Abstract
The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.
Keywords:
chemotherapy; immunotherapy; monitoring; nanoparticle; reporter.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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B7-H1 Antigen / immunology
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Caspase 3 / chemistry
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Carriers / administration & dosage*
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Drug Carriers / chemistry
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Drug Carriers / therapeutic use
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Drug Monitoring / methods*
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Drug Resistance, Neoplasm / drug effects
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Esterases / chemistry
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Esterases / metabolism
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Female
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Fluorescent Dyes / administration & dosage
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Fluorescent Dyes / chemistry
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Fluorescent Dyes / therapeutic use
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Humans
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Immunoglobulin G / immunology
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Male
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Microscopy, Fluorescence
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Monitoring, Immunologic / methods*
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Nanoparticles / administration & dosage*
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Nanoparticles / chemistry
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Nanoparticles / therapeutic use
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Neoplasms / diagnostic imaging*
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology
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Oligopeptides / administration & dosage
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Oligopeptides / chemistry
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Oligopeptides / therapeutic use
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Paclitaxel / administration & dosage
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Paclitaxel / chemistry
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Paclitaxel / therapeutic use
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Polymers / administration & dosage
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Polymers / chemistry
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Polymers / therapeutic use
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Treatment Outcome
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Tumor Burden / drug effects
Substances
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Antineoplastic Agents
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B7-H1 Antigen
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Drug Carriers
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Fluorescent Dyes
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Immunoglobulin G
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Oligopeptides
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Polymers
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poly(isobutylene-alt-maleic acid)
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Esterases
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Caspase 3
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Paclitaxel