2016
DOI: 10.1073/pnas.1603018113
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Abstract: Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CR… Show more

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Cited by 141 publications
(93 citation statements)
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References 19 publications
(21 reference statements)
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“…Several possibilities could explain the lack of efficacy. CRLX101 accumulation could be less in human tumors than what had been observed previously in preclinical mouse xenograft models, consistent with what was observed in the gastric pharmacodynamic study, though the assay was not quantitative (9). Second, mechanisms of resistance to camptothecin and its derivatives likely could be present contributing to the lack of anti-tumor activity.…”
Section: Discussionsupporting
confidence: 81%
See 1 more Smart Citation
“…Several possibilities could explain the lack of efficacy. CRLX101 accumulation could be less in human tumors than what had been observed previously in preclinical mouse xenograft models, consistent with what was observed in the gastric pharmacodynamic study, though the assay was not quantitative (9). Second, mechanisms of resistance to camptothecin and its derivatives likely could be present contributing to the lack of anti-tumor activity.…”
Section: Discussionsupporting
confidence: 81%
“…This trial further highlights the challenge of drug resistance that develops in gastric cancer which appears to be universal regardless of choice of first-line cytotoxic chemotherapy utilized. We were able to demonstrate that CRLX101 exhibits evidence of preferential uptake of drug into patient gastric tumor tissue as well as evidence of downregulation of putative drug targets such as carbonic anhydrase IX and HIF-1α (9). Consistent with the lack of non-tumor tissue camptothecin uptake, CRLX101 demonstrated a favorable toxicity profile.…”
Section: Discussionmentioning
confidence: 74%
“…However, recent findings from CRLX101 clinical trial demonstrate EPR is at work in humans [72]. CRLX101 is also a prodrug consisting of a cyclodextrin-containing polymer-conjugate of camptothecin (CPT), which self-assemble into nanoparticles with 20–30 nm diameter and 10 wt% CPT.…”
Section: Main Challenges and Strategiesmentioning
confidence: 99%
“…enhance understanding of nanoparticle performance in animal models (24)(25)(26)(27), strategies to normalize tumor vasculature (28), systematic investigations into ideal nanoparticle characteristics (24,29), and a focus on smaller (20-30-nm-sized) nanocarriers (24,30,31). Despite the promise of these approaches, the diversity of human cancers necessitates equivalently diverse delivery approaches (23,32) and opportunity for improvement remains, particularly in the area of enhancing uniformity of tumor distribution.…”
mentioning
confidence: 99%