Journal
ACS APPLIED BIO MATERIALS
Volume 4, Issue 2, Pages 1450-1460Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsabm.0c01336
Keywords
hypoxia; nanotechnology; polymersomes; targeted drug delivery; nanoparticles
Funding
- NIH (NIGMS) [2R01GM 114080, U54 GM12872]
- NSF EPSCoR Track-1 Cooperative Agreement OIA [1946202]
- NIGMS COBRE award [1P20 GM109024]
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Triple-negative breast cancer (TNBC) is characterized by high recurrence and metastasis, with low vascular oxygen tension promoting resistance to chemotherapy and radiation therapy. The iRGD peptide interacts with the NRP-1 receptor, enhancing tumor penetration. Targeted polymersomes showed promising antitumor activity in TNBC models, with potential as drug carriers for TNBC treatment.
High recurrence and metastasis to vital organs are the major characteristics of triple-negative breast cancer (TNBC). Low vascular oxygen tension promotes resistance to chemo- and radiation therapy. Neuropilin-1 (NRP-1) receptor is highly expressed on TNBC cells. The tumor-penetrating iRGD peptide interacts with the NRP-1 receptor, triggers endocytosis and transcytosis, and facilitates penetration. Herein, we synthesized a hypoxia-responsive diblock PLA-diazobenzene-PEG copolymer and prepared self-assembled hypoxia-responsive polymersomes (Ps) in an aqueous buffer. The iRGD peptide was incorporated into the polymersome structure to make hypoxia-responsive iRGD-conjugated polymersomes (iPs). Doxorubicin (DOX) was encapsulated in the polymersomes to prepare both targeted and nontargeted hypoxia-responsive polymersomes (DOX-iPs and DOX-Ps, respectively). The polymeric nanoparticles released less than 30% of their encapsulated DOX within 12 h under normoxic conditions (21% oxygen), whereas under hypoxia (2% oxygen) doxorubicin release remarkably increased to over 95%. The targeted polymersomes significantly decreased TNBC cells' viability in monolayer and spheroid cultures under hypoxia compared to normoxia. Animal studies displayed that targeted polymersomes significantly diminished tumor growth in xenograft nude mice. Overall, the targeted polymersomes exhibited potent antitumor activity in monolayer, spheroid, and animal models of TNBC. With further developments, the targeted nanocarriers discussed here might have the translational potential as drug carriers for the treatment of TNBC.
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