Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice

Abstract

Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti–programmed death 1 (α-PD1) or anti–programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 + and CD8 + T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials.

Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer

“…Albumin has been a focus of research for many years with varying conclusions. Albumin can coat nanoparticles to increase their solubility and adsorption, such as nab-paclitaxel, but differing conclusions have been drawn over the stability of this formulation (26,49). Stability of albumin binding to drug (directly or indirectly) would be required for a transcytotic function in the CNS.…”

“…Nanoparticles have been coated with albumin in many preclinical experiments for metastatic cancer. A recent formulation of an albumin stably coating a nanoparticle and containing a PI3Kγ inhibitor and paclitaxel, when administered with checkpoint therapy, shrank metastatic mammary tumors in a genetically engineered mouse model (26) and may represent an example of an efficacious stable formulation that can be tested for brain metastases. Two reports of stable incorporation of albumin into nanoparticles have produced promising results in brain cancers: A BSA-tetramethylindotricarbocyanide iodide (DIR) nanoparticle showed limited distribution in the normal mouse brain but a several-fold enhancement in brains containing intracerebrally inoculated glioma; in vitro uptake of albumin-DIR by endothelial cells was sensitive to depletion of membrane cholesterol but did not alter the expression of paracellular permeability proteins such as ZO-1 or Occludin (25), consistent with a transcytotic mechanism.…”

“…Another investigation used LRP peptide-conjugated liposomes in an intracranial xenograft where membrane fluidity was a significant factor in controlling intracranial tumor growth (23). A third pathway, albumin, has also been used to coat nanoparticles, either temporarily to improve solubility or in a more stable manner (rev in (24)); some preclinical efficacy in primary brain tumor and brain metastasis models has been reported (25,26). The transcytotic pathway for albumin in normal or diseased brain is unresolved and could include binding to the endothelial neonatal Fc receptor (FcRn) (27) or other proteins including SPARC (28), or entry via fluid filled large pinocytotic vesicles (29,30).…”

Targeted Cancer Immunotherapy: Nanoformulation Engineering and Clinical Translation

“…recently designed an albumin nanoparticle containing PI3K γ inhibitor (IPI‐549) and paclitaxel (PTX), which remodeled the TAM in both tumor‐dLNs and tumor sites via the repolarization of M2 to M1 phenotype, thereby regressing metastatic breast cancer in murine models. [ 107 ]…”

Intraperitoneal administration of thermosensitive hydrogel Co-loaded with norcantharidin nanoparticles and oxaliplatin inhibits malignant ascites of hepatocellular carcinoma

“…PEG-PCL-PEG copolymer-based thermosensitive hydrogels are promising injectable materials for biomedical applications (Fang et al, 2009 ; Feng et al, 2016 ; Lee & Jeong, 2020 ). In addition to hydrogels, polymeric nanoparticles (NPs) are also highly suitable carriers for the targeted delivery of anti-cancer agents to tumor sites, which can improve clinical efficacy and reduce systemic toxicity (Ansari et al, 2022 ; Song et al, 2022 ). The NPs have better pharmacokinetics, bioavailability and enhanced tissue targeting capabilities compared to the free drugs, all of which contribute to improved anti-cancer efficiency (Srivastava et al, 2016 ; Zheng et al, 2019 ).…”