Sustained Drug Release From Liposomes for the Remodeling of Systemic Immune Homeostasis and the Tumor Microenvironment

Abstract

Myeloid Derived Suppressor Cells (MDSCs) play important roles in constituting the immune suppressive environment promoting cancer development and progression. They are consisted of a heterogeneous population of immature myeloid cells including polymorphonuclear MDSC (PMN-MDSC) and monocytes MDSC (M-MDSC) that are found in both the systemic circulation and in the tumor microenvironment (TME). While previous studies had shown that all-trans retinoic acid (ATRA) could induce MDSC differentiation and maturation, the very poor solubility and fast metabolism of the drug limited its applications as an immune-modulator for cancer immunotherapy. We aimed in this study to develop a drug encapsulated liposome formulation L-ATRA with sustained release properties and examined the immuno-modulation effects. We showed that the actively loaded L-ATRA achieved stable encapsulation and enabled controlled drug release and accumulation in the tumor tissues. In vivo administration of L-ATRA promoted the remodeling of the systemic immune homeostasis as well as the tumor microenvironment. They were found to promote MDSCs maturation into DCs and facilitate immune responses against cancer cells. When used as a single agent treatment, L-ATRA deterred tumor growth, but only in immune-competent mice. In mice with impaired immune functions, L-ATRA at the same dose was not effective. When combined with checkpoint inhibitory agents, L-ATRA resulted in greater anti-cancer activities. Thus, L-ATRA may present a new IO strategy targeting the MDSCs that needs be further explored for improving the immunotherapy efficacy in cancer.

Intra-articular treatment of temporomandibular joint osteoarthritis by injecting actively-loaded meloxicam liposomes with dual-functions of anti-inflammation and lubrication

“…It is interesting to observe that the nano-bowel structure covers only a part of the inner surface of liposomes. A similar phenomenon has been reported in previous study, where a poorly water soluble drug ( all-trans-retinoic acid) is actively loaded with calcium acetate gradient [ 53 ]. It is suggested that incorporation of hydrophobic drugs to the lipid bilayer can change its original ordered structure and fluidize the membrane [ 54 ].…”

Identification and verification of aging-related lncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma

“…The low-risk group with higher immune scores had smaller IC50 in 15 immunotherapeutic agents (Fig. 7B) [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] and was more sensitive to 18 targeted therapeutics (e.g., Nilotinib) and six chemotherapeutic agents (e.g., Vinblastine) than the highrisk group. All 39 chemicals were shown in Fig.…”

A landscape of recent advances in lipid nanoparticles and their translational potential for the treatment of solid tumors

“…148 Zheng et al investigated how a liposomal formulation of alltrans-retinoic acid (ATRA) can remodel the immunosuppressive TME by inducing MDSC differentiation and maturation. 159 They developed a sustained release formulation of actively loaded ATRA. Using a CT26 colon cancer mouse model, the authors found that liposomal ATRA alone, and in combination with immune checkpoint PD-1 inhibitors, significantly reduced tumor growth.…”

“…Using a 4T1 breast cancer mouse model, the authors found a time‐dependent accumulation of the formulation in the TME resulting in a synergistic immune response that was able to inhibit tumor growth in primary and spontaneously metastatic tumors as shown in Figure 7a–c 148 . Zheng et al investigated how a liposomal formulation of all‐trans‐retinoic acid (ATRA) can remodel the immunosuppressive TME by inducing MDSC differentiation and maturation 159 . They developed a sustained release formulation of actively loaded ATRA.…”