Sequential delivery of an anticancer drug and combined immunomodulatory nanoparticles for efficient chemoimmunotherapy

Abstract

Chemoimmunotherapy combines chemotherapy based on anticancer drugs with immunotherapy based on immune activators to eliminate or inhibit the growth of cancer cells. In this study, water-insoluble paclitaxel (PTX) was dispersed in water using hyaluronic acid (HA) to generate a tumor-associated antigen in the tumor microenvironment. Cytosine–phosphate–guanosine oligodeoxynucleotides (CpG ODNs) were used to enhance the T helper (Th) 1 immune response. However, CpG ODNs also induced the secretion of interleukin-10 (IL-10) that reduces the Th1 response and enhances the T helper 2 (Th2) response. Therefore, RNA interference was used to downregulate IL-10 secretion from bone marrow-derived den-dritic cells (BMDCs). For the combined immunomodulation of BMDCs, we fabricated two types of poly(lactic- co -glycolic acid) (PLGA) nanoparticles (NPs) containing CpG ODNs to activate BMDCs via Toll-like receptor 9 (CpG ODN-encapsulated PLGA NPs, PCNs) or a small interfering RNA to silence IL-10 (IL-10 small interfering RNA-encapsulated PLGA NPs, PINs). Treatment of BMDCs with both types of PLGA NPs increased the Th1/Th2 cytokine (IL-12/IL-10) expression ratio, which is important for the effective induction of an antitumor immune response. After primary injection with the HA/PTX complex, the tumor-associated antigen was generated and taken up by tumor-recruited BMDCs. After a secondary injection with immunomodulating PCNs and PINs, the BMDCs became activated and migrated to the tumor-draining lymph nodes. As a result, the combination of chemotherapy using the HA/PTX complex and immunotherapy using PCNs and PINs not only efficiently inhibited tumor growth but also increased the animal survival rate. Taken together, our results suggest that the sequential treatment of cancer cells with a chemotherapeutic agent and immunomodulatory nanomaterials represents a promising strategy for efficient cancer therapy.

Effective chemoimmunotherapy by co-delivery of doxorubicin and immune adjuvants in biodegradable nanoparticles

“…Our findings are consistent with those of other groups, who have reported the benefits of NPs for delivery of chemotherapy and non-specific innate immunotherapy 41-44. For instance, Roy et al and Heo et al treated murine B16 melanoma tumors with PLGA NPs containing paclitaxel and either a TLR4 or a TLR9 agonist, respectively 41,43. The authors observed an initial delay in tumor growth and a significant influx of lymphocytes into the tumors.…”

Dual-mode imaging and therapeutic effects of drug-loaded phase-transition nanoparticles combined with near-infrared laser and low-intensity ultrasound on ovarian cancer

“…And poly (lactic-co-glycolic acid) (PLGA) is a good choice for a drug delivery vehicle because of its biocompatibility and safety. Moreover, several studies have demonstrated that dyes-loaded or drug-loaded PLGA nanoparticles can induce PDT/SDT or enhance cytotoxicity (McEwan et al., 2014 ; Heo et al., 2015 ; Pakulska et al., 2016 ; Abou-ElNaga et al., 2017 ). Herein, our ideal drug delivery platform is based on PLGA, which has the following advantages: (1) high drug loading efficiency; (2) PTX-based chemotherapy combined with ICG-based PDST; (3) oxygen carried PFC improve hypoxia of tumor (McEwan et al., 2015 ; McEwan et al., 2016 ); (4) controlled drug release.…”

A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy

“…One is that immunotherapeutic agent can be delivered in appropriate NPs, and the chemotherapy drug was administered in free form. Yong Taik Lim et al have designed two poly(lactic-co-glycolic acid) (PLGA) NPs combined with chemotherapy drug paclitaxel (PTX), one is CpG-loaded PLGA NPs (PCNs) to activate BMDCs, the other is IL-10 small interfering RNA-loaded PLGA NPs (PINs) to silence IL-10 [96]. The treatment of PTX followed by PCNs and PINs could enhance antitumor effect and increase survival rate in B16-F10-bearing melanoma mice compare to PTX alone (p < 0.05).…”