Controlling injectability and in vivo stability of thermogelling copolymers for delivery of yttrium-90 through intra-tumoral injection for potential brachytherapy
Introduction
Intra-tumoral brachytherapy administration is an attractive treatment option to surgically unresectable solid tumors such as locally advanced hepatocellular carcinoma [[1], [2], [3], [4], [5], [6], [7], [8]]. The delivery of radiopharmaceuticals such as yttrium-90 (90Y) or phosphorus-32 (32P) directly into the tumor allows the maximum effective dose of radioactivity to be delivered to the tumor and at the same time minimizes the damage to the surrounding healthy tissues [[9], [10], [11], [12], [13], [14]]. Our previous translational and clinical research demonstrated complete remission in some hepatocellular carcinoma patients using intra-tumoral brachytherapy [15,16]. However, our experience also showed that radiopharmaceuticals can potentially leak out from the tumor injection site (including back-leak into the peritoneal cavity and leaking into other parts of the body) due to existing high intra-tumoral pressure that is further aggravated by the injection procedure. This limits the clinical use of intra-tumoral brachytherapy. There is thus a compelling need for technical solutions to overcome this disadvantage so that intra-tumoral brachytherapy can be delivered more efficaciously and safely.
There have been a number of reports using thermogelling copolymers that can be injected into tumor site and subsequently solidify as hydrogel in vivo, to overcome the problems with intra-tumoral brachytherapy [[17], [18], [19], [20], [21]]. We also synthesized biodegradable thermogelling polyurethane copolymers comprising blocks of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and polyesters such as poly(3-hydroxylbutyrate) (PHB), poly(ε-caprolactone) (PCL), and poly(1,4-butylene adipate) (PBA) for injectable drug delivery applications [[22], [23], [24], [25]]. With these thermogelling copolymers, the radionuclide 90Y can be simply added and dispersed in a copolymer solution at low temperatures, which is subsequently injected into the tumor site, and then forms solidified hydrogels at higher temperatures (e.g. body temperature), to prevent the leaking of the radionuclide out of the tumor tissue. Ideally, the copolymer solution should have very low viscosity at low temperatures for easy injection, and its hydrogel formed at the body temperature should be solid-like or highly viscoelastic, having high stability in vivo in the tumor tissue without leaking of the hydrogel itself as well as the encapsulated radionuclide into other parts of the body. However, practically it is a challenge to achieve the above results with a given type of copolymers. There have been no studies reporting on in vitro evaluation criteria and methodologies to guide the copolymer designs to suit them for the proposed in vivo application, as well as on the controlling of the injectability and in vivo stability of thermogelling copolymers and hydrogels to prevent the leaking of radionuclide through designing the copolymers with desired structures and compositions.
Polyoxazoline as a thermoresponsive polymer chemically labeled with 90Y was tested in vivo for therapeutic efficacy of tumor [17]. However, the polymer is not biodegradable. PCL-PEG-PCL triblock copolymers as an in situ forming thermosensitive hydrogel was studied for radiotherapy combined with chemotherapy in a mouse model of hepatocellular carcinoma [18]. Thermosensitive hydrogels based on chitosan and β-glycerophosphate [19], Pluronic F-127 and sodium hyaluronate [20], and poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethyleneglycol)-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) triblock copolymer [21], were also studied for brachytherapy. However, the injectability and in vitro and in vivo stability of the hydrogel were not investigated, and there was no optimization of the materials for their injectability and stability.
Herein we designed, synthesized and characterized a series of thermogelling polyurethane copolymers comprising blocks of Pluronic F127, poly(3-hydroxylbutyrate) (PHB), and poly(propylene glycol) (PPG), namely poly(F127/PHB/PPG urethane), to prevent the leaking during and after the intra-tumoral injection of radio-therapeutic agents. Pluronic F127 (F127 in short) is a PEG-PPG-PEG triblock thermogelling copolymer for many pharmaceutical and drug delivery applications, but it only forms hydrogels at very high polymer concentrations, which can dissolve in aqueous media very fast [25]. Our poly(F127/PHB/PPG urethane) copolymers synthesized in this study were designed to have higher molecular weights than F127 and be more hydrophobic by introducing PHB, which are expected to form hydrogels at lower concentrations, and have higher stability in the aqueous environment in the body. The PHB-diol precursor was synthesized by anionic ring opening polymerization of racemic β-butyrolactone, aiming to better control of the molecular weight and end functionality. Through a detailed investigation of the viscoelastic properties of the copolymers, analyzing the storage modulus (G′), loss modulus (G″), phase angle (δ), and complex viscosity (η*) as a function of time, temperature, and/or copolymer composition, we elucidated the injectability of the copolymer solutions at low temperatures, and the stability of the hydrogels at the body temperature. Based on the analyses, we could identify one copolymer with balanced composition, which is most suitable for intra-tumoral injection at low temperatures as well as for preventing the leaking at the body temperature. Finally, the injectability and body temperature stability of the copolymer solutions and hydrogels loaded with 90Y were further demonstrated in a mouse tumor model, and the in vivo biodistribution of 90Y showed that the radionuclide could be retained at the tumor site.
