CRLX101, a Nanoparticle–Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α

Abstract

Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared to standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF-1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil (5-FU) producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared to CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567).

Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer

“…Therefore, novel anticancer strategies should include immunomodulatory approaches to subvert the tolerance to Nevertheless, a deep understanding of the tumor microenvironment is obligatory to overcome the related obstacles, as the entry and retention of NPs into the tumors, their fate and functionality as well as the challenging clinical translation in humans due to individual differences among patients, and tumors' heterogeneity [46]. Currently, most of the nanostrategies to enhance radiotherapeutic effects relies on the combination with chemotherapeutic agents [47,48], with several clinical trials ongoing [49]; anti-vascular agents [50]; radiosensitizers such as camptothecin [51], DNA repair inhibitors [52] and Pi3K inhibitors [53], which are generally very toxic when delivered systemically in their free forms. Also, the use of inorganic NPs as radiosensitizers has been extensively reported [54,55], despite remaining a challenge for clinical translation.…”

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

“…Up to now, various kinds of nanoparticles formulation of radiosensitive drugs for increasing the efficacy of RT have been designed . For example, based on the effective radiosensitization effect of chemodrug CDDP, Fan et al designed rattle‐structured multifunctional upconversion core/porous silica shell nanotheranostics (UCSNs) to deliver CDDP into tumor cells for achieving chemotherapy/RT synergetic treatment .…”

The Rational Design and Biological Mechanisms of Nanoradiosensitizers

“…A series of polymer NPs can be used as drug carriers to enhance the radiosensitization effect by promoting DNA damage. Polymeric NPs containing camptothecin (CRLX101, 20-30 nm) promoted the formation and persistence of radiation-induced DSBs and inhibited radiation-induced HIF1α activation, which resulted in enhanced radiosensitization of HT-29 cells and xenograft models [101]. Irradiation can induce site-specific expression of receptors in tumor cells, such as tax-interaction protein 1 (TIP-1).…”