Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Abstract

Receptor-mediated drug delivery presents an opportunity to enhance therapeutic efficiency by accumulating drug within the tissue of interest and reducing undesired, off-target effects. In cancer, receptor overexpression is a platform for binding and inhibiting pathways that shape biodistribution, toxicity, cell binding and uptake, and therapeutic function. This review will identify tumor-targeted drug delivery vehicles and receptors that show promise for clinical translation based on quantitative in vitro and in vivo data. The authors describe the rationale to engineer a targeted drug delivery vehicle based on the ligand, chemical conjugation method, and type of drug delivery vehicle. Recent advances in multivalent targeting and ligand organization on tumor accumulation are discussed. Revolutionizing receptor-mediated drug delivery may be leveraged in the therapeutic delivery of chemotherapy, gene editing tools, and epigenetic drugs.in the site of interest. This is clinically important as reaching a therapeutic dosage locally and reducing systemic toxicity can be life-threatening or life-saving events for cancer patients.The design of targeted DDVs can be optimized by altering the size, shape, material, ligand, and ligand orientation. For systemic delivery, spherical DDVs less than 200 nm in diameter are standard, which is balanced by the trade off between surface area and volume ratio. DDVs are prepared from biomaterials based on the size, hydrophobicity, and ideal release of the drug. There are a diverse range of ligand candidates for DDV functionalization, including monoclonal antibodies (mAbs), peptides, oligosaccharides, small molecules, and aptamers. [5] These ligands can be tethered to vehicles or conjugated directly to drugs by covalent (typically thiol or amide-based reactions, or "click" chemistry) or noncovalent attachment; the type of reaction is often based on the material of the DDV. [6] Multi-targeted and patterned DDVs improved cancer cell binding and the overall therapeutic benefit in vivo. The ideal DDV platform may be rationally designed by evaluating the drug, release mechanism, mode of delivery into the body, and target cells.Utilizing these approaches, targeted DDVs were successfully translated from the research setting into clinical use, or are currently in preclinical trials. [7] Liposomal based DDVs were approved for use in cancer therapy, treating fungal diseases, analgesics, photodynamic therapy, and viral vaccines. [8] Specifically, FDA approved liposomal drug formulations, such as Mepact, Maribo, and Epaxal were proven to be effective for the treatment of nonmetastatic osteosarcoma, acute lymphoblastic leukemia, and hepatitis A, respectively. [9] Many targeted DDVs in clinical use are utilized for the treatment of multiple cancer types, as there is often broad overlap in malignant receptor overexpression across various carcinogenic tissues (Figure 1). The widely successful drug Pembrolizumab (Keytruda), a humanized IgG4 isotype mAb that targets the programmed cell death (PD-1) rec...

Cell Membrane Nanotherapeutics: From Synthesis to Applications Emerging Tools for Personalized Cancer Therapy

“…Consisting of a range of specific cell membrane antigens, a cancer cell‐membrane coated nanomedicine is effectively a multimodal anticancer therapeutic with the ability to homotypically target its own population in addition to promoting a highly specific immune response. [ 84,118,120,147–149 ] Derived from cancer cells, cancer cell membrane together with the antigens associated with tumor was coated onto adjuvant‐loaded nanocores to yield a nanoparticulate anticancer vaccine. Cancer cell membrane‐coated nanomaterials were loaded with CpG oligodeoxynucleotide in the biodegradable PLGA cores.…”

Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy

“…Mostly, via receptor-based targeting, a nanocarrier can be rapidly transported to the required target site with a high degree of accuracy. Thus, by combining the superiority of receptor overexpression with an uncommon binding motif, LPHNPs can be functionalized with different ligands to preferentially bind to the receptors via ligand-receptor interaction at the cell surface [ 67 ]. The ligand-engineered hybrid NPs are internalized by cancer cells via receptor-mediated endocytosis with a higher affinity towards the targeted tissues and a lower affinity towards the healthy tissues [ 68 ].…”

Plasmonic Material Engineering for Targeted Therapeutics

“…NPs can be either functionalized or engineered into having desirable features, that is, prolonging circulation time in the blood stream, incorporation of cargo molecules, or being activatable by lasers for a controlled release of drugs. [ 8–11 ] Additionally, NPs such as FDA‐approved poly(lactic‐ co ‐glycolic acid) (PLGA) and poly(caprolactone) (PCL) particles are biodegradable and have been studied as drug cargo vehicles. [ 9 ]…”