In basic investigation of this study, we compounded a novel drug combination of thermogelling hydrogel carboplatin to satisfy the unmet clinical need for glioma treatment.
Through the comprehensive biomaterial, cell, and animal experiment design, we significantly demonstrated that thermogelling hydrogel carboplatin simplified the drug delivery method
42
and frequency without compromising the synergistic effect with RT, which makes intraoperative single drug injection followed by RT a feasible and potential clinical treatment.
We chose carboplatin with well-established CCRT effects and hydrogel with well-accepted biocompatible features as a novel drug delivery combination, which helps accelerate the application process for further clinical trials. The impact of our study results is that we significantly demonstrated intratumoral injection of hydrogel carboplatin with RT as an effective, convenient, and safe treatment combination for malignant gliomas which is potential for clinical application.
43
Figure 1. The clinical and basic research perspectives of our glioblastoma study. We
proposed a comprehensive study, including imaging analysis and drug delivery investigation, to satisfy the clinical unmet needs for glioblastoma treatment.44
Figure 2. The correlation between tumor location with edema and tumor migration.
The interactions between the anatomical factor subventricular zone (red line) and corpus callosum (green line) the pathophysiological factor preoperative edema (blue color wash) and the associated clinical impacts, including tumor migration ability and directions (black line with arrow) [64].
45
Figure 3. The rationale and purpose in the current basic study: by comparing the
characteristics of the intratumoral delivery modalities and drugs for malignant gliomas to propose a novel combination to satisfy the unmet clinical need [59].46
Figure 4. The method of evaluating the preoperative edema extent in our clinical study.
(A) Select the image section that presents the maximum diameter of preoperative tumor. (B) Create a 2-cm expansion of tumor edge along SVZ (the lateral wall of lateral ventricles) or CC if these structures are invaded. Otherwise, draw tangential lines to the tumor edge and then use their normal lines to expand a 2-cm margin of the tumor edge. (C) Use the 2-cm expansion margin of tumor edge as a reference boundary to evaluate the PE extent. (D) Apply the 2-cm expansion margin of the preoperative tumor edge on the similar image sections after CCRT to evaluate the PD extent [64].
47
Figure 5. The definitions of edema extent and progression patterns. (A) Illustrations of
(A1) EPE (PE ≥ 2 cm from the tumor margin) combined with (A2) sSVZCC invasion to evaluate the rates of EPD (continuous or discrete progression of tumors spreading along the48
PE areas and > 2 cm from the tumor margin), (A3) SVZEPD, and CCEPD after CCRT. (B) Illustrations of (B1) EPE− and (B2) sSVZCC+/− invasion to evaluate the rate of (B3) EPD after CCRT. (C) Illustrations of (C1) EPE+ and (C2) sSVZCC+/− invasion to evaluate the rates of (C3) EPD, SVZEPD, and CCEPD [64].
Figure 6. The workflow of our basic study design: biomaterial, in vitro, and in vivo
investigations [59].49
Figure 7. Drug preparation: the procedures of (A) oxi-HA/ADH hydrogel and (B)
hydrogel carboplatin preparation. (Figures courtesy of Xue-Shi Lai, MSc.)50
Figure 8. The treatment regimens and evaluation protocol of our mice study: (A)
low-dose carboplatin (first-stage experiment) and (B) high-low-dose carboplatin (second-stage experiment) [59].15 µg/g 3 µg/g
51
Figure 9. Kaplan-Meier’s estimates of (A1) OS and (A2) PFS for patients with and
without EPE, (B1) OS and (B2) PFS for patients with and without sSVZCC invasion [64].52
Figure 10. MRI demonstration of patients with different tumor locations. Distinct
progression patterns after CCRT in 4 patients categorized according to the different combinations of the SVZ and CC invasion. (A1, A2) The patient with synchronous left occipital horn of the SVZ (red dashed lines) and left posterior CC (green dashed lines) invasion exhibited distant progression to the left cerebellum (blue arrow). (A3) Other53
progression (blue arrow) developed in the preoperative edematous areas (blue dashed lines), which migrated across the posterior CC to the contralateral hemisphere (yellow dashed arrows). (B1, B2) The patient with synchronous left frontal horn of the SVZ (red dashed lines) and left anterior CC (green dashed lines) invasion showed progression in the tumor bed of the left anterior CC (red arrows) and the distant area at the left posterior CC along the occipital horn (blue arrows). (C) The patient with left temporal horn of the SVZ (red dashed lines) but without CC invasion exhibited progression involving the tumor bed only (red arrow). (D) The patient with neither SVZ nor CC invasion showed progression involving the tumor bed only (red arrow) [23].
