Targeted Treatment of Sarcomas by Single Protein Encapsulated Doxorubicin with Undetectable Cardiotoxicity and Superior Efficacy

Abstract

As rare tumors, sarcomas represent ~0 [...].

Keywords: Ewing sarcoma; FcRn expression level; SPEDOX-6; cardiotoxicity; doxorubicin; single protein encapsulation; soft tissue sarcoma; toxicokinetic; triple negative breast cancer.

Figure 1

Computer docking images of SPEDOX-6 (HSA:DOX = 1:9, A₅₄₇/A₄₈₁ = 0.53).

Figure 2

SPEDOX-6’s antitumor efficacy study in HT-1080 animal model, drug injections on Days 0, 6, and 13 indicated by arrow signs. (A) Mean TV vs. treatment time for all mice. Mice # for each group, control (n = 8), DOX treatment (n = 8), SPEDOX-6 A at 15 mg/kg (n = 9), and SPEDOX-6 Bat 17.5 mg/kg (n = 10). On Day 6, control group is significantly different from the 3 treatment groups (****, p < 0.0001); on Day 20, SPEDOX-6 B group significantly reduced TV compared to DOX group (*, p = 0.0175). (B) Comparison of the final TV for the treatment groups on Day 20. (C) Mean BW change vs. treatment time for all mice, not significantly different from each other.

Figure 3

Photographic images of tumors of each group at the end of experiments. (Top) Control groups on Days 6 and 9 when mice were euthanized due to fast tumor growth. (Bottom) Treatment groups on Day 20 when the experiment ended. One male was sacrificed on Day 12 due to large tumor size. On Day 20, 2/5 and 1/5 males reached tumor-free status (complete remission).

Figure 4

SPEDOX-6’s antitumor efficacy study in SK-ES-1 animal model drug injections at Days 0, 6, and 13, indicated by arrow signs. (A) Mean TV vs. treatment time for all mice. Each testing group contains 4 male and 4 female mice. On Day 8, DOX had 18.4% TGI, lower than control group (NS, p = 0.557); Doxil treatment reached 36.4% TGI, significantly lower than control group (*, p = 0.0116); SPEDOX-6 achieved 54.0% TGI, significantly lower than control group (***, p < 0.0001); SPEDOX-6 significantly reduced tumor volume compared to DOX group (*, p = 0.0183). On Day 21, SPEDOX-6 significantly reduced tumor volume compared to Doxil group (**, p = 0.0016), calculated by 2-way ANOVA and mixed-effects analysis. (B) Mean BW change vs. treatment time for all mice, not significantly different from each other (ns, p > 0.05).

Figure 5

Immunohistochemical tissue following drug treatment. (A) Staining images (40X) of paraffin-embedded tumor tissues (SK-ES-1) sections for H&E, Ki67, and cleaved/active caspase-3 for tumor tissues for control group, DOX (3.5 mg/kg), Doxil (4.0 mg/kg), and SPEDOX-6 (30 mg/kg). (B) Comparison of Ki67-positive cells among different treatments. The difference is significant between SPEDOX-6 and Doxil (***, p = 0.001) and between SPEDOX-6 and control (****, p < 0.0001), but no significance is found between SPEDOX-6 and Dox (ns, p = 0.2827). (C) Comparison of caspase-3 active cells. There is significant statistical difference between SPEDOX-6 and the other 3 samples (****, p < 0.0001).

Figure 6

Antitumor efficacy of different tumor models in relation to DOX IC₅₀ and FcRn expression levels. (A) Mean TV vs. treatment times for STS, TNBC, and ES mouse models treated with SPEDOX-6 at 20, 17.5, and 30 mg/kg, respectively; (B) TV change at end of the treatment vs. DOX IC₅₀ values for STS, TNBC, and ES; (C) TV change at end of the treatment vs. FcRn levels of ES, TNBC, and STS mouse models; (D) plot of TV change at end of treatment vs. log FcRn value of the three mouse models.