Pharmacokinetics and biodistribution of the camptothecin–polymer conjugate IT-101 in rats and tumor-bearing mice

Schluep, Thomas; Cheng, Jianjun; Khin, Kay T.; Davis, Mark E.

doi:10.1007/s00280-005-0091-7

Cited by 137 publications

(128 citation statements)

References 22 publications

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“…The synthesis and properties of preclinical nanoparticles of CRLX101 have been described previously (12)(13)(14)(15)(16)(17)(18). The nanoparticles were 20 to 30 nm in diameter, and characterization studies demonstrated that all the polymer chains were contained within the nanoparticles (i.e., no free polymer chains) (13).…”

Section: Resultsmentioning

confidence: 99%

“…However, the biodistribution of CRLX101 has been investigated in animals, and accumulations in kidney, liver, and spleen are observed in addition to tumor (13,14). In mice, the total amount of CPT per gram of tissue (14) and polymer (that is indicative of CRLX101 nanoparticles) are the highest in the tumor tissue at 24 h after administration (13). Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulation of CRLX101 into mouse tumor xenografts has been investigated previously (13)(14)(15)(16), and the time-dependent localization in one tumor type is illustrated in Fig. 5 A and B.…”

Section: Discussionmentioning

confidence: 99%

“…CRLX101 has been shown to circulate in rodents with a t 1/2 of approximately 1 d (13,14) and accumulate in solid tumor xenografts as an intact nanoparticle (13). Additionally, the CRLX101 nanoparticles have been observed [by transmission EM (TEM) images] to localize into cancer cells in a mouse xenograft from a tail vein injection (15).…”

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confidence: 99%

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Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Eliasof

Lazarus

Peters

et al. 2013

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

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Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20-to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.nanomedicine | clinical translation | interspecies scaling | pharmacodynamics | Nanoparticles

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Eliasof

Lazarus

Peters

et al. 2013

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

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124

114

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“…These effects likely play a significant role in the enhanced antitumour activity of CRLX101 when compared to CPT alone or CPT-11. 138 Notably, CRLX101 tumour growth inhibition of squamous and nonsquamous NSCLC was superior to approved therapeutic agents such as TPT, docetaxel (Taxotere s ; Aventis), erlotinib (Tarceva s ), gemcitabine (Gemzar s ; Lilly) and carboplatin (Paraplatin s ; Bristol-Myers Squibb). Thanks to its sustained levels within penetrated tumour tissue, CRLX101 inhibited cell proliferation uniformly.…”

Section: Crlx101 Preclinical Resultsmentioning

confidence: 99%