Name: a comprehensive procedure to evaluate the in vivo performance of cancer nanomedicines
Uploaded: 2017-03-04T14:00:00
Description: Watch this Scientific Journal Video about A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines at JoVE.com

The authors would like to thank Drs. Helene Salmon and Miriam Merad from Icahn School of Medicine at Mount Sinai for providing the B16-F10-YFP cells and for their expert advice on melanoma mouse models. The authors further thank the Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probes Core Facility, and the Molecular Cytology Core Facility at Memorial Sloan Kettering Cancer Center (MSK) for their support. This work was supported by National Institutes of Health grants NIH 1 R01 HL125703 (W.J.M.M.), R01CA155432 (W.J.M.M.), K25 EB016673 (T.R.) and P30 CA008748 (MSK Center Grant). The authors also thank the Center for Molecular Imaging and Nanotechnology (CMINT) at MSK for their financial support (T.R.).

The procedure consists of the dual radioactive and fluorescent labeling of nanoparticles, in vivo PET-CT imaging, ex vivo biodistribution measurements, and ex vivo immunostaining and flow cytometry analyses. All animal experiments were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center.
1. Preparation of Dual-labeled Liposomes
NOTE: Syngeneic B16 melanoma tumors can be induced by injecting 3...

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Critical Steps within the Protocol:
The high quality of dual-labeled liposomes is the key to producing consistent results over a long period of time. Free fluorescent dyes or 89Zr ions can generate totally different targeting patterns and must be completely removed during the purification step. In addition, if the immune system significantly affects experimental cancer nanomedicine performance, the use of immunocompetent mouse models should be preferable, such as the B16-F10 melanoma m...

Nanomedicine is shifting the paradigm of cancer treatment development1. Inspired by the tremendous clinical impact of previous cancer nanomedicines, such as liposome- and albumin-based nanotherapies2,3, many novel formulations have been produced in the past decade. However, recent analyses of the clinical translation success of these cancer nanomedicines indicate that only a few of them have been approved for clinical use4,5. One major obstacle to the clinical translation of new cancer nanomedicines is their limited improvement of the therapeutic index compared with the direct administration of the free therapeutic compounds6. As such, accurate evaluation of the in vivo performance of nanomedicines at systemic, tissue, and cellular levels in preclinical animal models is essential to identify those with optimal therapeutic indices for future clinical translation.
Nanomaterials can be radiolabeled for quantitative characterization in living animals with positron emission tomography (PET) imaging, which has superb sensitivity and reproducibility among all clinical imaging modalities7. For example, 89Zr-labeled long-circulating nanomedicines have been characterized in mouse models for cancer8,9,10, as well as in other disease models11. In addition, the blood half-life and biodistribution of the nanomedicines can be extensively evaluated by using ex vivo radioactivity measurements in individual tissues8. Therefore, radiolabeling allows for the quantitative evaluation of nanomedicines at systemic and tissue levels.
Importantly, radiolabeled nanomedicines generally cannot be analyzed at the single-cell or subcellular levels due to the limited spatial resolution of the radioactive signal. Therefore, fluorescent labeling proves to be a complementary modality for the evaluation of nanoparticles with optical imaging techniques such as flow cytometry and fluorescence microscopy12. To this end, nanoparticles labeled with radioisotopes and fluorescent tags can be quantitatively evaluated in vivo by nuclear imaging and ex vivo by radioactivity counting, and they can also be extensively characterized at the cellular level by optical imaging.
Previously, we have developed modular procedures to incorporate radioactive and fluorescent labels into various nanoparticles, including high-density lipoprotein (HDL)11, liposomes9,10, polymeric nanoparticles, antibody fragments, and nanoemulsions10,13. These labeled nanoparticles have allowed for quantitative characterization in relevant animal models at different levels, which guided the optimization of these nanomaterials for their specific applications. In the current study, the aim is to use liposomal nanoparticles&#8212;the most established nanomedicine platform14&#8212;as an example to demonstrate comprehensive procedures to generate a dual-labeled nanoparticle and to thoroughly characterize it in a classic syngeneic melanoma B16-F10 mouse model15. From the results, we are confident this nanoparticle characterization approach can be adapted to evaluate other cancer nanomedicines in relevant mouse models.

