Patient-Specific\nNanoparticle Targeting in Human Leukemia\nBlood

Antibody-directed targeting of chemotherapeutic nanoparticles\nto\nprimary human cancers holds promise for improving efficacy and reducing\noff-target toxicity. However, clinical responses to targeted nanomedicines\nare highly variable. Herein, we prepared and examined a matrix of\n9 particles (organic and inorganic particles of three surface chemistries\nwith and without antibody functionalization) and developed an <i>ex vivo</i> model to study the person-specific targeting of\nnanoparticles in whole blood of 15 patients with chronic lymphocytic\nleukemia (CLL). Generally, anti-CD20-functionalized poly(ethylene\nglycol) (PEG) nanoparticles efficiently targeted CLL cells, leading\nto low off-target phagocytosis by granulocytes and monocytes in the\nblood. However, there was up to 164-fold patient-to-patient variability\nin the CLL targeting. This was further exemplified through using clinically\nrelevant PEGylated doxorubicin-encapsulated liposomes, which showed\nhigh interpersonal differences in CLL targeting (up to 234-fold differences)\nand off-target phagocytosis (up to 65- and 112-fold differences in\ngranulocytes and monocytes, respectively). Off-target phagocytosis\nled to almost all monocytes being killed within 24 h of treatment.\nVariance of the off-target association of PEGylated liposomes with\ngranulocytes and monocytes significantly correlated to anti-PEG immunoglobulin\nG levels in the blood of CLL patients. A negative correlation between\nCLL targeting of PEG particles and anti-PEG immunoglobulin M levels\nwas found in the blood. Taken together, our study identifies anti-PEG\nantibodies as key proteins in modulating patient-specific targeting\nof PEGylated nanoparticles in human leukemia blood. Other factors,\nsuch as the antigen expression of targeted cells and fouling properties\nof nanoparticles, also play an important role in patient-specific\ntargeting. The human leukemia blood assay we developed provides an <i>ex vivo</i> model to evaluate interpersonal variances in response\nto targeted nanomedicines.