Nano-Hydroxyapatite/PLGA Mixed Scaffolds as a Tool for Drug Development and to Study Metastatic Prostate Cancer in the Bone

Abstract

(1) Background: Three-dimensional (3D) in vitro, biorelevant culture models that recapitulate cancer progression can help elucidate physio-pathological disease cues and enhance the screening of more effective therapies. Insufficient research has been conducted to generate in vitro 3D models to replicate the spread of prostate cancer to the bone, a key metastatic site of the disease, and to understand the interplay between the key cell players. In this study, we aim to investigate PLGA and nano-hydroxyapatite (nHA)/PLGA mixed scaffolds as a predictive preclinical tool to study metastatic prostate cancer (mPC) in the bone and reduce the gap that exists with traditional 2D cultures. (2) Methods: nHA/PLGA mixed scaffolds were produced by electrospraying, compacting, and foaming PLGA polymer microparticles, +/− nano-hydroxyapatite (nHA), and a salt porogen to produce 3D, porous scaffolds. Physicochemical scaffold characterisation together with an evaluation of osteoblastic (hFOB 1.19) and mPC (PC-3) cell behaviour (RT-qPCR, viability, and differentiation) in mono- and co-culture, was undertaken. (3) Results: The results show that the addition of nHA, particularly at the higher-level impacted scaffolds in terms of mechanical and degradation behaviour. The nHA 4 mg resulted in weaker scaffolds, but cell viability increased. Qualitatively, fluorescent imaging of cultures showed an increase in PC-3 cells compared to osteoblasts despite lower initial PC-3 seeding densities. Osteoblast monocultures, in general, caused an upregulation (or at least equivalent to controls) in gene production, which was highest in plain scaffolds and decreased with increases in nHA. Additionally, the genes were downregulated in PC3 and co-cultures. Further, drug toxicity tests demonstrated a significant effect in 2D and 3D co-cultures. (4) Conclusions: The results demonstrate that culture conditions and environment (2D versus 3D, monoculture versus co-culture) and scaffold composition all impact cell behaviour and model development.

Current Advances in the Use of Tissue Engineering for Cancer Metastasis Therapeutics

“…In a recent work, 3D PLGA and nanohydroxyapatite were fabricated using electro-spraying, compacting, and foaming techniques. These scaffolds were used to evaluate drug toxicity and PC3 cells’ proliferation in bone-like environments [ 112 ]. Researchers have also impregnated curcumin into poly(lactic-co-glycolic) acid (PLGA) scaffolds [ 113 ].…”

“…Table 2 summarizes the various polymeric, composite, and biological materials that are used in the development of tissue-engineered scaffolds to mimic the bone site of prostate cancer metastasis. PLA-PLGA PLGA and nanohydroxyapatite scaffolds PC3 [112] Curcumin-impregnated poly(lactic-co-glycolic) acid (PLGA) scaffolds [113] PEG Polyethylene glycol hydrogel PCa and LNCaP [114] Scaffolds fabricated with poly(ethylene glycol)-fibrinogen matrix supplemented with poly(ethylene glycol)-diacrylate PC3 with BJ-5ta fibroblasts [115] One of the early studies reported the development of a three-dimensional type I collagen gel cell culture system with co-culture of human MG-63 osteoblast-like cells with highly metastatic human PC3 prostate cancer cells. This model was used to study the pathophysiology of prostate cancer at the bone [97].…”

Nanostructured Biomaterials in Tumor Tissue Engineering: Regenerative Medicine and Immunotherapies

“…In a recent study by Dozzo et al [94], 3D scaffolds of nano-hydroxyapatite (nHA)/PLGA were developed to evaluate the effect of scaffold composition on the metastatic potential of prostate cancer cells in the bone. The presence of nHA in the 3D scaffolds highly affected the mechanical properties resulting in weaker structures, and the degradation behavior promoting cell viability.…”

Let’s Go 3D! New Generation of Models for Evaluating Drug Response and Resistance in Prostate Cancer

“…Finally, an important feature to investigate during PC development and metastasis is the spread of PC to the bone [ 196 ]. PC most often metastasizes to the bone, and this is the primary cause of PC-related morbidity and mortality [ 197 ].…”