Patient-Specific Nanoparticle Targeting in Human Leukemia Blood
Yi Ju1,2, Shiyao Li1, Abigail Er Qi Tan2
1School of Science, RMIT University, Melbourne, Victoria 3000, Australia.
Abstract:
Antibody-directed targeting of chemotherapeutic nanoparticles to primary human cancers holds promise for improving efficacy and reducing off-target toxicity. However, clinical responses to targeted nanomedicines are highly variable. Herein, we prepared and examined a matrix of 9 particles (organic and inorganic particles of three surface chemistries with and without antibody functionalization) and developed an ex vivo model to study the person-specific targeting of nanoparticles in whole blood of 15 patients with chronic lymphocytic leukemia (CLL). Generally, anti-CD20-functionalized poly(ethylene glycol) (PEG) nanoparticles efficiently targeted CLL cells, leading to low off-target phagocytosis by granulocytes and monocytes in the blood. However, there was up to 164-fold patient-to-patient variability in the CLL targeting. This was further exemplified through using clinically relevant PEGylated doxorubicin-encapsulated liposomes, which showed high interpersonal differences in CLL targeting (up to 234-fold differences) and off-target phagocytosis (up to 65- and 112-fold differences in granulocytes and monocytes, respectively). Off-target phagocytosis led to almost all monocytes being killed within 24 h of treatment. Variance of the off-target association of PEGylated liposomes with granulocytes and monocytes significantly correlated to anti-PEG immunoglobulin G levels in the blood of CLL patients. A negative correlation between CLL targeting of PEG particles and anti-PEG immunoglobulin M levels was found in the blood. Taken together, our study identifies anti-PEG antibodies as key proteins in modulating patient-specific targeting of PEGylated nanoparticles in human leukemia blood. Other factors, such as the antigen expression of targeted cells and fouling properties of nanoparticles, also play an important role in patient-specific targeting. The human leukemia blood assay we developed provides an ex vivo model to evaluate interpersonal variances in response to targeted nanomedicines.
Insights
Patient-specific targeting of cancer nanomedicines varies greatly. Anti-PEG antibodies in patient blood significantly impact nanoparticle delivery, affecting treatment efficacy and toxicity in chronic lymphocytic leukemia.
Area of Science:
- Nanomedicine
- Immunology
- Oncology
Background:
- Antibody-targeted nanoparticles offer potential for cancer therapy by enhancing efficacy and reducing toxicity.
- Clinical outcomes with targeted nanomedicines show significant patient-to-patient variability.
Purpose of the Study:
- To investigate patient-specific targeting of nanoparticles in chronic lymphocytic leukemia (CLL) using an ex vivo whole blood model.
- To identify factors contributing to the variability in nanomedicine response.
Main Methods:
- Prepared and tested nine different nanoparticle formulations with varying surface chemistries and antibody functionalization.
- Developed an ex vivo assay using whole blood from 15 CLL patients to assess nanoparticle targeting and phagocytosis.
- Quantified patient-specific targeting efficiency and off-target effects of nanoparticles.
Main Results:
- Anti-CD20 functionalized nanoparticles showed efficient targeting of CLL cells with low phagocytosis by immune cells.
- Significant patient-to-patient variability (up to 164-fold) was observed in nanoparticle targeting of CLL cells.
- Interpersonal differences in targeting and off-target phagocytosis were also noted for clinically relevant PEGylated liposomes.
- Anti-PEG immunoglobulin G levels correlated with off-target nanoparticle association with granulocytes and monocytes.
- Anti-PEG immunoglobulin M levels showed a negative correlation with nanoparticle targeting of CLL cells.
Conclusions:
- Anti-PEG antibodies are key modulators of patient-specific nanoparticle targeting in human leukemia blood.
- Nanoparticle fouling and target cell antigen expression also influence patient-specific delivery.
- The developed ex vivo assay is valuable for evaluating interpersonal variances in targeted nanomedicine response.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...