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. 2021 Apr 1;109(5):1483-1494.
doi: 10.1016/j.ijrobp.2020.11.052. Epub 2020 Nov 27.

Localized Delivery of Cisplatin to Cervical Cancer Improves Its Therapeutic Efficacy and Minimizes Its Side Effect Profile

Cinzia Federico  1 , Jennifer Sun  1 , Barbara Muz  2 , Kinan Alhallak  1 , Pippa F Cosper  3 , Naoshad Muhammad  2 , Amanda Jeske  1 , Amanda Hinger  2 , Stephanie Markovina  4 , Perry Grigsby  4 , Julie K Schwarz  4 , Abdel Kareem Azab  5
Affiliations

Localized Delivery of Cisplatin to Cervical Cancer Improves Its Therapeutic Efficacy and Minimizes Its Side Effect Profile

Cinzia Federico et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects.

Methods and materials: Twenty patient biopsies and 5 cell lines treated with cisplatin were analyzed for platinum content using inductively coupled plasma mass spectrometry. Polymeric implants loaded with cisplatin were developed and evaluated for degradation and drug release. The effect of local or systemic cisplatin delivery on drug biodistribution as well as tumor burden were evaluated in vivo, in combination with radiation therapy.

Results: Platinum levels in patient biopsies were 6-fold lower than the levels needed for efficacy and radiosensitization in vitro. Cisplatin local delivery implant remarkably improved drug specificity to the tumor and significantly decreased accumulation in the blood, kidney, and other distant normal organs, compared with traditional systemic delivery. The localized treatment further resulted in complete inhibition of tumor growth.

Conclusions: The current standard-of-care systemic administration of cisplatin provides a subtherapeutic dose. We developed a polymeric drug delivery system that delivered high doses of cisplatin directly into the cervical tumor, while lowering drug accumulation and consequent side effects in normal tissues. Moving forward, these data will be used as the basis of a future first-in-human clinical trial to test the efficacy of localized cisplatin as adjuvant or neoadjuvant chemotherapy in local and regional cervical cancer.

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Conflict of interest statement

Conflict of interest: C.F., J.S., J.K.S. and A.K.A. have a patent pending regarding the technology described in this paper.

