Simulation of spatial diffusion of platinum from carboplatin-impregnated calcium sulfate hemihydrate beads by use of an agarose gelatin tissue phantom

Heidi Phillips Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

Search for other papers by Heidi Phillips in
Current site
Google Scholar
PubMed
Close
 VMD
,
Elizabeth A. Maxwell Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

Search for other papers by Elizabeth A. Maxwell in
Current site
Google Scholar
PubMed
Close
 DVM
,
David J. Schaeffer Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

Search for other papers by David J. Schaeffer in
Current site
Google Scholar
PubMed
Close
 PhD
, and
Timothy M. Fan Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

Search for other papers by Timothy M. Fan in
Current site
Google Scholar
PubMed
Close
 DVM, PhD

Click on author name to view affiliation information

Abstract

OBJECTIVE To characterize spatial release of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads by use of an agarose tissue phantom.

SAMPLE 3-mm-diameter beads (n = 60) containing 4.6 mg of carboplatin (2.4 mg of platinum)/bead.

PROCEDURES 18 L of 1% agarose was prepared and poured into 36 containers (10 × 10 × 10 cm), each of which was filled half full (0.5 L/container). After the agarose solidified, 1, 3, 6, or 10 CI-CSH beads were placed on the agar in defined patterns. An additional 36 blocks of agar (0.5 L/block) were placed atop the beads, positioning the beads in the center of 1 L of agar. The experiment was replicated 3 times for each bead pattern for 24, 48, and 72 hours. At these times, representative agarose blocks were sectioned in the x-, y-, and z-planes and labeled in accordance with their positions in shells radiating 1, 2, 3, 4, and 5 cm from the center of the blocks. Agarose from each shell was homogenized, and a sample was submitted for platinum analysis by use of inductively coupled plasma–mass spectroscopy.

RESULTS Platinum diffused from CI-CSH beads at predicted anticancer cytotoxic concentrations for 2 to 5 cm.

CONCLUSIONS AND CLINICAL RELEVANCE Results provided information regarding the spatial distribution of platinum expected to occur in vivo. Agarose may be used as a diffusion model, mimicking the characteristics of subcutaneous tissues. Measured platinum concentrations might be used to guide patterns for implantation of CI-CSH beads in animals with susceptible neoplasms.

Abstract

OBJECTIVE To characterize spatial release of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads by use of an agarose tissue phantom.

SAMPLE 3-mm-diameter beads (n = 60) containing 4.6 mg of carboplatin (2.4 mg of platinum)/bead.

PROCEDURES 18 L of 1% agarose was prepared and poured into 36 containers (10 × 10 × 10 cm), each of which was filled half full (0.5 L/container). After the agarose solidified, 1, 3, 6, or 10 CI-CSH beads were placed on the agar in defined patterns. An additional 36 blocks of agar (0.5 L/block) were placed atop the beads, positioning the beads in the center of 1 L of agar. The experiment was replicated 3 times for each bead pattern for 24, 48, and 72 hours. At these times, representative agarose blocks were sectioned in the x-, y-, and z-planes and labeled in accordance with their positions in shells radiating 1, 2, 3, 4, and 5 cm from the center of the blocks. Agarose from each shell was homogenized, and a sample was submitted for platinum analysis by use of inductively coupled plasma–mass spectroscopy.

RESULTS Platinum diffused from CI-CSH beads at predicted anticancer cytotoxic concentrations for 2 to 5 cm.

CONCLUSIONS AND CLINICAL RELEVANCE Results provided information regarding the spatial distribution of platinum expected to occur in vivo. Agarose may be used as a diffusion model, mimicking the characteristics of subcutaneous tissues. Measured platinum concentrations might be used to guide patterns for implantation of CI-CSH beads in animals with susceptible neoplasms.

  • 1. Page RL, McEntee MC, George SL, et al. Pharmacokinetic and phase I evaluation of carboplatin in dogs. J Vet Intern Med 1993;7:235240.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Mittal A, Chitkara D, Kumar N. HPLC method for the determination of carboplatin and paclitaxel with cremophorEL in an amphiphilic polymer matrix. J Chromatogr B Analyt Technol Biomed Life Sci 2007;855:211219.

