John D Schneible1, Ashlyn T Young2, M A Daniele3,4, S Menegatti5,6. 1. Department of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Raleigh, North Carolina, USA. 2. Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina, Chapel Hill, North Carolina, USA. 3. Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina, Chapel Hill, North Carolina, USA. mdaniel6@ncsu.edu. 4. Department of Electrical and Computer Engineering, North Carolina State University, 890 Oval Drive, Raleigh, North Carolina, USA. mdaniel6@ncsu.edu. 5. Department of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Raleigh, North Carolina, USA. smenega@ncsu.edu. 6. Biomanufacturing Training and Education Center, North Carolina State University, 850 Oval Dr, Raleigh, North Carolina, USA. smenega@ncsu.edu.
Abstract
PURPOSE: This study aimed to develop a hydrogel system for treating aggressive triple negative breast cancer (TNBC) via kinetically-controlled delivery of the synergistic drug pair doxorubicin (DOX) and gemcitabine (GEM). A 2D assay was adopted to evaluate therapeutic efficacy by determining combination index (CI), and a 3D assay using cancer spheroids was implemented to assess the potential for translation in vivo. METHODS: The release of DOX and GEM from an acetylated-chitosan (ACS, degree of acetylation χAc = 40 ± 5%) was characterized to identify a combined drug loading that affords release kinetics and dose that are therapeutically synergistic. The selected DOX/GEM-ACS formulation was evaluated in vitro with 2-D and 3-D models of TNBC to determine the combination index (CI) and the tumor volume reduction, respectively. RESULTS: Therapeutically desired release dosages and kinetics of GEM and DOX were achieved. When evaluated with a 2-D model of TNBC, the hydrogel afforded a CI of 0.14, indicating a stronger synergism than concurrent administration of DOX and GEM (CI = 0.23). Finally, the therapeutic hydrogel accomplished a notable volume reduction of the cancer spheroids (up to 30%), whereas the corresponding dosages of free drugs only reduced growth rate. CONCLUSIONS: The ACS hydrogel delivery system accomplishes drug release kinetics and molar ratio that affords strong therapeutically synergism. These results, in combination with the choice of ACS as affordable and highly abundant source material, provide a strong pre-clinical demonstration of the potential of the proposed system for complementing surgical resection of aggressive solid tumors.
PURPOSE: This study aimed to develop a hydrogel system for treating aggressive triple negative breast cancer (TNBC) via kinetically-controlled delivery of the synergistic drug pair doxorubicin (DOX) and gemcitabine (GEM). A 2D assay was adopted to evaluate therapeutic efficacy by determining combination index (CI), and a 3D assay using cancer spheroids was implemented to assess the potential for translation in vivo. METHODS: The release of DOX and GEM from an acetylated-chitosan (ACS, degree of acetylation χAc = 40 ± 5%) was characterized to identify a combined drug loading that affords release kinetics and dose that are therapeutically synergistic. The selected DOX/GEM-ACS formulation was evaluated in vitro with 2-D and 3-D models of TNBC to determine the combination index (CI) and the tumor volume reduction, respectively. RESULTS: Therapeutically desired release dosages and kinetics of GEM and DOX were achieved. When evaluated with a 2-D model of TNBC, the hydrogel afforded a CI of 0.14, indicating a stronger synergism than concurrent administration of DOX and GEM (CI = 0.23). Finally, the therapeutic hydrogel accomplished a notable volume reduction of the cancer spheroids (up to 30%), whereas the corresponding dosages of free drugs only reduced growth rate. CONCLUSIONS: The ACS hydrogel delivery system accomplishes drug release kinetics and molar ratio that affords strong therapeutically synergism. These results, in combination with the choice of ACS as affordable and highly abundant source material, provide a strong pre-clinical demonstration of the potential of the proposed system for complementing surgical resection of aggressive solid tumors.
Entities:
Keywords:
Chitosan hydrogel; combination chemotherapy; drug delivery; drug synergism; tumor spheroids
Authors: Douglas R Vogus; Michael A Evans; Anusha Pusuluri; Alexandra Barajas; Mengwen Zhang; Vinu Krishnan; Maksymilian Nowak; Stefano Menegatti; Matthew E Helgeson; Todd M Squires; Samir Mitragotri Journal: J Control Release Date: 2017-08-18 Impact factor: 9.776