A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated

Abstract

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood–brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin α v β 3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb α v β 3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.

Single-shot AAV-vectored vaccine against SARS-CoV-2 with fast and long-lasting immunity

“…SARS-CoV-2 RBD-binding antibody titers was detected by ELISAs 33 , 96-well high binding plates (Corning, USA, #9018) were coated at 4 °C with 80 ng/mL of SARS-CoV-2 spike RBD recombinant protein (Sino biological, China, #40592-V08H) overnight. Plates were washed twice with PBS containing 0.05% Tween 20 (PBS-T) and blocked with PBS pH 7.4 in 1% BSA at 37 °C for 1.5 h and washed again.…”

Smart Lipid-Based Nanosystems for Therapeutic Immune Induction against Cancers: Perspectives and Outlooks

“…; TLR (Toll-like receptor); EPC (1,2-dioleoyl-sn-glycero-3-ethylphosphocholine); OVA (B16F10-OVA is a murine melanoma cell line expressing the chicken ovalbumin gene); gp70 RNA (Moloney murine leukemia virus); WES (whole-exome sequencing). * Efficacy of vaccinations is shown according to the following binary (present/not present) criteria: 1 Tumor shrinkage; 2 Stimulation of tumor-specific T cells; 3 Induction in cytokine production; 4 Induction of APCs or DCs; 5 Other factors (including increased numbers of immunoinhibitory cells such as MDSCs, Tregs and macrophages [169,170]; complement effect [171], also NK cells [180] and B cells (for humoral immunity and antibody production) [171], and lymph node or spleen enlargement and increased function [179,180].…”

“…Abbreviations: CoPoP (cobalt-porphyrin-phospholipid); PHAD (a synthetic derivative of MPLA); QS-21 (Quillaja saponaria extract); CpG ODN (CpG oligodeoxynucleotides); DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine); SPC (1-stearoyl-sn-glycero-3-phosphocholine); DOTAP (1,2-dioleoyl-3-trimethylammonium-propane); DSPE (1,2-Distearoyl-sn-glycero-3phosphoethanolamine); PEG (polyethylene glycol); TC-1 (E7-transformed tumor cells derived from murine pulmonary epithelial cells); Pam2CAG (dipalmitoyl-cysteine-alanyl-glycine); MPLA (monophosphoryl lipid A); C12iEDAP (acylated derivative of the dipeptide γ-D-Glu-mDAP); PC (phosphatidyl choline); PG (phosphatidyl glycerol); DPPG (1,2-dipalmitoyl-snglycero-3-phosphoglycerol); mn (a linear pentapeptide); AL3810 (reversible ATP-competitive inhibitor aiming at the ATP pocket on intracellular region of VEGFR and FGFR); HSPC (Hydrogenated soy l-α-phosphatidylcholine); HER2 (The human epidermal growth factor receptor 2); DSPC (1,2-Distearoyl-sn-glycero-3-phosphocholine); DSPG (1,2-Distearoyl-snglycero-3-phosphoglycerol); DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine); BCMA 72-80 (a member of the TNF receptor superfamily and the receptor for binding of B cell activating factor and the proliferation-inducing ligand); gp100/TRP2 180-188 (melanocyte differentiation antigen); POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine); DDAB (dimethyl dioctadecyl ammonium bromide); TUBO cells (a cloned line established in vitro from a BALB-neu T mouse mammary carcinoma); LHRH (Luteinizing-hormone-releasing hormone); TLR (Toll-like receptor); EPC (1,2-dioleoyl-sn-glycero-3-ethylphosphocholine); OVA (B16F10-OVA is a murine melanoma cell line expressing the chicken ovalbumin gene); gp70 RNA (Moloney murine leukemia virus); WES (whole-exome sequencing). * Efficacy of vaccinations is shown according to the following binary (present/not present) criteria:1 Tumor shrinkage; 2 Stimulation of tumor-specific T cells; 3 Induction in cytokine production;4 Induction of APCs or DCs;5 Other factors (including increased numbers of immunoinhibitory cells such as MDSCs, Tregs and macrophages[169,170]; complement effect[171], also NK cells[180] and B cells (for humoral immunity and antibody production)[171], and lymph node or spleen enlargement and increased function[179,180].…”

Smart Nanomedicine to Enable Crossing Blood–Brain Barrier Delivery of Checkpoint Blockade Antibody for Immunotherapy of Glioma

“…With the purpose of improving the intracerebral delivery efficiency of therapeutics, massive efforts have been devoted to realize BBB-crossing macromolecule penetration. − One strategy is temporarily disrupting the tight junctions by focused ultrasonication or using tight junction regulating agents to improve the cross-BBB permeability of therapeutics. − However, with as an instantaneous disruption, some toxic agents may also be allowed to enter the CNS, resulting in harmful changes of CNS functions. − Alternatively, there are special types of transporters on the BBB that may be utilized to enable BBB-crossing drug delivery. − As a widely expressed transporter on the luminal brain capillary endothelial cells, choline transporter (ChT) could actively transport the corresponding acetylcholine and choline analogues from the circulating blood into the CNS. , In particular, a choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) has been utilized to fabricate protein nanocapsulates, which were able to transport various types of proteins into the CNS. However, such a method by encapsulating individual proteins via in situ polymerization could hardly be scaled up. − Moreover, with chemical modification of proteins via noncleavable bonds, the biological activity of functional proteins (e.g., antibodies) might be partly affected.…”