Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis

Abstract

High accumulation of hyaluronan (HA) in the tumor microenvironment leads to an increase in the interstitial pressure and reduction perfusion of drugs. Furthermore, high molecular-weight (HMW)-HA suppresses M1 macrophage polarization, enhances M2 polarization, and induces immunosuppression. Hyaluronidase treatment have attempted to decrease the quantity of HA in tumors. However, hyaluronidase-driven HA degradation driven accelerates tumor cell metastasis, which is a major cause of mortality in cancer patients. Thus, we designed a novel exosome-based drug delivery system (DDS), named Exos-PH20-FA, using genetic engineering to express human hyaluronidase (PH20) and self-assembly techniques to modify the exosomes with folic acid (FA). Our results show that Exos-PH20-FA degraded HMW-HA to low-molecular-weight (LMW)-HA. Moreover, LMW-HA polarized macrophages to the M1 phenotype and reduced the number of relevant immunosuppressive immunocytes which changed the immune microenvironment from an immunosuppressive to immunosupportive phenotype. Furthermore, we demonstrated Exos-PH20-FA directly reduced hyaluronidase-induced metastasis of tumor cells. This tumor treatment also allowed an enhanced delivery of chemotherapy by tumor-targeting effect with FA modification. Our findings indicate that Exos-PH20-FA improves tumor treatment efficiency and reduces the side effects of hyaluronidase treatment, namely tumor cell metastasis. This all-in-one exosome-based HA targeting DDS maybe a promising treatment that yields more efficient and safer results.

Synergistic Cascade Strategy Based on Modifying Tumor Microenvironment for Enhanced Breast Cancer Therapy

“…The main advantages of combination SDDS with chemotherapy are (i) the decrease of toxicity of chemotherapeutic agents [5,53]; (ii) the local delivery of anticancer agents with higher payloads and optimal distribution [54]; (iii) the use of nanocarriers to delivery immunomodulatory agents that can activate immune cells and modulate TME [11,14,39]; (iv) the incorporation of diagnostic agents for imaging the tumor or TME [9,55], and (v) the incorporation of active targeting molecules and speci c stimuli to have synergistic cascade effects to enhance anti-tumor e cacy. The results obtained in this study fully demonstrates the virtue of SDDS.…”

“…High IFP in TME may compress blood vessels, resulting in reduced intratumoral blood ow and nanodrug delivery [12,13]. Since the TME is involved in the proliferation, angiogenesis, apoptosis inhibition, immune system suppression and drug resistance of metastatic breast cancer, it becomes recently an important target of TNBC therapy [14][15][16].…”

Biofunctional Peptide-Modified Extracellular Vesicles Enable Effective Intracellular Delivery via the Induction of Macropinocytosis

“…Feng et al developed human hyaluronidase expressing exosomes using genetic engineering by introducing folic acid (FA) modification of 1,2-distearoyl-sn-glycero-3phosphoethanolamine-N-[folate(polyethylene glycol)] (DSPE-PEG-FA) (collectively termed Exo-PH20-FA). These can degrade high molecular weight hyaluronan to low molecular weight analogs in the tumor stroma, leading to reorientation of pro-tumorigenic M2-like tumor-associated macrophages (TAMs) to anti-tumorigenic M1-like TAMs [62]. Due to its effective use of therapeutic molecules (e.g., anticancer drugs such as doxorubicin) encapsulated in exosomes, the Exo-PH20-FA system could emerge as a strong candidate to attain combined chemotherapy and immune therapy strategies [62].…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…The hydrophobic fragment ( d -α-tocopherol succinate (TOS)) can inhibit tumor resistance and increase the apoptosis of many cancer cell types, including B16F10 melanoma cells [ 115 ]. Moreover, overexpressed FA receptors on the tumor cell membrane are associated with malignant and metastatic cancer phenotypes [ 116 , 117 ]. Therefore, these FA-modified nanocarriers provide an effective method for the treatment of solid melanoma and metastatic tumor.…”