Nanoparticle Interactions with the Immune System: Clinical Implications for Liposome-Based Cancer Chemotherapy

Abstract

The development of stable and long-circulating liposomes provides protection of the drug cargo from degradation and increases tumor drug delivery, leading to the design of liposome formulations with great potential in cancer therapy. However, despite the sound pharmacologic basis, many liposomal as well as other nanoparticle-based drug formulations have failed to meet regulatory criteria for approval. The question that arises is whether we have missed key liposome–host interactions that can account for the gap between the major pharmacologic advantages in preclinical studies and the modest impact of the clinical effects in humans. We will discuss here the nanoparticle–immune system interactions that may undermine the antitumor effect of the nanodrug formulations and contribute to this gap. To overcome this challenge and increase clinical translation, new preclinical models need to be adopted along with comprehensive immunopharmacologic studies and strategies for patient selection in the clinical phase.

Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury

“…In the present study, we investigated the potential for reprogramming of circulating innate immune cells through NP administration to enhance functional regeneration following SCI. When innate immune cells are activated in the blood and spleen, they have high phagocytic capacity for scavenging apoptotic cells, cellular debris, and foreign invasive materials (24,25). Generally, NPs may be perceived by inflammatory monocytes and neutrophils as foreign material and are then rapidly internalized (13,26,27).…”

Liposome-induced immunosuppression and tumor growth is mediated by macrophages and mitigated by liposome-encapsulated alendronate

“…Aminobisphosphonates have been shown to have immune stimulatory effects such as induction of proinflammatory cytokines, sensitization of macrophages to inflammatory stimuli, and activation of gamma-delta T-cells [57]. In contrast, non-aminobisphosphonates such as clodronate, primarily act via production of toxic ATP analogues and have been shown to inhibit production of inflammatory mediators and cause overall macrophage suppression and toxicity [18,57]. Encapsulation of alendronate into liposomes is likely to modify the immune modulatory effects of the drug, as the carrier will dictate the pharmacokinetic profile and may drastically alter cellular and molecular interactions.…”

Liposomes and PEGylated liposomes as drug delivery system

“…EPR was described for the first time by Maeda and co-workers [43]. Also, it is demonstrated that EPR effect is the major mechanism for the selective accumulation of nanotherapeutics in tumors [44]. Nanocarrier therapies such as PEGylated liposomes have been extensively utilized as drug delivery system to achieve tumor tissues targeting via EPR effect.…”

“…Moreover, Yang and Lai reported an even higher titers of PEG-antibodies of about 42 % in patients with no history of treatment with PEGylated products [52]. Also pre-existing anti-PEG antibodies may be represented in 56-72 % of people [44]. This could be explained by some researchers due to the common use of PEG products.…”

“…It was demonstrated that nanocarrier drug delivery systems interact with the natural immune system, involving the mononuclear phagocytic system as well as the complement system in different degrees and these interactions with the innate immune system emerged important clinical effects. They can produce an infusion reaction referred to as complement activation-related pseudoallergy (CARPA) through the activation of complement system proteins which usually circulate in the blood stream [44]. CARPA cause various symptoms in most of body organs, including dyspnea, facial swelling, chest pain, flushing, skin rash, hypotension or hypertension and pain in the heart [81].…”