    • Search Google Scholar
    • Export Citation
  • 3. Xiong Y, Jiang W, Shen Y, et al. A poly(gamma, L-glutamic acid)-citric acid based nanoconjugate for cisplatin delivery. Biomaterials 2012;33:71827193.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. Gavini E, Manunta L, Giua S, et al. Spray-dried poly(D,L-lactide) microspheres containing carboplatin for veterinary use: in vitro and in vivo studies. AAPS PharmSciTech 2005;6:E108E114.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Withrow SJ, Liptak JM, Straw RC, et al. Biodegradable cisplatin polymer in limb-sparing surgery for canine osteosarcoma. Ann Surg Oncol 2004;11:705713.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Araki H, Tani T, Kodama M. Antitumor effect of cisplatin incorporated into polylactic acid microcapsules. Artif Organs 1999;23:161168.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Manunta ML, Gavini E, Chessa G, et al. Carboplatin sustained delivery system using injectable microspheres. J Vet Med A Physiol Pathol Clin Med 2005;52:416422.

    • Search Google Scholar
    • Export Citation
  • 8. Havlicek M, Straw RS, Langova V, et al. Intra-operative cisplatin for the treatment of canine extremity soft tissue sarcomas. Vet Comp Oncol 2009;7:122129.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Arlt M, Haase D, Hampel S, et al. Delivery of carboplatin by carbon-based nanocontainers mediates increased cancer cell death. Nanotechnology 2010;21:335101.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10. Atilla A, Boothe HW, Tollett M, et al. In vitro elution of amikacin and vancomycin from impregnated plaster of Paris beads. Vet Surg 2010;39:715721.

    • Search Google Scholar
    • Export Citation
  • 11. Chen C, Wang W, Zhou H, et al. Pharmacokinetic comparison between systemic and local chemotherapy by carboplatin in dogs. Reprod Sci 2009;16:10971102.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Hewes CA, Sullins KE. Use of cisplatin-containing biodegradable beads for treatment of cutaneous neoplasia in equidae: 59 cases (2000–2004). J Am Vet Med Assoc 2006;229:16171622.

    • Search Google Scholar
    • Export Citation
  • 13. Straw RC, Withrow SJ, Douple EB, et al. Effects of cis-diamminedichloroplatinum II released from D, L-polylactic acid implanted adjacent to cortical allografts in dogs. J Orthop Res 1994;12:871877.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Venable RO, Worley DR, Gustafson DL, et al. Effects of intratumoral administration of a hyaluronan-cisplatin nanoconjugate to five dogs with soft tissue sarcomas. Am J Vet Res 2012;73:19691976.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15. Lana SE, Dernell WS, LaRue SM. Slow release cisplatin combined with radiation for the treatment of canine nasal tumors. Vet Radiol Ultrasound 1997;38:474478.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16. Simcock JO, Withers SS, Prpich CY, et al. Evaluation of a single subcutaneous infusion of carboplatin as adjuvant chemotherapy for dogs with osteosarcoma: 17 cases (2006–2010). J Am Vet Med Assoc 2012;241:608614.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Santschi EM, McGarvey L. In vitro elution of gentamicin from plaster of Paris beads. Vet Surg 2003;32:128133.

  • 18. Bowyer GW, Cumberland N. Antibiotic release from impregnated pellets and beads. J Trauma 1994;36:331335.

  • 19. Seddighi MR, Griffon DJ, Constable PD, et al. Effects of porcine small intestinal submucosa on elution characteristics of gentamicin-impregnated plaster of Paris. Am J Vet Res 2007;68:171177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Dacquet V, Varlet A, Tandogan RN, et al. Antibiotic-impregnated plaster of Paris beads. Trials with teicoplanin. Clin Orthop Relat Res 1992; (282):241249.

    • Search Google Scholar
    • Export Citation
  • 21. Rosenblum SF, Frenkel S, Ricci JR, et al. Diffusion of fibroblast growth factor from a plaster of Paris carrier. J Appl Biomater 1993;4:6772.

  • 22. Phillips H, Boothe DM, Bennett RA. In vitro elution of clindamycin and enrofloxacin from calcium sulfate hemihydrate beads. Vet Surg 2015;44:10031011.

