubulin binding, conjugated paclitaxel does not interact with b-tubulin and is biologically inactive . Paclitaxel poliglumex is relatively stable in circulation; the ar...

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“…Therefore, any activation or suppression of hPXR activity would affect CYP3A4 levels, and depending on liver extraction ratios of drugs, plasma drug concentrations would have very little predictive effect on the degree of hPXR activation. Hepatic extraction of microtubulebinding drugs are extensive; therefore, it is conceivable that much higher liver tissue concentrations could be attained even when plasma concentrations fall below that predicted to activate hPXR (33). Furthermore, because taxanes are given in a dose-intense schedule for the objective of attaining a cure in certain malignancies (e.g., breast cancer), even higher doses are used more frequently with growth factor support (34).…”

Section: Discussionmentioning

confidence: 99%

Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents

Mani

Huang

Sundarababu

et al. 2005

Clinical Cancer Research

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Purpose: Because induction of drug efflux transporters is one of the major underlying mechanisms of drug resistance in cancer chemotherapy, and human pregnane X receptor (hPXR) is one of the principal''xenobiotic''receptors whose activationinduces transporter and drug-metabolizing enzyme gene transcription, it would be ideal to develop chemotherapy drugs that do not activate hPXR.This report describes studies undertaken to explore the characteristics of hPXR stimulation and mechanisms of drug-receptor interactions in vitro with new anti-tubulin drugs. Experimental Design: In vitro transient transcription, glutathione S-transferase pull-down assays, and mammalian one-hybrid and two-hybrid systems were used to explore drug-receptor interactions. Loss of righting reflex was used to assess effects of drugs on PXR activity in vivo. Results: The current study showed that paclitaxel, discodermolide, and an analogue of epothilone B, BMS-247550, induced CYP3A4 protein expression in HepG2 hepatoma cells. Transient transcription assays of a luciferase reporter in the presence and absence of a GAL4-steroid and xenobiotic receptor (SXR) plasmid in HepG2 cells showed that these drugs activate hPXR. This was not true for the inactive analogue of paclitaxel, baccatin III, or for an analogue of epothilone A, analogue 5, none of which stabilizes microtubules. To determine the mechanisms by which paclitaxel, discodermolide, and BMS-247550 activate hPXR, a mammalian two-hybrid assay was done usingVP16SRC-1 (coactivator) and GAL4-SXR. SRC-1preferentially augmented the effects of these drugs on hPXR. Expression of SMRT (corepressor) but not NCoR suppressed the drug-induced activation of SXR by f50%, indicating a selectivity in corepressor interaction with hPXR. These drugs resulted in shortened duration of loss of righting reflex in vivo, indicating drug-induced activation of PXR in mice. Conclusion: These findings suggest that activation of hPXR with selective displacement of corepressors is an important mechanism by which microtubule-stabilizing drugs induce drugmetabolizing enzymes both in vitro and in vivo.

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Biodistribution of paclitaxel and poly( l -glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor

Cited by 112 publications

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In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents

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Biodistribution of paclitaxel and poly( l -glutamic acid)-paclitaxel conjugate in mice with ovarian OCa-1 tumor

Cited by 112 publications

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In vivo evaluation of cetuximab-conjugated poly(&gamma;-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

In vivo evaluation of cetuximab-conjugated poly(&gamma;-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer

Activation of the Steroid and Xenobiotic Receptor (Human Pregnane X Receptor) by Nontaxane Microtubule-Stabilizing Agents

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Product

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In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts