Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy.
Harsh conditions of the gastrointestinal tract hinder the oral delivery of many drugs. Developing oral drug delivery systems based on commercially available materials is becoming more challenging due to the demand for simultaneously delivering physicochemically different drugs for treating complex diseases. A novel architecture, namely nanotube-in-microsphere, was developed as a drug delivery platform by encapsulating halloysite nanotubes (HNTs) in a pH-responsive hydroxypropyl methylcellulose acetate succinate polymer using microfluidics. HNTs were selected as orally acceptable clay mineral and their lumen was enlarged by selective acid etching. Model drugs (atorvastatin and celecoxib) with different physicochemical properties and synergistic effect on colon cancer prevention and inhibition were simultaneously incorporated into the microspheres at a precise ratio, with atorvastatin and celecoxib being loaded in the HNTs and polymer matrix, respectively. The microspheres showed spherical shape, narrow particle size distribution and pH-responsive dissolution behavior. This nanotube/pH-responsive polymer composite protected the loaded drugs from premature release at pH⩽6.5, but allowed their fast release and enhanced the drug permeability, and the inhibition of colon cancer cell proliferation at pH 7.4. Overall, the nano-in-micro drug delivery composite fabricated by microfluidics is a promising and flexible platform for the delivery of multiple drugs for combination therapy.



Halloysite nanotubes (HNTs) are attracting increasing attention for drug delivery applications. However, conventional HNTs-based oral drug delivery systems are lack of the capability to precisely control the drug release at a desired site in the gastrointestinal tract. In this study, a nanotube-in-microsphere drug delivery platform is developed by encapsulating HNTs in a pH-responsive polymer using microfluidics. Drugs with different physicochemical properties and synergistic effect on colon cancer therapy were simultaneously incorporated in the microspheres. The prepared microspheres prevented the premature release of the loaded drugs after exposure to the harsh conditions of the gastrointestinal tract, but allowed their simultaneously fast release, and enhanced the drug permeability and the inhibition of colon cancer cell proliferation in response to the colon pH.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Wei
W
Li
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Dongfei
D
Liu
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Hongbo
H
Zhang
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Alexandra
A
Correia
Laboratory of Industrial Physics, Department of Physics, University of Turku, FI-20014 Turku, Finland.
Ermei
E
Mäkilä
Laboratory of Industrial Physics, Department of Physics, University of Turku, FI-20014 Turku, Finland.
Jarno
J
Salonen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Jouni
J
Hirvonen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland. Electronic address: helder.santos@helsinki.fi.
Hélder A
HA
Santos
D000538:Aluminum Silicates; D000069059:Atorvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D018938:Caco-2 Cells; D000068579:Celecoxib / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077215:Clay; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D044085:Microfluidics / Q000379:methods*; D008863:Microspheres; D043942:Nanotubes / Q000737:chemistry* / Q000648:ultrastructure; D010539:Permeability; D011108:Polymers / Q000737:chemistry*
D000538:Aluminum Silicates; D011108:Polymers; D000069059:Atorvastatin; D000068579:Celecoxib; D000077215:Clay
Dual delivery; Halloysite nanotubes; Microfluidics; Oral delivery; pH responsive