    • Search Google Scholar
    • Export Citation
  • 23. Tulipan RJ, Phillips H, Garrett LD, et al. Elution of platinum from carboplatin-impregnated calcium sulfate hemihydrate beads in vitro. Am J Vet Res 2016;77:12521257.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Tulipan RJ, Phillips H, Garrett LD, et al. Characterization of long-term elution of platinum from carboplatin-impregnated calcium sulfate hemihydrate beads in vitro by two distinct sample collection methods. Am J Vet Res 2017;78:618623.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25. Bergman NS, Urie BK, Pardo AD, et al. Evaluation of local toxic effects and outcomes for dogs undergoing marginal tumor excision with intralesional cisplatin-impregnated bead placement for treatment of soft tissue sarcomas: 62 cases (2009–2012). J Am Vet Med Assoc 2016;248:11481156.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Johnson JG III, Naples LM, Chu C, et al. Cutaneous squamous cell carcinoma in a panther chameleon (Furcifer pardalis) and treatment with carboplatin implantable beads. J Zoo Wildl Med 2016;47:931934.

    • Search Google Scholar
    • Export Citation
  • 27. Maxwell EA, Phillips H, Schaeffer DJ, et al. In vitro chemosensitivity of feline injection site-associated sarcoma cell lines to carboplatin. Vet Surg 2018;47:219226.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Knapp DW, Chan TC, Kuczek T, et al. Evaluation of in vitro cytotoxicity of nonsteroidal anti-inflammatory drugs against canine tumor cells. Am J Vet Res 1995;56:801805.

    • Search Google Scholar
    • Export Citation
  • 29. Simon D, Knebel JW, Baumgartner W, et al. In vitro efficacy of chemotherapeutics as determined by 50% inhibitory concentrations in cell cultures of mammary gland tumors obtained from dogs. Am J Vet Res 2001;62:18251830.

    • Search Google Scholar
    • Export Citation
  • 30. de Brito Galvao JF, Kisseberth WC, Murahari S, et al. Effects of gemcitabine and gemcitabine in combination with carboplatin on five canine transitional cell carcinoma cell lines. Am J Vet Res 2012;73:12621272.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31. Jensen SS, Jensen H, Møller EH, et al. In vitro release studies of insulin from lipid implants in solution and in a hydrogel matrix mimicking the subcutis. Eur J Pharm Sci 2016;81:103112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32. Klose D, Azaroual N, Siepmann F, et al. Towards more realistic in vitro release measurement techniques for biodegradable microparticles. Pharm Res 2009;26:691699.

    • Search Google Scholar
    • Export Citation
  • 33. Leung DH, Kapoor Y, Alleyne C. Development of a convenient in vitro gel diffusion model for predicting the in vivo performance of subcutaneous parenteral formulations of large and small molecules. AAPS PharmSciTech 2017;18:22032213.

    • Search Google Scholar
    • Export Citation
  • 34. Kreye F, Siepmann F, Siepmann J. Lipid implants as drug delivery systems. Expert Opin Drug Deliv 2008;5:291307.

  • 35. Larsen C, Larsen SW, Jensen H, et al. Role of in vitro release models in formulation development and quality control of parental depot. Expert Opin Drug Deliv 2009;6:12831295.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36. Kinnunen HM, Mrsny RJ. Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site. J Control Release 2014;182:2232.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37. Medlicott NJ, Waldron NA, Foster TP. Sustained release veterinary parenteral products. Adv Drug Deliv Rev 2004;56:13451365.

  • 38. Richter WF, Bhansali SG, Morris ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 2012;14:559570.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39. Scott JE. Extracellular matrix, supramolecular organisation and shape. J Anat 1995;187:259269.

  • 40. Gietz U, Arvinte T, Mader E, et al. Sustained release of injectable zinc-recombinant hirudin suspensions: development and validation of in vitro release model. Eur J Pharm Biopharm 1998;45:259264.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Pernodet N, Maaloum M, Tinland B. Pore size of agarose gels by atomic force microscopy. Electrophoresis 1997;18:5558.

  • 42. Maaloum M, Pernodet N, Tinland B. Agarose gel structure using atomic force microscopy: gel concentration and ionic strength effects. Electrophoresis 1998;19:16061610.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43. Pluen A, Netti PA, Jain RK, et al. Diffusion of macromolecules in agarose gels: comparison of linear and globular configurations. Biophys J 1999;77:542552.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44. D'Souza WD, Madsen EL, Orhan U. Tissue mimicking materials for a multi-imaging modality prostate phantom. Med Phys 2001;28:688700.

