Amphiphilic nanoparticle delivery enhances the anticancer efficacy of a TLR7 ligand via local immune activation

Abstract

Although immunotherapy shows great promise for the long-term control of cancer, many tumors still fail to respond to treatment. To improve the outcome, the delivery of immunostimulants to the lymph nodes draining the tumor, where the antitumor immune response is initiated, is key. Efforts to use nanoparticles as carriers for cancer immunotherapy have generally required targeting agents and chemical modification of the drug, and have unfortunately resulted in low delivery and therapeutic efficiency. Here, we report on the efficacy of gold nanoparticles with approximately 5 nm hydrodynamic diameter coated with a mixture of 1-octanethiol and 11-mercaptoundecanesulfonic acid for the delivery of an immunostimulatory TLR7 ligand to tumor-draining lymph nodes. The drug was loaded without modification through nonspecific adsorption into the ligand shell of the nanoparticles, taking advantage of their amphiphilic nature. After loading, nanoparticles retained their stability in solution without significant premature release of the drug, and the drug cargo was immunologically active. Upon subcutaneous injection into tumor-bearing mice, the drug-loaded particles were rapidly transported to the tumor-draining lymph nodes. There, they induced a local immune activation and fostered a cytotoxic T-cell response that was specific for the tumor. Importantly, the particle-delivered TLR7 ligand blocked the growth of large established tumors and significantly prolonged survival compared to the free form of the drug. Thus, we demonstrate for the first time that nanoparticle delivery of a TLR7 immunostimulant to the tumor-draining lymph nodes enhances antitumor immunity and improves the outcome of cancer immunotherapy.

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

“…An amphiphilic gold nanoparticle 5 nm in size coated with 1-octanethiol and 11mercaptoundecanesulfonic acid was used to deliver a TLR7 ligand to tumor draining lymph nodes to act as an immunostimulant [150]. Nanoparticles were administered subcutaneously and caused local immune activation.…”

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

“…A delivery system composed of gold nanoparticles of 5 nm in diameter coated with an amphiphilic shell was developed, which allowed loading of resiquimod through non-specific adsorption. After subcutaneous injection of these resiquimod-loaded particles into tumorbearing mice, they accumulated in the tumor-draining lymph nodes where they led to activation of the dendritic cells in situ causing a cytotoxic T-cell response 61 . This treatment completely blocked the growth of the large tumor and extended the survival of the mice much more than the free drug 61 .…”

“…After subcutaneous injection of these resiquimod-loaded particles into tumorbearing mice, they accumulated in the tumor-draining lymph nodes where they led to activation of the dendritic cells in situ causing a cytotoxic T-cell response 61 . This treatment completely blocked the growth of the large tumor and extended the survival of the mice much more than the free drug 61 . Thus, the delivery of resiquimod to the tumor-draining lymph node, which is the site of initiation of the immune response against the tumor, was highly effective for triggering an anti-tumor response.…”

Nanomedicine-mediated alteration of the pharmacokinetic profile of small molecule cancer immunotherapeutics

“…Kasturi et al have shown a synergistic effect of combining MPLA and R837 in PLGA nanoparticles on antibody production [ 101 ]. Many more examples exist of encapsulating adenine and imidazoquinoline TLR agonists into nanocarriers [ 98 , 102 , 103 ]. Fewer studies have been performed on the delivery of guanosine analogs such as 7-thia-8-oxoguanosine (TOG) and loxoribine (Fig.…”