A nanoparticle-based approach to improve the outcome of cancer active immunotherapy with lipopolysaccharides

Abstract

This study sought to develop a simple nanoparticle-based approach to enhance the efficiency and tolerability of lipopolysaccharide (LPS), a potent ligand of Toll-like Receptor 4 (TLR4), for immunotherapy in cancer. Despite holding promise within this context, the strong pro-inflammatory properties of LPS also account for its low tolerability given localized and systemic side effects, which restrict the administrable dosage. Herein, we investigated the effect of LPS decoration as a surface-active molecule on a polymeric matrix upon its efficiency and tolerability. The LPS-decorated nanoparticles (LPS-NP) were about 150 nm in size, with slightly negative zeta potential (about −15 mV) and acceptable LPS incorporation (about 70%). In vitro, the particles accounted for a higher induction of apoptosis in tumor cells cultured with murine splenocytes compared to LPS solution. When used for the treatment of a murine syngeneic colorectal tumor model, higher intratumoral deposition of the particle-bound LPS was observed. Furthermore, unlike LPS solution, which accounted for localized necrosis at high concentrations, treatment of tumor-bearing animals with equivalent doses of LPS-NP was well tolerated. We propose that the observed localized necrosis can be Shwartzman phenomenon, which, due to modulated 24-h post-injection systemic TNF-α and LPS concentrations, have been avoided in case of LPS-NP. This has in turn enhanced the therapeutic efficiency and enabled complete tumor regression at concentrations at which LPS solution was intolerable. The findings indicate that nanoparticles can serve as beyond carriers for the delivery of superficially decorated LPS molecules, but impact their overall efficiency and tolerability in cancer therapy.

A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers

“…In this regard, the most widely known mechanism is that the presence of hypoxia induces tumor-associated macrophages and promotes tumor progression. (TAMs) [ 21 ]. Besides, tumor cells can protect themselves from the immune system by reducing the levels of MHC class I molecules or inducing mutation in MHC class I genes.…”

“…Nanosystems can help in reducing the amount of immunotherapeutic required for treatment. Moreover, they can help the active ingredient to accumulate at the tumor site avoiding other organs to overcome systemic side effects [ 21 , 56 ]. Besides active targeting, it is also possible to benefit passive targeting in cancer immunotherapy.…”

“…According to the findings, it was observed that nanoparticles decreased the systemic toxicity of LPS and increased TNF-α and IL-6 levels compared to the LPS solution. On the other hand, it was observed that PLGA nanoparticles prevent the recurrence of tumors when injected into peritumors in mice [ 21 ]. As mentioned before, some chemotherapeutic agents have an immunogenic effect in addition to the antitumor response.…”

Nanotechnology as a Platform for the Development of Injectable Parenteral Formulations: A Comprehensive Review of the Know-Hows and State of the Art

“…Examples include but are not limited to the amphiphilic polyanhydride nanoparticles [ 382 ], Poly(methyl vinyl ether-co-maleic anhydride) nanoparticles [ 383 ], amphiphilic γ-glutamic acid (γ-PGA) nanoparticles [ 384 ], cationic lipid nanoparticles [ 385 ], ammonio methacrylate copolymer nanoparticles [ 386 ], stable nucleic acid lipid particles prepared with cationic lipid-like structures (lipodoids) [ 387 ], DiC14-amidine liposomes [ 388 , 389 ], graphene-based nanomaterials [ 390 ], and titanium dioxide nanoparticles [ 391 , 392 ]. Alternatively, conventional adjuvants with appropriate physicochemical properties can be incorporated as a structural components of their respective nanoparticulate carriers, thus strengthening the particles’ inherent immunostimulatory properties [ 374 ]. Hence, the nanoparticle-mediated combined activation of the TLR and NLRP3 can be exploited to obtain a desirable level of vaccination efficacy [ 393 ].…”

“…Furthermore, nanocarriers can increase the visibility of molecular adjuvants to the cells of the innate immunity and thus increase their uptake thereby. This would also enhance the generated immune response compared to when adjuvants are used in a free form [373,374]. Nevertheless, the inherent immunostimulatory potentials of various nanoparticulate Affinity proteins possess a high selectivity in binding to certain molecular structures and are hence of great interest in active targeting approaches.…”