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

Abstract

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

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

“…Studies with liposome nanoparticles suggest that allometric scaling based on body weight works reasonably well (20). However, the AUC of a polymer-based nanoparticle of camptothecin (CRLX101) scaled best across species based on body-surface area (21). Here, we find that allometric scaling across species best correlates with body weight rather than with body-surface area.…”

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing

“…The pharmacologically active component of CRLX101-CPT-has intrinsic fluorescence (Excitation max = 370 nm and Emission max = 435 nm), and can be used for the detection of CRLX101 in tissue via fluorescence microscopy (5,6,8). Fig.…”

“…CRLX101 first enters mouse model xenografts within 6 h of i.v. administration and slowly diffuses away from blood vessels and deeper into tumors over several days (5). Therefore, the quantity of CPT present in the patient samples 24 h after treatment may strongly depend on location of the biopsy relative to vasculature.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…CRLX101 has also been shown to be a radiosensitiser in an animal model of head and neck cancer, suggesting that CRLX101 may achieve clinical utility in combination with radiotherapy. 6,134 It has further been demonstrated in preclinical studies that CRLX101 is a potent and durable inhibitor of HIF-1a. 7,149 The camptothecin family of compounds (including CPT and TPT) have been described as inhibitors of HIF-1a in the past.…”

“…This unique feature of CRLX101 grants favourable pharmacokinetics with minimal a toxicity profile (Figure 8.2). 1,133,134 Lactone ring stabilisation is a key feature of CRLX101, since CPT is conjugated to the polymer in such a way as to protect the lactone ring from being opened up. CPT is functionalised to form an ester bond at the 20-hydroxyl group and a glycine linker was used to provide optimal antitumour efficacy with low toxicity.…”