Decreased nonspecific adhesivity, receptor-targeted therapeutic nanoparticles for primary and metastatic breast cancer

Abstract

Development of effective tumor cell–targeted nanodrug formulations has been quite challenging, as many nanocarriers and targeting moieties exhibit nonspecific binding to cellular, extracellular, and intravascular components. We have developed a therapeutic nanoparticle formulation approach that balances cell surface receptor-specific binding affinity while maintaining minimal interactions with blood and tumor tissue components (termed “DART” nanoparticles), thereby improving blood circulation time, biodistribution, and tumor cell–specific uptake. Here, we report that paclitaxel (PTX)–DART nanoparticles directed to the cell surface receptor fibroblast growth factor–inducible 14 (Fn14) outperformed both the corresponding PTX-loaded, nontargeted nanoparticles and Abraxane, an FDA-approved PTX nanoformulation, in both a primary triple-negative breast cancer (TNBC) model and an intracranial model reflecting TNBC growth following metastatic dissemination to the brain. These results provide new insights into methods for effective development of therapeutic nanoparticles as well as support the continued development of the DART platform for primary and metastatic tumors.

Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies

“…ITEM4 or Fn14 monoclonal antibody binds specifically human as well as murine Fn14 extracellular domain. Paclitaxel loaded-DART nanoparticles is an FDA-approved nanoformulation for TNBC models as well as an intracranial model thus indicating that there is TNBC growth which is followed by metastatic propagation to the brain [207]. Furthermore, Xu et al developed Hyaluronic acid-coated pH sensitive poly (Beta-amino ester) nanoparticles for the delivery of both embelin (anti-cancer drug) as well as pTRAIL (tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasmid for anti-TNBC efficacy [208].…”

Nanomedicines: Nano based Drug Delivery Systems Challenges and Opportunities

“…Another obstacle for tumor-targeted nanoformulations in particular is the heterogeneity and heterogeneous nature of tumors. Different gene expression profiles, molecular patterns and degree of drug resistance between different tumors may impede penetration and decrease the efficacy of tumor-targeted NPs [114,115]. This challenge could lead to an unsuccessful clinical trial (despite promising animal preclinical data) and to rejection of the nanoformulations examined.…”

“…This challenge could lead to an unsuccessful clinical trial (despite promising animal preclinical data) and to rejection of the nanoformulations examined. Relevant drug penetration into tumors, the efficacy of the release of drugs into the target cells, and the quality of the drug loaded nanoparticles, are other factors that involve a precise professional experimentation [114]. Owing to time and money problems, this comprehensive research may not be possible in all biomedical laboratories which itself is another concern.…”

Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies

“…In one study, a PTX loaded nanoscale polymer was designed to specifically target the cell surface receptor Fn14. Targeting to Fn14 enhanced the inhibition of breast tumors and significantly minimized the nonspecific binding to blood serum proteins and tumor tissue components [ 115 ]. Another study reported an RNA four-way junction NPs with ultra-thermodynamic stability covalently loaded with high-density PTX (RNA-PTX) for targeted cancer therapy.…”