54
55
Figure 11. MRI demonstration of patients with different edema extents and tumor locations. Distinct progression patterns after CCRT in five patients categorized according to
the different combinations of EPE and sSVZCC invasion. A patient with (A1,2) EPE−/sSVZCC− before surgery presented with (A3) local progression without EPD. Another patient with (B1,2) EPE−/sSVZCC+ before surgery presented with (B3) local progression without EPD. Panels C1,2 demonstrate a patient with EPE+/sSVZCC− before surgery, who presented with (C3) local progression with EPD. Panels D1,2 show a patient with EPE+/sSVZCC+ and CCEPE before surgery, who presented with (D3) local progression with EPD along the CC. Panels E1,2 describe a patient with EPE+/sSVZCC+ and SVZEPE before surgery, who presented with (E3) local progression with EPD along the SVZ [64].Figure 12. Illustrations of by FTIR analysis: (A1) the spectrum peak at 1730 cm-1 of
oxi-HA disappeared after mixing oxi-oxi-HA with ADH and the appearance of a new forming peak at 1528 cm-1 of oxi-HA/ADH and (A2) the appearance of a new forming peak at 545 cm-1 of oxi-HA/ADH hydrogel carboplatin [59].56
Figure 13. The rheological properties of HA/ADH: (A1) the gelation of
HA/ADH started at temperature higher than 27.6 °C and (A2) the gelling time of oxi-HA/ADH from liquid state to gel state were 17 seconds at 37 °C (body temperature) [59].Figure 14. Degradation properties of oxi-HA/ADH hydrogel: At 72 and 120 h,
degradation percentages for oxi-HA/ADH (Figure 4C) were 5.2% and 18.2%, respectively [59].
57
Figure 15. Drug release profile: The ICP-MS result demonstrates two phases of the
carboplatin release from hydrogel, including a burst release of 63.7% during the first 24 h, followed by a steady release of 16.6% over the 24 to 96 h [59].Figure 16. Biocompatibility of oxi-HA/ADH: (A) The WST-1 analysis demonstrated the
cell viability of 3T3 cells cultured in oxi-HA/ADH hydrogel extraction medium was not significantly different compared with those in the control and negative control groups (p = 0.644). (B) The LDH assay indicated the cytotoxicity oxi-HA/ADH is not significantly different from the negative control group (p = 0.173) [59].58
Figure 17. The LIVE/DEAD staining: Nearly all the 3T3 cells were viable in the
oxi-HA/ADH hydrogel after 3 days’ cultivation [59].Figure 18. The IC
50test of carboplatin: The in vitro concentrations of carboplatin to inhibit
50% ALCS1C1 cells to proliferation was 44.4 and 18.5 µg/mL after 1-day and 3-day treatment, respectively [59].59
Figure 19. The BLIs evolution of the first-stage in vivo experiment. Comparing with the
sham group, the BLIs demonstrate the relatively delayed tumor progression in all treatment groups [59].60
Figure 20. The tumor volume evolution of the first-stage in vivo experiment.
On day 24, the tumor volume analysis (excepting sham group) by one-way ANOVA showed no difference of tumor progression for RT with and without low-dose carboplatin (p = 0.787) [59].61
Figure 21. The BLIs evolution of the second-stage in vivo experiment. The BLIs
demonstrate the tumor nearly complete response in HCR and ACR groups, while tumor progression in other treatment groups [59].Figure 22. The bioluminescence signal of the second-stage in vivo experiment [59].
62
Figure 23. The tumor volume evolution of the second-stage in vivo experiment. In ACR
and HCR groups, the tumor volume curves demonstrate good tumor control without difference (p = 0.904) [59].Figure 24. The survival curves of the second-stage in vivo experiment: The HCR and
ACR groups had 104-day survival rates of 50% and 66.7% without significant difference (p= 0.648) [59].
63
Figure 25. The gross and histopathological findings of the second-stage in vivo
experiment: (A) The blue area illustrated the diameters of dye distribution 1 day and 3 days
after oxi-HA/ADH hydrogel dye injection were 7 and 9 mm, respectively. (B1) The H&E stain of tumor receiving RT showed both cell death (yellow rectangular area at 100× and yellow arrow at 400×) and tumor cell proliferation (red rectangular area at 100× and red arrow at 400×). The H&E stain of tumor receiving either aqueous carboplatin with RT (B2) or hydrogel carboplatin with RT (B3) showed prominent cell death. Contrastingly, H&E stain of tumor cell growth under no treatment (C1) and injection of hydrogel (C2), aqueous carboplatin (C3), and hydrogel carboplatin (C4) all showed tumor cell proliferation only [59].64
Figure 26. The weight change and skin reaction of mice in the second-stage in vivo
experiment: (A) Mice weight change in the second-stage experiment. (B) No skin ulcer after
treatment of RT with high-dose (C1) hydrogel carboplatin or (C2) aqueous carboplatin [59].65
Figure 27. The proposed personalized glioblastoma treatment strategies [59].
66
Figure 28. Progression patterns and sSVZCC invasion. The comprehensive progression
conditions for sSVZCC invasion patients (C1) after CCRT. (C2) The progression sites analysis classified by the anatomical structures. (C3) The progression patterns analysis based on the progressive tumor locations corresponding to the tumor bed and preoperative edematous areas. Abbreviations: C, corpus callosum; D, distant; E, edema; H, bilateral hemispheres; L, local; V, ventricles [23]67
TABLES
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