Active Tumoral/Tumor Environmental Dual-Targeting by Non-Covalently Arming with Trispecific Antibodies or Dual-Bispecific Antibodies on Docetaxel-Loaded mPEGylated Nanocarriers to Enhance Chemotherapeutic Efficacy and Minimize Systemic Toxicity

Wei Jie Cheng, Shyr Yi Lin, Michael Chen, Ling Chun Chen, Hsiu O. Ho, Kuo Hsiang Chuang, Ming Thau Sheu

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. Methods: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. Results: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. Conclusion: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.

Original languageEnglish
Pages (from-to)4017-4030
Number of pages14
JournalInternational Journal of Nanomedicine
Volume16
DOIs
Publication statusPublished - 2021

Keywords

  • Animals
  • Antibodies, Bispecific/administration & dosage
  • Antineoplastic Agents, Immunological/administration & dosage
  • Cancer-Associated Fibroblasts/drug effects
  • Cell Line, Tumor
  • Coculture Techniques
  • Docetaxel/administration & dosage
  • Drug Carriers/administration & dosage
  • Drug Delivery Systems/methods
  • ErbB Receptors/antagonists & inhibitors
  • Humans
  • Injections, Intradermal
  • Lecithins/chemistry
  • Male
  • Mice, Nude
  • Micelles
  • Particle Size
  • Polyethylene Glycols/chemistry
  • Rats, Sprague-Dawley
  • Tumor Microenvironment/drug effects
  • Xenograft Model Antitumor Assays

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