Figures

Figure 1.
Figure 1.. The effect of intracellular cisplatin (Cis-Pt) on anti-tumor efficacy.
(A) Platinum (Pt) concentration in patient biopsy samples (n=20) and in cell lines treated at Av-IC50 (n=5), measured by inductively coupled plasma mass spectrometry (ICP-MS). (B) Relatively number of surviving clones as % of untreated. P-values represent comparisons against 0μM Cis-Pt condition in respective radiation dose (** p < 0.01).
Figure 1.
Figure 1.. The effect of intracellular cisplatin (Cis-Pt) on anti-tumor efficacy.
(A) Platinum (Pt) concentration in patient biopsy samples (n=20) and in cell lines treated at Av-IC50 (n=5), measured by inductively coupled plasma mass spectrometry (ICP-MS). (B) Relatively number of surviving clones as % of untreated. P-values represent comparisons against 0μM Cis-Pt condition in respective radiation dose (** p < 0.01).
Figure 2.
Figure 2.. Characterization of polyethylene glycol (PEG) implants.
(A) In vitro dissolution profile of empty implants, calculated as percent of original size at 0 min. (B) In vitro drug release profile of Cis-Pt loaded implants, calculated as % of total dose. (C) Representative images for in vivo dissolution of DiR-loaded implants in mice (n=5). (D) In vivo dissolution profile, calculated as percent area in the abdomen with DiR signal.
Figure 2.
Figure 2.. Characterization of polyethylene glycol (PEG) implants.
(A) In vitro dissolution profile of empty implants, calculated as percent of original size at 0 min. (B) In vitro drug release profile of Cis-Pt loaded implants, calculated as % of total dose. (C) Representative images for in vivo dissolution of DiR-loaded implants in mice (n=5). (D) In vivo dissolution profile, calculated as percent area in the abdomen with DiR signal.
Figure 2.
Figure 2.. Characterization of polyethylene glycol (PEG) implants.
(A) In vitro dissolution profile of empty implants, calculated as percent of original size at 0 min. (B) In vitro drug release profile of Cis-Pt loaded implants, calculated as % of total dose. (C) Representative images for in vivo dissolution of DiR-loaded implants in mice (n=5). (D) In vivo dissolution profile, calculated as percent area in the abdomen with DiR signal.
Figure 2.
Figure 2.. Characterization of polyethylene glycol (PEG) implants.
(A) In vitro dissolution profile of empty implants, calculated as percent of original size at 0 min. (B) In vitro drug release profile of Cis-Pt loaded implants, calculated as % of total dose. (C) Representative images for in vivo dissolution of DiR-loaded implants in mice (n=5). (D) In vivo dissolution profile, calculated as percent area in the abdomen with DiR signal.
Figure 3.
Figure 3.. In vivo localized Cis-Pt delivery compared to systemic Cis-Pt delivery.
(A) Schematic for in vivo subcutaneous tumor model and the local delivery of the device. (B) In vivo biodistribution profile of Cis-Pt (n=5), measured by Pt levels in various organs, 24 hours after Cis-Pt-Implant or Cis-Pt-IV administration. (* p < 0.05; ** p < 0.01; *** p < 0.001). Insert on top right shows a zoomed in view of the biodistribution profile. (C) Ratios for Pt levels in tumor, blood, and kidney, as well as tumor/blood Pt ratios seen in Cis-Pt-Implant and Cis-Pt-IV groups.
Figure 3.
Figure 3.. In vivo localized Cis-Pt delivery compared to systemic Cis-Pt delivery.
(A) Schematic for in vivo subcutaneous tumor model and the local delivery of the device. (B) In vivo biodistribution profile of Cis-Pt (n=5), measured by Pt levels in various organs, 24 hours after Cis-Pt-Implant or Cis-Pt-IV administration. (* p < 0.05; ** p < 0.01; *** p < 0.001). Insert on top right shows a zoomed in view of the biodistribution profile. (C) Ratios for Pt levels in tumor, blood, and kidney, as well as tumor/blood Pt ratios seen in Cis-Pt-Implant and Cis-Pt-IV groups.
Figure 3.
Figure 3.. In vivo localized Cis-Pt delivery compared to systemic Cis-Pt delivery.
(A) Schematic for in vivo subcutaneous tumor model and the local delivery of the device. (B) In vivo biodistribution profile of Cis-Pt (n=5), measured by Pt levels in various organs, 24 hours after Cis-Pt-Implant or Cis-Pt-IV administration. (* p < 0.05; ** p < 0.01; *** p < 0.001). Insert on top right shows a zoomed in view of the biodistribution profile. (C) Ratios for Pt levels in tumor, blood, and kidney, as well as tumor/blood Pt ratios seen in Cis-Pt-Implant and Cis-Pt-IV groups.
Figure 4.
Figure 4.. In vivo tumor penetration of Cis-Pt released from implants.
(A) Assessment of Pt distribution in different sections of the tumors after treatment with empty or Cis-Pt implants using two different methods: ICP-MS and immunofluorescence (IF). (B) Pt concentration in each tumor layer from Cis-Pt implant group (n=3) by ICP-MS analysis, adjusted with background signal from empty implant group (n=3). (C) Fluorescence microscopy images of regions of tumor sections, stained with antibody for Cis-Pt induced DNA adducts (AF488) and counterstained with DAPI. Gray lines indicate the edge of the tissue.
Figure 4.
Figure 4.. In vivo tumor penetration of Cis-Pt released from implants.
(A) Assessment of Pt distribution in different sections of the tumors after treatment with empty or Cis-Pt implants using two different methods: ICP-MS and immunofluorescence (IF). (B) Pt concentration in each tumor layer from Cis-Pt implant group (n=3) by ICP-MS analysis, adjusted with background signal from empty implant group (n=3). (C) Fluorescence microscopy images of regions of tumor sections, stained with antibody for Cis-Pt induced DNA adducts (AF488) and counterstained with DAPI. Gray lines indicate the edge of the tissue.
Figure 4.
Figure 4.. In vivo tumor penetration of Cis-Pt released from implants.
(A) Assessment of Pt distribution in different sections of the tumors after treatment with empty or Cis-Pt implants using two different methods: ICP-MS and immunofluorescence (IF). (B) Pt concentration in each tumor layer from Cis-Pt implant group (n=3) by ICP-MS analysis, adjusted with background signal from empty implant group (n=3). (C) Fluorescence microscopy images of regions of tumor sections, stained with antibody for Cis-Pt induced DNA adducts (AF488) and counterstained with DAPI. Gray lines indicate the edge of the tissue.
Figure 5.
Figure 5.. In vivo efficacy of Cis-Pt implants for cervical cancer.
(A) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, without irradiation. (B) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, with 2 Gy/day irradiation for 5 consecutive days. (C) Tumor progression for Cis-Pt-Implant with fractioned radiation (2 Gy/day x 5 days) or high dose brachytherapy (8 Gy once). (* p < 0.05; ** p < 0.01; *** p < 0.001).
Figure 5.
Figure 5.. In vivo efficacy of Cis-Pt implants for cervical cancer.
(A) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, without irradiation. (B) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, with 2 Gy/day irradiation for 5 consecutive days. (C) Tumor progression for Cis-Pt-Implant with fractioned radiation (2 Gy/day x 5 days) or high dose brachytherapy (8 Gy once). (* p < 0.05; ** p < 0.01; *** p < 0.001).
Figure 5.
Figure 5.. In vivo efficacy of Cis-Pt implants for cervical cancer.
(A) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, without irradiation. (B) Tumor progression for treatment conditions Vehicle-IV, Cis-Pt-IV, or Cis-Pt-Implant, with 2 Gy/day irradiation for 5 consecutive days. (C) Tumor progression for Cis-Pt-Implant with fractioned radiation (2 Gy/day x 5 days) or high dose brachytherapy (8 Gy once). (* p < 0.05; ** p < 0.01; *** p < 0.001).
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References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. - PubMed
    1. Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020;8(2):e191–e203. - PMC - PubMed
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. - PubMed
    1. WHO. Cervical cancer. World Health Organization. https://www.who.int/cancer/prevention/diagnosis-screening/cervical-cance.... Published 2018. Accessed March 18, 2019.
    1. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393(10167):169–182. - PubMed

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