Sheddable Prodrug Vesicles Combating Adaptive Immune Resistance for Improved Photodynamic Immunotherapy of Cancer

Abstract

Photodynamic therapy (PDT) capable of eliciting a robust antitumor immune response has been considered an attractive therapeutic approach. However, adaptive immune resistance in PDT underlines the need to develop alternative strategies. The exquisite power of checkpoint blockade can be harnessed to reinvigorate antitumor immune response. Here, we demonstrate that PDT-triggered adaptive immune resistance can be overcome by inactivating indoleamine 2,3-dioxygenase 1 (IDO-1). We rationally designed a tumor-microenvironment-sheddable prodrug vesicle by integrating a PEGylated photosensitizer (PS) and a reduction-sensitive prodrug of IDO-1 inhibitor. The prodrug vesicles were inert during the blood circulation, whereas they specifically accumulated and penetrated at the tumor site through matrix metalloproteinase-2 (MMP-2)-mediated cleavage of the PEG corona to achieve fluorescence-imaging-guided photodynamic therapy (PDT). Compared to PDT alone, the prodrug-vesicle-mediated combination immunotherapy provoked augmented antitumor immunity to eradicate the tumor in both CT26 colorectal and 4T1 breast immunocompetent mouse models. The prodrug vesicles dramatically suppressed tumor reoccurrence, particularly in overexpressing IDO-1 tumor models, i.e., CT26. This study might provide novel insight into the development of new nanomedicine to enhance the efficacy of photodynamic immunotherapy while addressing the adaptive immune resistance.

Predicting the Loading Capability of mPEG‐PDLLA to Hydrophobic Drugs Using Solubility Parameters†

“…In recent years, nanomedicine prepared by using polymers as a carrier has attracted widespread attention . Polymer nanomedicine can be used to improve the solubility of insoluble drugs, prepare sustained‐release preparations with long circulation time, prepare targeted drugs with high efficacy and load biological macromolecules . There are three main methods for preparing polymer nanomedicine: chemical bonding method, polyion complex method and physical encapsulation method.…”

Recent Progress on Activatable Nanomedicines for Immunometabolic Combinational Cancer Therapy

“…[18b,34,48] Gao et al designed a matrix metalloproteinase-2 (MMP-2)/ GSH-activatable prodrug vesicle (EAPV) to deliver a PEGylated photosensitizer (PPa) and a reduction-sensitive prodrug IDO-1 inhibitor (NLG919) for photo-immunometabolic cancer therapy ( Figure 5a). [49] The PEGylated PPa was synthesized by conjugating PPa to a PEG chain via an MMP-2-cleavable peptide (GPLGLAG), and the NLG919 prodrug was prepared by coupling In vitro HPPH and IND release in PBS buffer (pH 7.4) and HAc/NaAc buffer (pH 5.0). c) IDO expression and P-S6K activation in IFN-γ-stimulated B16F10 cells after treatment with different IND formulations.…”

“…Gao et al designed a matrix metalloproteinase‐2 (MMP‐2)/GSH‐activatable prodrug vesicle (EAPV) to deliver a PEGylated photosensitizer (PPa) and a reduction‐sensitive prodrug IDO‐1 inhibitor (NLG919) for photo‐immunometabolic cancer therapy ( Figure a). [ 49 ] The PEGylated PPa was synthesized by conjugating PPa to a PEG chain via an MMP‐2‐cleavable peptide (GPLGLAG), and the NLG919 prodrug was prepared by coupling NLG919 with palmitoyl lyso‐phosphocholine via a GSH‐liable space. EAPV could keep stable to avoid drug leakage during the circulation.…”

Coordination Polymers Integrating Metalloimmunology with Immune Modulation to Elicit Robust Cancer Chemoimmunotherapy

“…5,6 On the other hand, the TILs-secreted cytokine IFN-γ would lead to upregulation of endogenous indoleamine 2, 3dioxygenase (IDO), which catalyzed tryptophan (Trp) to kynurenine (Kyn). [7][8][9] While Trp exhaustion would in turn suppress TILs activation, Kyn would promote the intratumoral recruitment of the immunosuppressive regulatory T (T reg ) cells, further worsening the immunosuppressive TME. [10][11][12][13] Thus, it has been reported that IDO inhibition could overcome immune suppression to enhance antitumor immune responses.…”