Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

Abstract

Background: The present study focuses on biodistribution profile and pharmacokinetic parameters of EGFR-targeted chitosan nanoparticles (TG CS nanoparticles) for siRNA/cisplatin combination therapy of lung cancer. Material & methods: Mad2 siRNA was encapsulated in EGFR targeted and nontargeted (NTG) CS nanoparticles by electrostatic interaction. The biodistribution of the nanoparticles was assessed qualitatively and quantitatively in cisplatin (DDP) sensitive and resistant lung cancer xenograft model. Results: TG nanoparticles showed a consistent and preferential tumor targeting ability with rapid clearance from the plasma to infiltrate and sustain within the tumor up to 96 h. They exhibit a sixfold higher tumor targeting efficiency compared with the NTG nanoparticles. Conclusion: TG nanoparticles present as an attractive drug delivery platform for RNAi therapeutics against NSCLC.

Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles

“…These nanoparticles show a high polydispersity index (PDI), which is consistent with natural polymers such as chitosan primarily since they have a higher degree of variation in chain length. We have always observed and reported a high PDI for these nanoparticles in all our previous work [[23, 33, 37]] and the same has been reported in literature as well [38, 39]. …”

“…Interestingly, our biodistribution and pharmacokinetic studies using the NTG and TG nanoparticles in the same tumor models revealed that TG system has tumor exposure than the NTG system and also demonstrate better targeting efficiency [37], we do not see a corresponding increase in efficacy. The in vitro data also corroborate that TG nanoparticles are able to internalize more efficiently than the NTG nanoparticles [23].…”

“…In our previous in vitro study, the EGFR-targeted CS nanoparticles demonstrated a very efficient and targeted delivery of the encapsulated Mad2 siRNA in the A549-WT and A549-DDP cells resulting in silencing the expression of Mad2 gene [23]. The pharmacokinetics and biodistribution of these nanoparticles in A549-WT and A549-DDP tumor-bearing mice also demonstrate a higher targeting efficiency and accumulation of the EGFR-peptide modified nanoparticles in comparison to non-targeted nanoparticles [37]. The study confirmed that the presence of the EGFR-targeting peptide leads to a higher tumor exposure and therefore can have tremendous therapeutic potential.…”

“…The PK/PD analysis of these nanoparticles in tumor bearing animals showed a significant concentration of the CS nanoparticles infiltrating into the liver and kidney and therefore a toxic impact to these organs was a major concern [37]. …”

Polymeric Nanoparticle-Mediated Gene Delivery for Lung Cancer Treatment

“…In a different study, EGFR-targeted chitosan nanoparticles successfully delivered a combination of cisplatin and Mad2 siRNA in cisplatin-sensitive and -resistant in vivo lung cancer models. Cisplatin-resistant tumors showed improved tumor inhibition with EGFR-targeted combination therapy, which showed reduced toxicity to normal tissues [119]. …”