Drug delivery into multicellular tumor spheroids (MCTS) by polymeric micelles

摘要

Introduction: Polymeric micelles have been used as promising nano drug carriers for cancer therapies. Two-dimensionally (2D) cultured tumor cells have been used as a standard model to study nanoparticle uptake and drug delivery in vitro. However, 2D cell models cannot represent all the features of real tumors and may lead to poor translation between the 2D monolayer in vitro results and in vivo tests. Multicellular tumor spheroid (MCTS) is considered as the first choice of 3D solid tumor models. Most MCTS exhibit higher similarity to in vivo tumor tissues than monolayer cells, and therefore have recently gained increasing recognition in biomedical research. More attempts have been made in using MCTS to investigate cellular responses to nano drug carriers for therapeutic applications. Interactions between nanoparticles and MCTS and the underlying mechanisms remain largely unknown. In this study, we investigated drug delivery efficiencies, anti-tumor and anti-metastasis activities of polymeric micelles with MCTS models. Materials and Methods: The multicellular tumor spheroids were prepared by culturing tumor cell lines with a hanging drop method or a liquid overlay method. Micelles were prepared by dialysis the block copolymers against water. Doxorubicin or Ruthenium-based anti-metastatic drug (RAPTA-C) was loaded into micelles. The MCTS were treated with micelles and the penetration, drug delivery, anti-tumor and anti-metastasis effects were investigated. Results and Discussion: HPMA-based polymeric micelles penetrated deeper and delivered more drug into MCTS than did free drug. The penetration of HPMA micelles depended more on transcellular transport than on diffusion through ECM between the cells. Stabilization via shell crosslinking improved the drug delivery efficiency of micelles in MCTS. RAPTA-C conjugated polymeric micelles showed improved anti-metastatic effects compared with free RAPTA-C for 2D cultured tumor cells. However, the anti-metastatic ability of RAPTA-C polymeric micelles exploited with MCTS showed contrary results to 2D cell culture models. Conclusion: Polymeric micelles improved the delivery of different drugs into MCTS compared with drugs in their free forms. However, the results with MCTS models were not inconsistent with those obtained from 2D cell models. Modifications to improve micellar delivery efficiency are highly desired to provide the greatest clinical benefit to cancer therapy. Introducing MCTS models into the evaluation of nanoparticles will be of great interest for the design of nano drug carriers.