The first‐line treatment of advanced and metastatic human epidermal growth factor receptor type 2 (HER2+) breast cancer requires two HER2‐targeting antibodies (trastuzumab and pertuzumab) and a taxane (docetaxel or paclitaxel). The three‐drug regimen costs over $320,000 per treatment course, requires a 4 h infusion time, and has many adverse side effects, while achieving only 18 months of progression‐free survival. To replace this regimen, reduce infusion time, and enhance efficacy, a single therapeutic is developed based on trastuzumab‐conjugated nanoparticles for co‐delivering docetaxel and siRNA against HER2 (siHER2). The optimal nanoconstruct has a hydrodynamic size of 100 nm and specifically treats HER2+ breast cancer cells over organ‐derived normal cells. In a drug‐resistant orthotopic HER2+ HCC1954 tumor mouse model, the nanoconstruct inhibits tumor growth more effectively than the docetaxel and trastuzumab combination. When coupled with microbubble‐assisted focused ultrasound that transiently disrupts the blood brain barrier, the nanoconstruct inhibits the growth of trastuzumab‐resistant HER2+ BT474 tumors residing in the brains of mice. The nanoconstruct has a favorable safety profile in cells and in mice. Combination therapies have become the cornerstone of cancer treatment and this versatile nanoparticle platform can co‐deliver multiple therapeutic types to ensure that they reach the target cells at the same time to realize their synergy.
The systemic delivery of doxorubicin (DOX) to treat osteosarcoma requires an adequate drug concentration to be effective, but in doing so, it raises the risk of increasing organ off-target toxicity and developing drug resistance. Herein, this study reveals a multiple therapeutic nanocarrier delivery platform that overcomes off-target toxicity by providing good specificity and imparting enhanced tumor penetration in a three-dimensional (3D) human MG-63 spheroid model. By synthesizing PEG-PLGA nanoparticles by the double emulsion method, encapsulating DOX and Na131I in the inner core, and conjugating with an epidermal growth factor receptor (EGFR) antibody, it is intended to specifically target human MG-63 cells. The nanocarrier is biocompatible with blood and has good stability characteristics. Na131I encapsulation efficiency was >96%, and radiochemical purity was >96% over 96 h. A DOX encapsulation efficacy of ~80% was achieved, with a drug loading efficiency of ~3%, and a sustained DOX release over 5 days. The nanocarrier EGFR antibody achieved a ~80-fold greater targeting efficacy to MG-63 cells (EGFR+) than fibroblast cells (EGFR−). The targeted multiple therapeutic DIE-NPs have a higher penetration and uptake of Na131I to the 3D model and a ~3-fold higher cytotoxicity than the DOX monotherapy (D-NPs). The co-administration of DOX and Na131I (DIE-NPs) disrupts DNA repair and generates free radicals resulting in DNA damage, triggering the activation of apoptosis pathways. This leads to inhibition of MG-63 cell proliferation and promotes cell cycle arrest in the G0/G1 phase. Furthermore, the PEGylated anti-EGFR functionalized DIE-NPs were found to be biocompatible with red blood cells and to have no adverse effects. This anti-EGFR targeted multifunctional I-131 radio-nanotherapeutic signifies a customizable specific targeted treatment for osteosarcoma.
Currently, breast-cancer treatment has a number of adverse side effects and is associated with poor rates of progression-free survival. Therefore, a radiolabeled anti-EpCAM targeted biomimetic coated nanocarrier (EINP) was developed in this study to overcome some of the treatment challenges. The double emulsion method synthesized the poly(lactic-co-glycolic acid) (PLGA) nanoparticle with Na131I entrapped in the core. The PLGA nanoparticle was coated in human red blood cell membranes and labeled with epithelial cell adhesion molecule (EpCAM) antibody to enable it to target EpCAM overexpression by breast-cancer cells. Characterization determined the EINP size as 295 nm, zeta potential as −35.9 mV, and polydispersity as 0.297. EINP radiochemical purity was >95%. Results determined the EINP efficacy against EpCAM positive MCF-7 breast cancer at 24, 48, and 72 h were 69.11%, 77.84%, and 74.6%, respectively, demonstrating that the EINPs achieved greater cytotoxic efficacy supported by NIS-mediated Na131I uptake than the non-targeted 131INPs and Na131I. In comparison, fibroblast (EpCAM negative) treated with EINPs had significantly lower cytotoxicity than Na131I and 131INPs (p < 0.05). Flow cytometry fluorescence imaging visually signified delivery by EINPs specifically to breast-cancer cells as a result of anti-EpCAM targeting. Additionally, the EINP had a favorable safety profile, as determined by hemolysis.
The development of biomimetic drug delivery systems for biomedical applications has attracted significant research attention. As the use of cell membrane as a surface coating has shown to be a promising platform for several disease treatments. Cell-membrane-coated nanoparticles exhibit enhanced immunocompatibility and prolonged circulation time. Herein, human red blood cell (RBC) membrane-cloaked nanoparticles with enhanced targeting functionality were designed as a targeted nanotheranostic against cancer. Naturally, derived human RBC membrane modified with targeting ligands coated onto polymeric nanoparticle cores containing both chemotherapy and imaging agent. Using epithelial cell adhesion molecule (EpCAM)-positive MCF-7 breast cancer cells as a disease model, the nature-inspired targeted theranostic human red blood cell membrane-coated polymeric nanoparticles (TT-RBC-NPs) platform was capable of not only specifically binding to targeted cancer cells, effectively delivering doxorubicin (DOX), but also visualizing the targeted cancer cells. The TT-RBC-NPs achieved an extended-release profile, with the majority of the drug release occurring within 5 days. The TT-RBC-NPs enabled enhanced cytotoxic efficacy against EpCAM positive MCF-7 breast cancer over the non-targeted NPs. Additionally, fluorescence images of the targeted cancer cells incubated with the TT-RBC-NPs visually indicated the increased cellular uptake of TT-RBC-NPs inside the breast cancer cells. Taken together, this TT-RBC-NP platform sets the foundation for the next-generation stealth theranostic platforms for systemic cargo delivery for treatment and diagnostic of cancer.
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