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  • br Nanoparticle Conjugated Topoisomerase Inhibitors

    2024-02-23


    Nanoparticle-Conjugated Topoisomerase Inhibitors The safety and efficacy of topotecan administered as LDM or MTD have been evaluated in several preclinical studies and a few clinical trials whose results showed that there can be significant adverse effects likely precluding its use in patients [53–56]. This problem helped contribute to the development of CRLX101, an investigational nanoparticle–drug conjugate containing a camptothecin payload designed to overcome instability and toxicity to achieve sustained drug delivery. Similarly to other nanoparticle formulations, CRLX101 accumulates in tumors through the enhanced permeability retention (EPR) effect (reviewed in [57]), undergoing intracellular hydrolysis of a glycine linker and subsequent sustained payload release [58,59]. Preclinical studies showed enhanced in vitro sensitivity to CRLX101 compared with camptothecin or topotecan that was paralleled with significant inhibition of tumor growth, angiogenesis, and hematogenous metastases [60,61]. CRLX101 was evaluated in human ovarian and breast cancer xenograft models in which MTD monotherapy resulted in potent tumor growth suppression, decreased HIF-1α protein levels, and improved survival compared with vehicle or topotecan monotherapy [62]. Moreover, recent data showed that sunitinib and bevacizumab elicited cancer stem cell (CSC) enrichment in a HIF-1α (but not -2α)-dependent manner, resulting in limited AA therapy efficacy in breast cancer xenografts [63]. Consistently, a later study indicated that CRLX101 administration blocked this CSC enrichment upon bevacizumab treatment, suggesting that HIF-α inhibition represents an effective strategy to overcome CSC-induced AA therapy resistance [27]. Clinical studies showed that CRLX101 decreased the Dexlansoprazole of Topo-1 and carbonic anhydrase-9 (CA9, a canonical HIF-α target) in biopsies obtained from patients with gastroesophageal cancer (NCT01612546) [58]. Another study showed that CRLX101 decreased Topo-1, CA9, VEGF-A, MVD, and tumor growth in metastatic or unresectable solid tumors from patients enrolled in a Phase 1–2a clinical trial [64]. A Phase 2 study in patients with relapsed platinum-resistant ovarian cancers (NCT01652079) showed that CRLX101 achieved tumor reduction in 74% of patients, with durable partial responses in 16% of cases [62]. A fourth clinical Phase 1–2a study in metastatic refractory RCCs demonstrated a favorable CRLX101 safety profile Dexlansoprazole and a 23% response rate [65], followed by a randomized Phase 2 clinical trial in which CRLX101 was combined with bevacizumab versus standard-of-care therapy, which, unfortunately, did not show added benefit. However, RCC is not clinically sensitive to topo-1 inhibitors or any other chemotherapeutics, thus raising the possibility that sufficient HIF-α inhibition was unattainable through CRLX101. An alternative possibility, based upon recent studies, is that HIF-1α and -2α exert opposite effects in RCC, whereby HIF-1α induces growth arrest while HIF-2α enhances tumor growth (reviewed in [66]). Within this context, it would be expected that non-selective HIF-α paralog inhibitors will not be as efficacious as selective compounds, thus explaining a less-than-ideal therapeutic response. Furthermore, most trials so far have not reported contemporaneous stratification data for HIF-α levels, downstream targets, or IH, thereby limiting their ability to identify the patients most likely to benefit from HIF-α blockade [67]. Finally, the observation that VHL loss-of-function mutations are present in ≈50% of spontaneous RCC cases and are heterogeneous in terms of their ability to stabilize HIF-α should prompt caution whenever assuming HIF-α stabilization as a universal pathobiological driver of RCC progression [66]. Irinotecan is a camptothecin-derived prodrug converted to its active metabolite SN-38, characterized by low solubility and tolerability, which limits its widespread use in humans, with the notable exception of CRC. To overcome these limitations, a new water-soluble polyethyleneglycol/SN38 conjugate (EZN-2208) was developed, demonstrating a favorable pharmacokinetic profile and enhanced tumor retention [68,69]. A single intravenous injection of EZN-2208 effectively downregulated HIF-1α and target gene transactivation while displaying favorable antitumor and AA effects compared with irinotecan in glioblastoma xenografts [68].