Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors

Abstract

Poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30-0.44 and 0.65-0.68 mg/mL in the presence of 5000-5000 and 5000-24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anticancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anticancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin-I and B.

STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease

“…We inhibited ERK 1/2 phosphorylation with SL327, a selective inhibitor of MEK 1/2, the upstream MAPKK, [17][18][19][20] and STAT-3 phosphorylation with cucurbitacin E and I, compounds that target upstream Janus kinases. [21][22][23][24] We first assessed whether inhibiting ERK 1/2 phosphorylation with SL327 could attenuate the proliferation of normal B6 splenic T cells in response to anti-CD3 ϩ CD28 stimulation in vitro, and found a dose-dependent suppression of proliferation ( Figure 2A). We evaluated the toxicity of SL327 and found that T cells were not significantly apoptotic at concentrations below 100 ng/mL (not shown).…”

Chemical Modification of Hydrophobic Block in Poly(Ethylene Oxide) Poly(Caprolactone) Based Nanocarriers: Effect on the Solubilization and Hemolytic Activity of Amphotericin B

“…[7,9] Nanocarriers formed from self assembly of MePEO-b-PCL bearing pendent benzyl groups on their PCL block have particularly shown superior capacity for the encapsulation and controlling the release of hydrophobic drugs containing aromatic as well as hydrogen bond forming groups in their structure. [29] A new member in this family of block copolymers, i.e., MePEO-b-PCL copolymers bearing aliphatic stearyl side groups on the PCL block were synthesized (Scheme 1) and their potential in the solubilization of an aliphatic and amphiphilic drug, AmB, was assessed here. A similar strategy has proven to be successful in the solubilization and controlling the delivery of AmB from MePEO-b-poly(L-aspartic acid) based micellar carriers.…”

Cucurbitacin-I inhibits Aurora kinase A, Aurora kinase B and survivin, induces defects in cell cycle progression and promotes ABT-737-induced cell death in a caspase-independent manner in malignant human glioma cells

“…41 Inhibition of JAK2/STAT3 signaling with cucurbitacin-I (JSI-124), 42 a natural plant product, has been shown to have potent anti-cancer activities in hematological malignancies and solid tumors. [43][44][45][46][47] Several lines of evidence have indicated that cucurbitacin-I promotes cell cycle arrest and/or apoptosis in glioma, 48,49 lung, 42,50 breast, 51 and other malignancies. [52][53][54][55] Previously we observed that blockade of the JAK/STAT pathway by cucurbitacin-I enhanced the efficacy of SRC family kinase (SFK) inhibition with dasatinib in glioma cells.…”