Peptide functionalized nanocarriers for targeted drug delivery in cancer therapy.

Abstract

The intrinsic limitations of conventional cancer therapies have prompted the development of nanocarriers for more effective and safer cancer treatment. Amongst these, nanocarriers functionalized with tumor-targeting moieties have been utilized to enhance delivery of cancer therapeutics. However, recent reports have revealed that only a modest increase in tumor targeting is typically achieved with this approach. Poor tumor accumulation is largely due to formation of a serum protein corona on the surface of the nanocarriers in circulation, which hinders targeting and leads to nonspecific tissue distribution, immune recognition and rapid blood clearance. Here, we present three highly efficient tumor-targeting nanocarriers that overcome the aforementioned issues. These nanocarriers are functionalized with the acidity-triggered rational membrane (ATRAM) peptide that facilitates internalization specifically into cancer cells within the acidic tumor microenvironment. The first system is a hybrid nanocarrier that consists of a drug-loaded polylactic-co-glycolic acid (PLGA) core covalently ‘wrapped’ with a crosslinked bovine serum albumin (BSA) shell. Second are upconversion mesoporous silica nanospheres (UMSNs), with combined photodynamic therapy, photothermal therapy and imaging capabilities, that consist of a lanthanide-doped core ‘wrapped’ with lipid-polyethylene glycol (DSPE-PEG-maleimide). The final system consists of drug-loaded mesoporous silica nanoparticles (MSNs) coated with a lipid bilayer composed of DPPC/Chol/DSPE-PEG-mal. The lipid coat is then functionalized with programmed death receptor ligand-1 antibody (anti-PD-L1 antibody, atezolizumab) to disrupt the programmed death 1 (PD-1) interaction that inhibits the anticancer activity of tumor-infiltrating immune cells. In all three systems, the BSA or lipid coats serve to minimize interactions with serum proteins, which allows the nanocarriers to evade immune recognition and extends the in vivo circulation half-life. All three systems exhibit remarkable tumor-targeting efficiency leading to highly potent anticancer activity, while exhibiting negligible toxicity to healthy tissue. Thus, all three systems represent highly promising nanoplatforms for the targeted delivery of cancer therapeutics.