Formulating Paclitaxel in Nanoparticles Alters Its Disposition

Yeh, Teng Kuang; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

doi:10.1007/s11095-005-4581-4

Cited by 87 publications

(30 citation statements)

References 20 publications

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“…Previous studies using the standard formulation of paclitaxel solubilized with polyethoxylated castor oil revealed a terminal t1/2 of 1.9 hours. 15 The prolonged t1/2 in CTI 52010 can be exploited for therapeutic gain in tumors of the liver and spleen, providing a potential therapeutic advantage over standard paclitaxel formulations. We chose a 28-day washout period between treatments based on the metabolism and clearance of other chemotherapeutic agents, and without prior knowledge of the extended half-life.…”

Section: Discussionmentioning

confidence: 99%

“…However, many nanoparticulate formulations use a polymeric coating such as gelatin. 15 CTI 52010 is produced using precipitation with compressed antisolvents, and polymeric coatings are not needed. Due to the production methods used, CTI 52010 contains only paclitaxel in nanoparticulate form, and avoids the toxicities associated with gelatin or other matrices used in other nanoparticle production methods.…”

Section: Discussionmentioning

confidence: 99%

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Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs

Axiak¹,

Selting²,

Decedue³

et al. 2011

IJN

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Background: Paclitaxel is highly effective in the treatment of many cancers in humans, but cannot be routinely used in dogs as currently formulated due to the exquisite sensitivity of this species to surfactant-solubilizing agents. CTI 52010 is a formulation of nanoparticulate paclitaxel consisting of drug and normal saline. Our objectives were to determine the maximally tolerated dose, dose-limiting toxicities, and pharmacokinetics of CTI 52010 administered intravenously to normal dogs. Methods: Three normal adult hound dogs were evaluated by physical examination, complete blood count, chemistry profile, and urinalysis. Dogs were treated with staggered escalating dosages of CTI 52010 with a 28-day washout. All dogs were treated with a starting dosage of 40 mg/m 2 , and subsequent dosages were escalated at 50% (dog 1), 100% (dog 2), or 200%(dog 3) with each cycle, to a maximum of 240 mg/m 2 . Dogs were monitored by daily physical assessment and weekly laboratory evaluation. Standard criteria were used to grade adverse events. Plasma was collected at regular intervals to determine pharmacokinetics. Dogs were euthanized humanely, and necropsy was performed one week after the last treatment. Results:The dose-limiting toxicity was grade 4 neutropenia and the maximum tolerated dosage was 120 mg/m 2 . Grade 1-2 gastrointestinal toxicity was noted at higher dosages. Upon post mortem evaluation, no evidence of organ (liver, kidney, spleen) toxicity was noted. Conclusion: CTI 52010 was well tolerated when administered intravenously to normal dogs. A starting dosage for a Phase I/II trial in tumor-bearing dogs is 80 mg/m 2 .

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs

Axiak¹,

Selting²,

Decedue³

et al. 2011

IJN

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“…3) when paclitaxel was administered. Aggregate toxicity is not likely for the reversed sequence because paclitaxel has a much shorter elimination halflife compared with doxorubicin HCl liposome (1-2 versus 20 -35 h) (Gabizon et al, 2003;Yeh et al, 2005), and over 99% of the paclitaxel dose would have been eliminated in 48 h when doxorubicin HCl liposome was administered. These data indicate tumor priming did not enhance the toxicity of doxorubicin HCl liposome.…”

Section: Enhances Delivery and Efficacy Of Nanomedicines 83mentioning

confidence: 99%

Tumor Priming Enhances Delivery and Efficacy of Nanomedicines

Lü

Wientjes²,

Lu³

et al. 2007

J Pharmacol Exp Ther

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124

159

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We have shown that high epithelial cell density is a major barrier to the distribution of protein-bound drugs in solid tumors, and tumor priming (expansion of interstitial space using an apoptosis-inducing pretreatment) can promote drug delivery. This study evaluated the optimal conditions of paclitaxel tumor priming (time window, particle size) and its effects on the delivery and efficacy of nanomedicines. Paclitaxel tumor priming was applied to mice bearing human xenograft tumors. The kinetics of paclitaxel-induced apoptosis was evaluated to identify the time window of tumor priming. The effects of tumor priming on the tumor delivery and interstitial dispersion of fluorescence-labeled nanoparticles of various sizes, the perfusion of tumor and normal tissues, the delivery of doxorubicin HCl liposomes to tumor and host tissues, and the antitumor activity and host toxicity were studied. Tumor priming by a single i.v. injection of paclitaxel induced apoptosis, expanded the interstitial space, vessel diameter and blood-perfused area, and promoted the delivery and interstitial dispersion of nanoparticles (100-and 200-nm diameter, administered 48 h after paclitaxel) in a tumor-selective manner. Tumor priming also enhanced the tumor delivery and antitumor activity of doxorubicin HCl liposomes (85 nm) without affecting the delivery to noncancerous host tissues or enhancing host toxicity. Tumor priming represents a potentially useful means to promote tumor-selective delivery and efficacy of nanomedicines. The current study will have significant impact on enhancing delivery and efficacy of nanomedicines and dosing regimen optimization of combination chemotherapy in the clinical setting.

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“…This prolonged circulation time together with EPR effects allowed for much higher accumulation of the drug at tumor sites (10-fold higher than PTX and 6-fold higher than PEG-PTX after 2 h of injection and 6-and 4-fold higher, respectively, after 24 h of injection) [109]. In conclusion, the high delivery efficacy of PTX by SWCNT subsequently resulted in tumor inhibition of SWCNT-PTX (5 mg/kg PTX) for the 4T1 tumor model known to be resistant to PTX treatments [138][139][140][141][142][143]. It has been shown that nanotube drug delivery is promising for high treatment efficacy and minimum side effects for future cancer therapy with low drug doses.…”

Section: Covalent Methodsmentioning

confidence: 99%

Modification of Carbon Nanotubes as an Effective Solution for Cancer Therapy

Tavakolifard¹,

Biazar²

2016

Nano BioMed ENG

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Carbon nanotubes (CNT) as a new class of nano-materials hold great potential for various biomedical applications. Owing to their unusual properties, carbon nanotubes have been extensively employed in electronics, nanotechnology and optics, among others. In spite of the great potential of carbon nanotubes in various domains of biomedicine, ineffcient dispersion in aqueous solutions and biological activities in vivo are still disputable. One important and feasible route in a struggle to overcome these obstacles is modification of CNTs with organic compounds and polymers, which have been widely studied and play a crucial role in biological and biomedical fields, particularly in the cancer therapy. This review focuses on the breakthrough of the recently used methods to functionalize onto the surface of carbon nanotubes with multiple chemical species in order to produce anticancer drug delivery systems for biomedical applications.

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Formulating Paclitaxel in Nanoparticles Alters Its Disposition

Abstract: These data indicate that formulation of paclitaxel affects its clearance and distribution into tissues, with preferential accumulation of nanoparticles in the liver, spleen, small intestine, and kidney.

Cited by 87 publications

References 20 publications

Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs

Phase I dose escalation safety study of nanoparticulate paclitaxel (CTI 52010) in normal dogs

Tumor Priming Enhances Delivery and Efficacy of Nanomedicines

Modification of Carbon Nanotubes as an Effective Solution for Cancer Therapy

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