Synchronized Ratiometric Codelivery of Metformin and Topotecan through Engineered Nanocarrier Facilitates In Vivo Synergistic Precision Levels at Tumor Site

Venkatesh Teja Banala, Shweta Sharma, Puja Barnwal, Sandeep Urandur, Ravi P. Shukla, Naseer Ahmad, Naresh Mittapelly, Gitu Pandey, Monika Dwivedi, Navodayam Kalleti, Kalyan Mitra, Srikanta Kumar Rath, Ritu Trivedi, Prabhat Ranjan Mishra

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The combination of metabolic modulators with chemotherapy holds vast promise for effective inhibition of tumor progression and invasion. Herein, a ratiometric codelivery platform is developed for metformin (MET), a known metabolic modulator and topotecan (TPT), a chemotherapeutic drug, by engineering lipid bilayer–camouflaged mesoporous silica nanoparticles (LB-MSNs). In an attempt to deliver and maintain high tumor site concentrations of MET and TPT, a novel ion pairing–assisted loading procedure is developed using pamoic acid (PA) as an in situ trapping agent. PA, a hydrophobic counterion, increases the hydrophobicity of MET and TPT and facilitates MSNs with exceptionally high payload capacity (>40 and 32 wt%, respectively) and controlled release profile. Further, the synergy between MET and TPT determined by a modeling approach helps to afford synchronized delivery of both the drugs. Coloaded MET and TPT LB-MSNs present synergistic cytotoxicity against MDA-MB-231/4T1 cells and effectively promote apoptosis via mitochondrial membrane depolarization and cell cycle arrest. Extended pharmacokinetic profiles in preclinical models with fourfold to sevenfold longer circulation half-life and 7.5–100 times higher tumor site concentrations correspond to a significant increase in pharmacodynamic efficacy. Taken together, the developed codelivery approach effectively addresses the challenges in the chemotherapeutic efficacy of MET and TPT collectively.

Original languageEnglish
Article number1800300
JournalAdvanced healthcare materials
Volume7
Issue number19
DOIs
StatePublished - 10 Oct 2018
Externally publishedYes

Keywords

  • breast cancer
  • codelivery
  • ion pairing
  • mesoporous silica nanoparticles
  • synergy

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