Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting

Abstract

The low therapeutic index of conventional chemotherapy and poor prognosis of patients diagnosed with metastatic cancers are prompting clinicians to adopt newer strategies to simultaneously detect cancer lesions at an early stage and to precisely deliver anticancer drugs to tumor sites. In this study, we employed a novel strategy to engineer a polyvalent theranostic nanocarrier consisting of superparamagnetic iron oxide nanoparticle core (SPIONs) decorated with folic acid-polyamidoamine dendrimers surface (FA-PAMAM). In addition, a highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin (CDF) was coloaded in the FA-PAMAM dendrimer to increase its solubility and assess its therapeutic potentials. The resulting targeted nanoparticles (SPIONs@FA-PAMAM-CDF) exhibited high MR contrast. When tested on folate receptor overexpressing ovarian (SKOV3) and cervical (HeLa) cancer cells, the CDF loaded targeted nanoformulations showed higher accumulation with a better anticancer activity as compared to the nontargeted counterparts, possibly due to multivalent folate receptor binding interaction with cells overexpressing the target. The results were corroborated by observation of a larger population of cells undergoing apoptosis due to upregulation of tumor suppressor phosphatase and tensis homologue (PTEN), caspase 3, and inhibition of NF-κB in groups treated with the targeted formulations, which further confirmed the ability of the multivalent theranostic nanoparticles for simultaneous imaging and therapy of cancers.

Folic acid conjugated polymeric micelles loaded with a curcumin difluorinated analog for targeting cervical and ovarian cancers

“…In figure 6a & b, we observed that FA-targeted micelle has higher cell uptake than the non-targeted formulation, which indirectly proves FR-mediated cell uptake. Previously, our lab has shown FR-competition experiment with various types of nanoparticles to prove the receptor mediated uptake [44–46]. Herein, we used folic acid conjugated polymeric micelles, thus one can expect FA-SMA micelle will follow FR-mediated endocytosis and there will be FR-competition.…”

Recent therapeutic applications of the theranostic principle with dendrimers in oncology

“…Recently, Luong et al [45] highlighted the synthesis and development of polyvalent theranostic nanocarriers. The construction of this nanoparticle is based on the superparamagnetic iron oxide nanoparticle core (Fe 3 O 4 ) decorated with a FA-G4 PAMAM dendrimer surface that encapsulates the highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin.…”

Nanodrug Delivery Systems for the Treatment of Ovarian Cancer

“…Targeted chemotherapy, such as intraperitoneal implantable treatment, provides targeted therapy within the peritoneal cavity ( Figure 1) [21][22][23][24][25]. In addition, the preparation of nanoformulations functionalized with specific ligands facilitates preferential targeting of OC tumours and ultimately increases the therapeutic effect in comparison to nonfunctionalized nanosystems [25][26][27][28][29][30]. Table 1.…”

“…Various prospective biomarkers of OC are reported. Epithelial ovarian tumours display modified cell antigens including, Human Epididymis Protein 4 (HE4 gene), Cancer Antigen 72-4(CA 72-4), Renal Estimated Glomerular Filtration Rate (EGFR), Soluble Mesothelin-Related Peptides (SMRP), Mesothelin, Osteopontin (OPN), Alpha-Fetoprotein (AFP), Cytotoxic T-Lymphocyte-associated Protein 4 (CTLA4), Interferon-alpha (IFNα), Kallikrein-6 (KLK6), phospholipase A2 group 2A (PLA2G2A), Erythroblastic Oncogene B2 (ErbB2), Interleukin-10 (IL-10) and Mucin-16 (MUC1-16), that differentiate cancerous cells from healthy ovarian tissue and other ordinary cells covering the intraperitoneum [23][24][25][26][27][28][29][30]. Mucin proteins (specifically MUC16) show prospective as biomarkers and antibody functionalized micelles to provide a broad range of prospects for OC therapy [32].…”