Reassembly of cancer cell membranes into nanovehicles as a PET-trackable carrier for tumor-targeted theranostics

Objectives: Integration of cell-membranes-derived nanovehicles with drug cargos and imaging agents holds great potential to revolutionize tumor targeted theranostics, and one of the biggest challenges as well. In addition, accurate in vivo pharmacokinetic understanding of these nanoplatforms is still evasive. Our goal is to develop a nanovehicles based on nanoengineering of cell membranes as a positron emission tomography (PET) trackable carrier for tumor-targeted theranostics.

Methods: The multicompartment liposomes (MCLs) are developed by reassembling cancer cell membranes with different amount of Tween-80, and are used to conjugate ⁸⁹Zr via deferoxamine chelator, and load tetrakis(4-carboxyphenyl) porphyrin (TCPP) for in vivo non-invasive positron emission tomography (PET) imaging and photodynamic therapy (PDT), respectively. The biosafety of MCLs was evaluated by H&E staining of main organs and liver functions marks of treated mice. In vivo metabolize process, biodistribution, and lymph node mapping of MCLs was systematically assessed via PET imaging. The 4T1 tumors model was utilized to confirm the tumor uptake and PDT efficient of MCLs after loading with TCPP.RESULTS: The obtained MCLs appear as a multicompartment nanostructure with a regular spherical morphology and an average diameter of 140 nm. The ratios of Tween-80 micelles to cell membranes was important to form MCLs. Additionally, the obtained MCLs are stable for up to 14 days both in the fetal bovine serum (FBS) and PBS. After conjugation with p-SCN-deferoxamine via the amino groups of proteins on the surface of MCLs, ⁸⁹Zr labeled Df-MCLs (⁸⁹Zr-Df-MCL) demonstrated excellent radiochemical stability in different biological media and in vivo. ⁸⁹Zr-Df-MCL demonstrate efficiently target 4T1 tumors by the enhanced permeability and retention (EPR) effect, and are retained over long-term for efficient and effective PDT, while over 63 %ID of ⁸⁹Zr-Df-MCL at 72 h p.i. was clearing from the reticuloendothelial system through hepatobiliary excretion. Toxicity evaluation confirmed MCLs do not impose acute or chronic toxicity in intravenously injected mice. Additionally, ⁸⁹Zr-labeled MCLs are able to execute highly sensitive lymph node mapping, for possible prediction and therapy of tumor metastasis via sentinel lymph nodes (SLNs).

Conclusions: The multicompartment liposomes as a PET-trackable tumor-targeted theranostics was developed by fusing cancer cell membrane nano-vesicles with Tween-80 nanomicelles. TCPP, as a model drug, was efficiently loaded in the MCLs and served as a fluorescence imaging and photodynamic agent in 4T1-tumor bearing mice. Thus, the biomimetic ⁸⁹Zr-DfMCLs could serve as a PET image-guided, cancer-targeting nanoplatforms to enable disease theranostics in the future

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