The Impact of Polymer Size and Cleavability on the Intravenous Pharmacokinetics of PEG-Based Hyperbranched Polymers in Rats

Abstract

A better understanding of the impact of molecular size and linkers is important for PEG-based hyperbranched polymers (HBPs) intended as tailored drug delivery vehicles. This study aimed to evaluate the effects of crosslinker chemistry (cleavable disulphide versus non-cleavable ethylene glycol methacrylate (EGDMA) linkers) and molecular weight within the expected size range for efficient renal elimination (22 vs. 48 kDa) on the intravenous pharmacokinetic and biodistribution properties of 89Zr-labelled HBPs in rats. All HBPs showed similar plasma pharmacokinetics over 72 h, despite differences in linker chemistry and size. A larger proportion of HBP with the cleavable linker was eliminated via the urine and faeces compared to a similar-sized HBP with the non-cleavable linker, while size had no impact on the proportion of the dose excreted. The higher molecular weight HBPs accumulated in organs of the mononuclear phagocyte system (liver and spleen) more avidly than the smaller HBP. These results suggest that HBPs within the 22 to 48 kDa size range show no differences in plasma pharmacokinetics, but distinct patterns of organ biodistribution and elimination are evident.

Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation

“…A radiolabelled HBP (size: 8 nm, zeta potential: −0.1 mV) targeted with an anti-PEG/anti-TAG72 bispecific antibody (BsAb) was found to accumulate in the spleen, liver, and kidneys roughly 4, 3.5, and 3 times more than at the tumour. 97 Similar results have been observed in systems containing dendrimers, 98–101 micelles, 102,103 and polymeric supramolecular assemblies 104 with favourable physiochemical properties. Similarly poor biological behaviour was observed for a PEGylated liposome (size: 105 nm, zeta potential: −8.0 mV) with no surface targeting moieties which was reported to have a plasma half-life of only 5.8 hours.…”

Thermoresponsive Triblock Copolymers as Widely Applicable 19F Magnetic Resonance Imaging Tracers

“…Nevertheless, triblock A- block -B- block -A or B- block -A- block -B copolymers have important advantages since they can take both states, including assembled particles and physically cross-linked gels as a function of their concentration. Together with feasible synthetic approaches, triblock copolymers can be seen as a smart toolbox, which covers almost the whole spectrum of potential medical applications of thermoresponsive/amphiphilic polymers. − Considering the non-biodegradability of polyacrylamides, these polymers in the form of particles or hydrogels can dissolve into individual polymer chains over a specific period of time, which can then be eliminated by renal excretion and therefore do not accumulate in the body. ,− …”

Nanoscale Coordination Polymers for Combined Chemotherapy and Photodynamic Therapy of Metastatic Cancer

“…Many small molecule drugs have nonspecific distributions throughout the body, rapid clearance, and low accumulation at tumor sites when given systemically. − After intravenous injection to tumor-bearing mice, carb/pyro prolongs carb blood circulation compared to free carb. This enhanced pharmacokinetics of carb/pyro is attributed to the appropriate and uniformed particle size (∼120 nm), PEG2K coating, − and structural stability of NCPs in extracelluar environments. The fact that PDT can cause vascular damage may contribute to the substantially enhanced drug delivery to tumors .…”