Effect of particle size on the biodistribution, toxicity, and efficacy of drug-loaded polymeric nanoparticles in chemoradiotherapy

Abstract

Nanoparticle (NP) therapeutics can improve the therapeutic index of chemoradiotherapy (CRT). However, the effect of NP physical properties, such particle size, on CRT is unknown. To address this, we examined the effects of NP size on biodistribution, efficacy and toxicity in CRT. PEG-PLGA NPs (50, 100, 150 nm mean diameters) encapsulating wotrmannin (wtmn) or KU50019 were formulated. These NP formulations were potent radiosensitizers in vitro in HT29, SW480, and lovo rectal cancer lines. In vivo, the smallest particles avoided hepatic and splenic accumulation while more homogeneously penetrating tumor xenografts than larger particles. However, smaller particles were no more effective in vivo. Instead, there was a trend towards enhanced efficacy with medium sized NPs. The smallest KU60019 particles caused more small bowel toxicity than larger particles. Our results showed that particle size significantly affects nanotherapeutics' biodistrubtion and toxicity but does not support the conclusion that smaller particles are better for this clinical application.

Co-delivery of paclitaxel and cisplatin with biocompatible PLGA–PEG nanoparticles enhances chemoradiotherapy in non-small cell lung cancer models

“…15,29–32 Therefore, we examined if our nanoformulations caused undue toxicity to these off-target organs. Although the combination had higher treatment potency in vivo , nephrotoxicity and hepatotoxicity remained low as indicated by normal creatine (Crea), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in the blood (Table S4).…”

“…Since size affects extravasation, this could cause the unequal tumor accumulation of one NP versus the other and shift the ratio of drug dose. 29 Second, the increased drug retention within the dual-drug loaded NPs may allow more of the drug to be delivered to the target site instead of escaping prior to NP permeation into the tumor. 28 Regardless, a full examination of the causative factors for the increased efficacy was outside the scope of this study, but ongoing work within the lab seeks to fully address possible mechanisms.…”

Nanoparticle Drug Delivery Can Reduce the Hepatotoxicity of Therapeutic Cargo

“…The PLGA‐core, PEG‐DSPE‐lecithin shell NPs were synthesized using a nanoprecipitation method . Drugs (Wtmn, CPZ or SN38) and PLGA were dissolved in acetonitrile with a final concentration of 1 mg mL −1 for drugs and 10 mg mL −1 for PLGA.…”

“…Polymeric micelles were employed because polymeric NPs are generally utilized for clinical formulations of hydrophobic/amphiphilic compounds such as CPZ, SN‐38, and Wtmn. In this study, the NPs were formulated using poly(lactic‐ co ‐glycolic acid) (PLGA) as core material for drug encapsulation and the lipid mixture of DSPE‐PEG (1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐ N ‐[carboxy(polyethylene glycol) and lecithin as shell material for the control of drug release ( Figure ) . Characterization of the NPs demonstrated spherical morphology with an average hydrodynamic diameter of 120.8 ± 1.9 nm for CPZ‐loaded NP, 107.5 ± 1.1 nm for Wtmn‐loaded NP, and 43.4 ± 2.6 nm for SN‐38‐loaded NP (Figure S1 and Table S1, Supporting Information).…”

Enhanced Cancer Therapy by Combining Radiation and Chemical Effects Mediated by Nanocarriers

“…Another study with wortmannin was carried out by Caster et al. They investigated whether the size of the particles affects chemo–radiotherapy, evaluating three sizes of methoxypoly(ethylene glycol)‐block‐poly(lactic‐ co ‐glycolic acid) (mPEG‐PLGA) nanocarriers in terms of therapeutic efficacy and toxicity . It is often thought that smaller particles are better due to their longer blood circulation and better tumor distribution.…”