Intravenous and intratumoral injection of Pluronic P94: The effect of administration route on biodistribution and tumor retention

doi:10.1016/j.nano.2017.04.015

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 13, Issue 7, October 2017, Pages 2179-2188

https://doi.org/10.1016/j.nano.2017.04.015 Get rights and content

Abstract

Pluronics P94 are block-copolymer showing prolonged circulation time and tumor-cell internalization in vitro, suggesting a potential for tumor accumulation and as a drug carrier. Here we report the results of the radiolabeled-P94 unimers (P94-¹¹¹In-DTPA) on tumor uptake/retention and biodistribution after intravenous and intratumoral injection to tumor-bearing mice. Intravenous administration results in a high radioactive signal in the liver; while in tumor and other healthy tissues only low levels of radioactivity could be measured. In contrast, the intratumoral injection of P94 resulted in elevated levels of radioactivity in the tumor and low levels in other organs, including the liver. Independently from the injection route, the tumor tissue presented long retention of radioactivity. The minimal involvement of off-target tissues of P94, together with the excellent tracer retention over-time in the tumor designates Pluronic P94 copolymer as a highly promising carrier for anti-tumor drugs.

Graphical Abstract

Compared to intravenous (IV) administrations, P94-¹¹¹In-DTPA administered intratumorally (IT) showed higher tumor retention and lower off-target accumulation. Results of ¹¹¹In-DTPA (IT-injected) suggest that tumor retention might be mediated by P94.

Section snippets

Functionalization and radiolabeling of Pluronic P94 copolymer with DTPA chelator (P94-DTPA)

Pluronic P94 (PEO₂₆PPO₄₈PEO₂₆; Mn PEO blocks: 2200 Da; Mn PPO block: 2800 Da,¹⁹ where PEO is poly(ethylene oxide) and PPO is poly(propylene oxide)) was supplied by BASF and end-functionalized with the chelator DTPA and radiolabeled with ¹¹¹In Fig. 1) following procedures described previously8, 20 and further specified in Supplementary Materials (Supp).

In vivo tumor model

Human small cell lung cancer cells H69 (ECACC, Salisbury, UK (~3 × 10⁶ cell/mouse) were inoculated subcutaneously in 20 young adult male Balb/c-nu

SPECT/CT imaging and in vivo quantification

After functionalization, P94-DTPA was successfully radiolabeled with ¹¹¹In (labeling yield >90%). P94-¹¹¹In-DTPA copolymers were injected in tumor bearing mice either IV or IT. The levels of radioactivity reached in selected organs were followed over-time and measured (Figure 3, Figure 4; Table 1, Table 2, Table 3).

In the SPECT/CT images, made 4 h pi of mice injected IV with P94-¹¹¹In-DTPA, we observe a strong radioactive signal in liver (~0.3 kBq/mm³) and bladder (~0.6 kBq/mm³), compatible with

Discussion

The results recently obtained with P94 copolymer have underlined valuable properties of this copolymer for in vivo application as nanocarrier.⁸ These properties are represented by the long lasting stability and potential anti-cancer cell effect, strongly indicating that P94 copolymer has the potential to be a carrier for drug delivery in tumors.7, 8 Successful application of a nanocarrier in vivo, however, depends on its capacity to target tumor tissue, in a safe, efficient and specific way.

Acknowledgments

This work was performed on the imaging equipment in the Applied Molecular Imaging at the Erasmus MC (AMIE) facility. The authors would like to thank all the members of the consortium under the Marie Curie Actions (“Trace'n’Treat”) and Mark Konijnenberg for their support, collaboration and fruitful discussions.

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: The research was funded by the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. PITN-GA-2012-317019‘TRACE‘n TREAT’. The authors have no conflicts of interest to declare.

: Author contribution: CS performed the radiolabeling of P94, the in vivo and ex vivo evaluations and the data analyses; CS wrote the manuscript. AA ad KM optimized the labeling procedure and participated in the experimental design; AGD, FS, EM, PD, MB and MdJ contributed to the design of the in vivo and ex vivo studies and provided helpful comments on the manuscript. MB supervised the study and helped to draft the manuscript. All authors read and approved the final manuscript.

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Original ArticleIntravenous and intratumoral injection of Pluronic P94: The effect of administration route on biodistribution and tumor retention

Abstract

Graphical Abstract

Section snippets

Functionalization and radiolabeling of Pluronic P94 copolymer with DTPA chelator (P94-DTPA)

In vivo tumor model

SPECT/CT imaging and in vivo quantification

Discussion

Acknowledgments

Eur J Pharm Biopharm

Trends Biotechnol

J Control Release

J Control Release

J Control Release

J Control Release

J Control Release

J Control Release

Biochim Biophys Acta

Pluronics and MDR reversal: an update

Mol Pharm

Pluronic[registered sign] block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances

Polym Chem

Poloxamer 188 (P188) as a membrane resealing reagent in biomedical applications

Recent Pat Biotechnol

SPECT/CT imaging of Pluronic Nanocarriers with varying poly(ethylene oxide) block length and aggregation state

Mol Pharm

Nanoparticles for imaging: top or flop?

Radiology

Original Article
Intravenous and intratumoral injection of Pluronic P94: The effect of administration route on biodistribution and tumor retention