Systemic Delivery of Monoclonal Antibodies to the Central Nervous System for Brain Tumor Therapy

Abstract

As an essential component of immunotherapy, monoclonal antibodies (mAbs) have emerged as a class of powerful therapeutics for treatment of a broad range of diseases. For central nervous system (CNS) diseases, however, the efficacy remains limited due to their inability to enter the CNS. A platform technology is reported here that enables effective delivery of mAbs to the CNS for brain tumor therapy. This is achieved by encapsulating the mAbs within nanocapsules that contain choline and acetylcholine analogues; such analogues facilitate the penetration of the nanocapsules through the brain–blood barrier and the delivery of mAbs to tumor sites. This platform technology uncages the therapeutic power of mAbs for various CNS diseases that remain poorly treated.

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas

“…They also demonstrated that Ang2 peptide played a key role in the BBB penetrating by receptor-mediated transcytosis, as was reported in the previous studies [38]. The effect of EP-1 peptide to enhance BBB penetration might be due to the synergistic effect by adsorption-mediated transcytosis [44,45]. The enhanced BBB penetration of DOX encapsulated in the non-functionalized dendrimer might be due to the slightly positive charge on the dendrimer that could improve the adsorptionmediate transcytosis.…”

“…Therefore, nanocarriers were modified with various BBB-penetrating ligands to improve the receptor-mediated transcytosis and transporter-mediated transcytosis, which could enhance the ability of drug carriers across the BBB and deliver the therapeutic reagents into lesions without disrupting homeostasis and biological barriers [5]. Previous researches have determined several receptors and transporters for BBB penetrating by transcytosis, including low-density lipoprotein receptor-relative protein-1 (LRP1) [38,39], insulin receptor [40,41], transferrin receptor (TfR) [42,43], nicotinic acetylcholine receptor and choline transporter [44,45] and a short peptide (RVG29) derived from rabies virus [29,33]. Among these receptors, LRP1, a large multi-ligand endocytic receptor belonging to the low-density lipoprotein receptor family, has attracted wide interest in the therapy and diagnose of CNS disease.…”

“…The modification of PEG chain reduced the positive charge greatly due to the shielding effect of the PEG, which would reduce the cytotoxicity and biotoxicity of the carriers. Meanwhile, the residual positive charge would benefit BBB penetrating of the carriers by adsorption-mediated transcytosis [45].…”

Tumor Microenvironment‐Tailored Weakly Cell‐Interacted Extracellular Delivery Platform Enables Precise Antibody Release and Function

“…Western Blot : The collagenase IV was pre‐added in to the culture medium of PC 9 and LN 229 cell at a concentration of 2 µg mL −1 . Then the WINNER‐Nimo, n‐WINNER‐Nimo, and free nimotuzumab was added respectively at a final concentration of 100 µg mL −1 according to literature . After 48 h, the related proteins were extracted and then separated by SDS‐PAGE gel.…”

“…In Vivo Antitumor Activity : When the tumor size reached ≈60 mm 3 , the mice were randomly divided into four groups (3 mice each group): 1) Control group: mice were intravenously injected with 200 µL of saline; 2) WINNER‐Nimo group: mice were intravenously injected with WINNER‐Nimo (nimotuzumab of 4.54 mg kg −1 ); 3) n‐WINNER‐Nimo group: mice were intravenously injected with n‐WINNER‐Nimo (nimotuzumab of 4.54 mg kg −1 ); and 4) nimotuzumab group: mice were intravenously injected with free nimotuzumab (nimotuzumab of 4.54 mg kg −1 ). The used dose of nimotuzumab was according to literature and in the range of suggested nimotuzumab dose for human (100–400 mg per time). The mice were intravenously administered every 3 days for 21 days.…”