Abstract
Complex cell cultures are more representative of in vivo conditions than conventionally used monolayer cultures, and are hence being investigated for predictive screening of therapeutic agents. Poly lactide co-glycolide (PLGA) polymer is frequently used in the development of porous substrates for complex cell culture. Substrates or scaffolds with highly interconnected, micrometric pores have been shown to positively impact tissue model formation by enhancing cell attachment and infiltration. We report a novel alginate microsphere (AMS)-based controlled pore formation method for the development of porous, biodegradable PLGA microspheres (PPMS), for tissue engineered lung tumor model development. The AMS porogen, non-porous PLGA microspheres (PLGAMS) and PPMS had spherical morphology (mean diameters: 10.3 ± 4, 79 ± 21.8, and 103 ± 30 μm, respectively). The PPMS had relatively uniform pores and a porosity of 45.5%. Degradation studies show that PPMS effectively maintained their structural integrity with time whereas PLGAMS showed shrunken morphology. The optimized cell seeding density on PPMS was 25 × 103 cells/mg of particles/well. Collagen coating on PPMS significantly enhanced the attachment and proliferation of co-cultures of A549 lung adenocarcinoma and MRC-5 lung fibroblast cells. Preliminary proof-of-concept drug screening studies using mono- and combination anti-cancer therapies demonstrated that the tissue-engineered lung tumor model had a significantly higher resistance to the tested drugs than the monolayer co-cultures. These studies indicate that the PPMS with controllable pore diameters may be a suitable platform for the development of complex tumor cultures for early in vitro drug screening applications.
Highlights
According to American Cancer Society estimates, lung cancer is the most commonly diagnosed human cancer, with 228,150 new cases (116,440 in men and 111,710 in women) and 142,670 deaths (76,650 in men and 66,020 in women) expected from this condition in 2019 (Siegel et al, 2019)
Energy-dispersive X-ray spectroscopy (EDS) spectra of PPMS without EDTA treatment showed the presence of prominent Ca++ ions peaks whereas the EDTA treated PPMS did not show the presence of Ca++ peak which confirms the efficient digestion of alginate microsphere (AMS) (Figures 3C,D)
PPMS have been used in various research applications, we report an innovative method of safe and controlled pore formation using AMS and EDTA on PLGA microspheres
Summary
According to American Cancer Society estimates, lung cancer is the most commonly diagnosed human cancer, with 228,150 new cases (116,440 in men and 111,710 in women) and 142,670 deaths (76,650 in men and 66,020 in women) expected from this condition in 2019 (Siegel et al, 2019). The differences in the outcomes can be partly attributed to the fact that currently available in vitro cancer models fail to recapitulate clinical cancer conditions, and often provide inaccurate results during drug development. A major barrier to cancer drug discovery today, is the lack of predictive experimental in vitro human tumor models for early screening of promising drug candidates
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