  • 45. Deepthi R, Bhargavi R, Jagadeesh K. Rheometric studies on agarose gel—a brain mimic material. SAS Tech J 2010;9:2730.

  • 46. Pomfret R, Miranpuri G, Sillay K. The substitute brain and the potential of the gel model. Ann Neurosci 2013;20:118122.

  • 47. Keall P, Kron T, Hoban P. A Monte Carlo technique to establish the water/tissue equivalence of phantom materials. Australas Phys Eng Sci Med 1993;16:125128.

    • Search Google Scholar
    • Export Citation
  • 48. Sidhu DS, Ruth JD, Lambert G, et al. An easy to produce and economical three-dimensional brain phantom for stereotactic computed tomographic-guided brain biopsy training in the dog. Vet Surg 2017;46:621630.

    • Search Google Scholar
    • Export Citation
  • 49. Bauman MA, Gillies GT, Raghavan R. Physical characterization of neurocatheter performance in a brain phantom gelatin with nanoscale porosity: steady-state and oscillatory flows. Nanotechnology 2004;15:9297.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50. Chen ZJ, Gillies GT, Broaddus WC. A realistic brain tissue phantom for intraparenchymal infusion studies. J Neurosurg 2004;101:314322.

  • 51. Luo B, Yang R, Ying P, et al. Elasticity and echogenicity analysis of agarose phantoms mimicking liver tumors, in Proceedings. 32nd Annu Inst Electr Electron Eng Northeast Biomed Conf 2006;8182.

    • Search Google Scholar
    • Export Citation
  • 52. Madsen EL, Hobson MA, Shi H. Tissue-mimicking agar/gelatin materials for use in heterogeneous elastography phantoms. Phys Med Biol 2005;50:55975618.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53. Saris DB, Mukherjee N, Berglund LJ. Dynamic pressure transmission through agarose gels. Tissue Eng 2000;6:531537.

  • 54. Marble GM, Sullins KE. A biodegradable matrix for cisplatin to treat equine skin neoplasia, in Proceedings. 10th Annu Am Coll Vet Surg Symp 2000;29:469.

    • Search Google Scholar
    • Export Citation
  • 55. Phillips H, Boothe DM, Shofer F, et al. In vitro elution studies of amikacin and cefazolin from polymethylmethacrylate. Vet Surg 2007;36:272278.

    • Search Google Scholar
    • Export Citation
  • 56. Mäkinen TJ, Veiranto M, Lankinen P, et al. In vitro and in vivo release of ciprofloxacin from osteoconductive bone defect filler. J Antimicrob Chemother 2005;56:10631068.

    • Search Google Scholar
    • Export Citation
  • 57. DiMaio FR, O'Halloran JJ, Quale JM. In vitro elution of ciprofloxacin from polymethylmethacrylate cement beads. J Orthop Res 1994;12:7982.

  • 58. Kanellakopoulou K, Panagopoulos P, Giannitsioti E, et al. In vitro elution of daptomycin by a synthetic crystallic semihydrate form of calcium sulfate, stimulan. Antimicrob Agents Chemother 2009;53:31063107.

    • Search Google Scholar
    • Export Citation
  • 59. Wichelhaus TA, Dingeldein E, Rauschmann M, et al. Elution characteristics of vancomycin, teicoplanin, gentamicin and clindamycin from calcium sulphate beads. J Antimicrob Chemother 2001;48:117119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60. Mitchell MD, Kundel HL, Axel L, et al. Agarose as a tissue equivalent phantom material for NMR. Magn Reson Imaging 1986;4:263266.

  • 61. Pomfret R, Sillay K, Miranpuri G. Investigation of the electrical properties of agarose gel: characterization of concentration using Nyquist plot phase angle and the implications of a more comprehensive in vitro model of the brain. Ann Neurosci 2013;20:99107.

    • Search Google Scholar
    • Export Citation
  • 62. Sartin EA, Barnes S, Toivio-Kinnucan M, et al. Heterogenic properties of clonal cell lines derived from canine mammary carcinomas and sensitivity to tamoxifen and doxorubicin. Anticancer Res 1993;13:229236.

    • Search Google Scholar
    • Export Citation

Advertisement