Cancer therapy is associated with severe side-effects due to non-specific targeting of healthy tissue. An additional drawback of chemo- and immunotherapy is the emergence of multidrug resistance (MDR) phenotypes. Here, we overcome these issues by developing a targeted cancer drug delivery nanoplatform that combines immuno- and chemotherapy. We utilize mesoporous silica nanoparticles (MSNs) that are characterized by a high drug loading capacity (within the pores of the nanoparticles) and subsequent controlled drug release (in target cancer cells). The MSNs were coated with a lipid bilayer composed of dipalmitoyl phosphatidyl choline/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide (DPPC/Chol/DSPE-PEG-mal; nanoparticles denoted LMSNs). The lipid layer coating extends the in vivo circulation half-life of the MSNs and allows them to evade recognition by neutrophils and macrophages and avoid interactions with blood serum components that lead to nonspecific tissue distribution. The maleimide group facilitates conjugation to the acidity-triggered rational membrane (ATRAM) peptide for internalization of the nanoparticles specifically into cancer cells within the acidic tumor microenvironment. The remaining maleimide groups are then used to couple the programmed death receptor ligand-1 antibody (anti-PD-L1, atezolizumab) to the surface of the LMSNs (PALMSNs). The anti-PD-L1 antibody disrupts the programmed death 1 (PD-1) interaction that inhibits the anticancer activity of tumor-infiltrating immune cells. Chemotherapeutic doxorubicin-loaded PALMSNs exhibited highly efficient cellular uptake and substantial cytotoxicity in A549 lung cancer cells in vitro. Importantly, in vivo studies revealed efficient tumor targeting and potent anticancer activity of the drug-loaded nanoparticles due to the combined effects of the anti-PD-L1 antibody and doxorubicin, with minimal toxicity to healthy tissue. Taken together, our results demonstrate that the novel PALMSNs are a promising targeted drug delivery nanoplatform that facilitates potent combinatorial cancer chemo- and immunotherapy.
Palanikumar et al. (Sun,) studied this question.