Triple-negative breast cancer (TNBC) accounts for 10-20% of breast cancer patients and is incompatible with most therapeutic methods currently available. While many breast cancers can be treated with receptor-targeted therapies, TNBC lacks the estrogen receptors, progesterone receptors, and HER2 proteins typically present in other types of breast cancer. In addition, hypoxia is a common characteristic found amongst the microtumor environments of various cancer types, including TNBC, as a result of the tumors consuming ambient oxygen resources. Although hypoxia is a common feature in cancer spheroids, breast cancer therapies using nanoparticle drug delivery have yet to be extensively explored under hypoxic (1% oxygen) environments in 3D. It is essential to understand the difference between 2D models and ultra-large 3D models during hypoxia and normoxia (21% oxygen) in order to determine which model more closely mimics a microtumor environment. In these hypoxic environments, the androgen receptors (AR) are resistant to conventional chemotherapeutic drugs that target these receptors, therefore having little effect on reducing the tumor size. Here we show that drug penetration and diffusion in hypoxia environments lead to dampening the therapeutic effects for the drugs doxorubicin, DoxovesTM, Dox-NPⓇ, and Enzalutamide. As expected Breast cancer cell lines, MDA-MB-231 and MCF-7 both exhibited proliferating cellular activity and appearance in normoxic conditions. While in hypoxic, invasive phenotypes which more precisely exhibited the characteristics and behaviors of cancer cells in vivo were seen in control cells. Drug-treated cells in hypoxic conditions experienced cell shape and morphology changes, some more significant than others as some behaved likewise in normoxia. There was however a significant discrepancy between cell viability, as hypoxia conditions lead to decreasing cell viability. Our results demonstrate that phenotype alterations caused by the hypoxia environment influence the therapeutic effectiveness of each drug as the cancer cells are characteristically behaving differently. Our results will provide a better understanding of drug-loaded nanoparticles’ efficacy and cell viability in a hypoxic environment. We will seek to further border scientific knowledge of the effects of dual targeting AR and hypoxia-inducible factor 1α-related pathways in breast cancer cells. We anticipate our research will help open new horizons for multimodal and dual-targeting drug therapies for breast cancer.