Section snippets
Materials
Pluronic® F-127 was obtained from Sigma, and dried under high vacuum at 60 °C for 24 h before use. Poly(propylene glycol) (PPG, average Mn ∼2700) and (±)-sodium 3-hydroxybutyrate (≥99.0%) was obtained from Aldrich, and dried under high vacuum at 60 °C for 24 h before use. (R,S)-β-butyrolactone (>95%, Tokyo Kasei Inc) and 1,2-dichloroethane (anhydrous, 99.8%) was dried over and vacuum distilled from CaH2 twice before use. Dibutyltin dilaurate (95%, Aldrich), 2-bromoethanol (95%, Aldrich),
Synthesis and molecular characterization of copolymers
PHB-diol with two hydroxyl end groups was first synthesized in a one pot fashion by anionic ring opening polymerization (ROP) of racemic β-butyrolactone, as shown in Fig. 1a. The ROP procedure proceeded with excellent control over the molecular weight, molecular weight distribution and end-group fidelity. This has allowed facile incorporation of hydroxyl functionality, through a judicious selection of anionic initiator and nucleophilic capping agent, onto a PHB precursor with desired molecular
Conclusion
Three poly(F127/PHB/PPG urethane) copolymers, FH1, FHP1, and FHP2, have been successfully designed and synthesized with different contents of PHB, PEG, and PPG segments, so as to adjust the rheological properties and the body temperature stability of the copolymer aqueous solutions and hydrogels. FH1 had a higher PHB content, but a lower PPG content, and FHP2 had a lower PHB content, but a higher PPG content, while FHP1 had a well-balanced PHB and PPG contents. All the three poly(F127/PHB/PPG
Notes
The authors declare no competing financial interest.
Acknowledgements
We acknowledge the financial support from Agency for Science, Technology and Research (A*STAR), Singapore (Grant No. 132 148 0007).
References (41)
- et al.
Loco-regional treatment of HCC: current status
Clin. Radiol.
(2017) - et al.
Thermoresponsive polymeric radionuclide delivery system—an injectable brachytherapy
Eur. J. Pharmaceut. Sci.
(2011) - et al.
Bioevaluation study of 32P-CP-PLLA particle brachytherapy in a rabbit VX2 lung tumor model
Appl. Radiat. Isot.
(2012) - et al.
A novel approach to brachytherapy in hepatocellular carcinoma using a phosphorous 32 (32P) brachytherapy delivery device—a first-in-man study
Int. J. Radiat. Oncol. Biol. Phys.
(2007) - et al.
Development of a thermosensitive hydrogel system for local delivery of 188Re colloid drugs
Appl. Radiat. Isot.
(2009) - et al.
Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel
Int. J. Radiat. Oncol. Biol. Phys.
(2014) - et al.
Co-delivery of doxorubicin and 131I by thermosensitive micellar-hydrogel for enhanced in situ synergetic chemoradiotherapy
J. Contr. Release
(2015) - et al.
Controlled synthesis and characterizations of amphiphilic poly[(R,S)-3-hydroxybutyrate]-poly(ethylene glycol)-poly[(R,S)-3-hydroxybutyrate] triblock copolymers
Polymer
(2008) - et al.
Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy
Biomaterials
(2018) - et al.
Smart polymeric gels: redefining the limits of biomedical devices
Prog. Polym. Sci.
(2007)
Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma
CA A Cancer J. Clin.
Survival analysis of transarterial radioembolization with yttrium-90 for hepatocellular carcinoma patients with HBV infection
Hepatobiliary Surg. Nutr.
National cancer centre Singapore consensus guidelines for hepatocellular carcinoma
Liver Canc.
Loco-regional treatment of hepatocellular carcinoma
Hepatology
Hepatocellular carcinoma: slow progress in a booming epidemic
J. Oncol. Pract.
Medical management of hepatocellular carcinoma
J. Oncol. Pract.
Hepatocellular carcinoma: where are we?
World J. Exp. Med.
Sensitization to radiation from an implanted 125I source by sustained intratumoral release of chemotherapeutic drugs
Radiat. Res.
Regional radiochemotherapy using in situ hydrogel
Pharm. Res. (N. Y.)
Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma-bearing mice
Cancer
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