Phagocytes mediate targeting of iron oxide nanoparticles to tumors for cancer therapy

Abstract

Nanotechnology has great potential to produce novel therapeutic strategies that target malignant cells through the ability of nanoparticles to get access to and be ingested by living cells. However its specificity for accumulation in tumors, which is the key factor that determines its efficacy, has always been a challenge. Here we tested a novel strategy to target and treat ovarian cancer, a representative peritoneal cancer, using iron oxide nanoparticles (IONPs) and an alternating magnetic field (AMF). Peritoneal tumors in general are directly accessible to nanoparticles administered intraperitoneally (IP), as opposed to the more commonly attempted intravenous (IV) administration. In addition, tumor-associated immunosuppressive phagocytes, a predominant cell population in the tumor microenvironment of almost all solid tumors, and cells that are critical for tumor progression, are constantly recruited to the tumor, and therefore could possibly function to bring nanoparticles to tumors. Here we demonstrate that tumor-associated peritoneal phagocytes ingest and carry IONPs specifically to tumors and that these specifically delivered nanoparticles can damage tumor cells after IONP-mediated hyperthermia generated by AMF. This illustrates therapeutic possibilities of intraperitoneal (IP) injection of nanoparticles and subsequent ingestion by tumor-associated phagocytes, to directly impact tumors or stimulate antitumor immune responses. This approach could use IONPs combined with AMF as done here, or other nanoparticles with cytotoxic potential. Overall, the data presented here support IP injection of nanoparticles to utilize peritoneal phagocytes as a delivery vehicle in association with IONP-mediated hyperthermia as therapeutic strategies for ovarian and other peritoneal cancers.

Quantitative Activity Measurements of Brown Adipose Tissue at 7 T Magnetic Resonance Imaging After Application of Triglyceride-Rich Lipoprotein 59Fe-Superparamagnetic Iron Oxide Nanoparticle

“…19 One explanation for the variable ability of the particles to overcome the peritoneum might be the uptake of SPIOs by peritoneal macrophages, which were not able to cross the peritoneal barrier. This phenomenon has been observed by Toraya-Brown et al 20 Liposomes were able to exit the peritoneal cavity effectively resulting in nearly constant blood liposome levels for a period of several hours. 12,13 In accordance with our results, differences in the biodistribution and pharmacokinetics of nanoparticles depending on their surface characteristics were reported by Chen et al 21 who demonstrated that 188 Re-BMEDA-labeled pegylated liposomes had a 5.3-fold higher terminal half-life in the blood than nonencapsulated 188 Re-BMEDA after IP injection.…”

Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo

“…49 The 5%-7% of initially injected IONP dose that was found in the tumor in the current study equaled that of a previous study that leveraged tumor-associated peritoneal phagocytes to localize non-targeted IONPs to ovarian tumor masses. 6 It is unclear whether the NSG mouse model of the current study possesses similar tumor-associated peritoneal phagocytes, but the lack of any negative control Bfab-targeted IONPs in the tumor mass might suggest that phagocyte-mediated trafficking of IONPs to the tumor is compromised in the NSG model. If true, we speculate that the use of FOLRα-targeted IONPs in a suitable immuno-competent model might result in additive tumor homing, and such a substantial IONP tumor accumulation would bode well for potential diagnostic and therapeutic applications.…”

“…8,11 One recent study co-opted tumor-associated peritoneal phagocytes to selectively deliver IONPs in an ovarian cancer model. 6 In other work, luteinizing hormone-releasing hormone (LHRH) peptide was used as an IONP-targeting moiety for ovarian cancer cells overexpressing the LHRH receptor. 12 Similarly, many ovarian cancers overexpress folate receptor alpha (FOLRα), 13,14 and this fact has been leveraged to selectively construction of Ffab and anti-botulinum toxin fab fragments…”

“…1 Hyperthermia represents one promising approach for peritoneal cancer therapy, as this modality has the capacity to kill cancer cells in a direct fashion and also indirectly stimulates an anticancer immune response. [2][3][4][5][6] In seeking to apply hyperthermia therapy to dispersed peritoneal tumors, however, delivering thermal doses to malignant cells in a precise and controlled fashion represents a substantial technical barrier.…”

Doxorubicin-loaded star-shaped copolymer PLGA-vitamin E TPGS nanoparticles for lung cancer therapy

“…In the meantime, the high hydrophobicity and slow-degradation property of PLGA also limit its application in human body [18]. D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) is a water-soluble PEG derivative of natural-source vitamin E with an amphiphilic structure which comprised of a hydrophilic polar head group (polyethylene glycol, PEG) and a lipophilic alkyl tail (tocopherol succinate) [15,19]. By introducing TPGS to PLGA, we can overcome these shortcomings [20,21].…”