<table border="0" cellpadding="0" cellspacing="0" width="638">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">DPPC</td>
			<td style="width:136px;">Avantilipids</td>
			<td align="right" style="width:119px;">850355</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Cholesterol</td>
			<td style="width:136px;">Sigma-Aldrich</td>
			<td style="width:119px;">C8667</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">DSPE-PEG2000</td>
			<td style="width:136px;">Avantilipids</td>
			<td style="width:119px;">880120P</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">DSPE-DFO</td>
			<td style="width:136px;">Home made</td>
			<td align="right" style="width:119px;">110634</td>
			<td>Perez-Medina et al, JNM, 2014</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">DiIC12[5]-DS</td>
			<td style="width:136px;">AAT Bioquest</td>
			<td align="right" style="width:119px;">22051</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Centrifugal filter</td>
			<td style="width:136px;">Vivaproducts</td>
			<td style="width:119px;">VS2061</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Rotary evaporator</td>
			<td style="width:136px;">Buchi</td>
			<td style="width:119px;">R-100</td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:216px;">Radio-HPLC</td>
			<td style="width:136px;">Shimadzu HPLC with 2 LC-10AT pumps</td>
			<td style="width:119px;">N/A</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">89Zr-oxalate</td>
			<td style="width:136px;">MSKCC</td>
			<td style="width:119px;">Synthesized in house</td>
			<td>TR19/9 variable beam cyclotron (Ebco Industries Inc)</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Micro PET-CT</td>
			<td style="width:136px;">Siemens</td>
			<td style="width:119px;">Inveon Micro-PET/CT</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Gamma counter</td>
			<td style="width:136px;">PerkinElmer</td>
			<td style="width:119px;">2470-0150</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Flow cytometry</td>
			<td style="width:136px;">BD Biosciences</td>
			<td style="width:119px;">Fortessa</td>
			<td>Any multi-parametric flow cytometry analyzers would suffice</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">C57BL/6 mice</td>
			<td style="width:136px;">Jackson Laboratories</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">B16-YFP melanoma cells</td>
			<td style="width:136px;">Home made</td>
			<td style="width:119px;">N/A</td>
			<td>Salmon et al, Immunity, 2016</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Ly6C (clone HK1.4)--APC-Cy7</td>
			<td align="right" style="width:136px;">128025</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">MHCII (M5/114/152)--APC</td>
			<td align="right" style="width:136px;">107613</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD45 (30-F11)--BV510</td>
			<td align="right" style="width:136px;">103137</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD64 (X54-5/7.1)--PE-Cy7</td>
			<td align="right" style="width:136px;">139313</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD11b (M1/70)--BV605</td>
			<td align="right" style="width:136px;">101237</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD3 (17A2)--BV711</td>
			<td align="right" style="width:136px;">100241</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD31 (13.3)--PE</td>
			<td align="right" style="width:136px;">561073</td>
			<td style="width:119px;">Biolegend</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD11c (M418)--PerCP-Cy5.5</td>
			<td align="right" style="width:136px;">117327</td>
			<td style="width:119px;">BD Biosciences</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">CD31 (13.3) no fluorophore</td>
			<td align="right" style="width:136px;">550274</td>
			<td style="width:119px;">BD Biosciences</td>
			<td></td>
		</tr>
	</tbody>
</table>

a comprehensive procedure to evaluate the in vivo performance of cancer nanomedicines

Inspired by the success of previous cancer nanomedicines in the clinic, researchers have generated a large number of novel formulations in the past decade. However, only a small number of nanomedicines have been approved for clinical use, whereas the majority of nanomedicines under clinical development have produced disappointing results. One major obstacle to the successful clinical translation of new cancer nanomedicines is the lack of an accurate understanding of their in vivo performance. This article features a rigorous procedure to characterize the in vivo behavior of nanomedicines in tumor-bearing mice at systemic, tissue, single-cell, and subcellular levels via the integration of positron emission tomography-computed tomography (PET-CT), radioactivity quantification methods, flow cytometry, and fluorescence microscopy. Using this approach, researchers can accurately evaluate novel nanoscale formulations in relevant mouse models of cancer. These protocols may have the ability to identify the most promising cancer nanomedicines with high translational potential or to aid in the optimization of cancer nanomedicines for future translation.

Figure 1 shows an overview of the procedure. Figure 2 presents the schematic synthesis procedure of the dual-labeled liposomes described in step 110. Figure 3 displays a representative PET-CT image (Figure 3a), radioactivity quantification from PET imaging (Figure 3b), blood half-life (Figure 3c), and biodistribution (Figure 3d) of radioactive nano...

Watch this Scientific Journal Video about A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines at JoVE.com

A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines

The poor understanding of the in vivo performance of nanomedicines stymies their clinical translation. Procedures to evaluate the in vivo behavior of cancer nanomedicines at systemic, tissue, single-cell, and subcellular levels in tumor-bearing immunocompetent mice are described here. This approach may help researchers to identify promising cancer nanomedicines for clinical translation.

A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines

Inspired by the success of previous cancer nanomedicines in the clinic, researchers have generated a large number of novel formulations in the past ...

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