Table 1.
Characterization of Noscapine self-microemulsifying drug delivery (SMEDD) and self-emulsifying solid dispersible (SESDs) formulations for oral delivery.
Fig 1.
Mannosylated microparticle retaines 50% of oral noscapine in 6 hours.
(a) The dissolution rate and release of total noscapine from HPMC-coated spray-dried Nos_SMEDD and Mann-Nos_SMEDD are shown in simulated gastric (pH 2.0) and intestinal (pH 6.8) buffers from 5 min to 24 hr. Results were presented as mean percent of Nos release vs time. (b) Kinetic release of Nos_SMEDD and Mann-Nos_SMEDD showing Higuchi relationship of drug amount released from solid microparticle into dissolution buffer against square root of time. Straight line equation obtained by linear regression. Both formulations were linear with R2 ranging between 0.9905 and 0.9968. Data represents 6 replicates of experiments repeated 2× and differences were not considered significant.
Fig 2.
Mannosylated microparticle saturates noscapine transcytosis.
Transport of Nos formulations across Caco-2 monolayers. (a) Absorptive apparent permeability (Papp) of Nos solution (2.50±0.17 × 10−6 cm/s), Nos_SMEDD (3.43±0.13 × 10−6 cm/s), and Mann-Nos_SMEDD (4.94±0.18 × 10−6 cm/s). (b) Concentration vs time plot of Nos solution and Mann-Nos_SMEDD across Caco-2 monolayers showing linear pseudo zero order transport and apparent first order transport, respectively. (c) Secretory apparent permeability (Papp) of Nos solution (13.66±1.01 × 10–6 cm/s), Nos_SMEDD (5.50±0.65 × 10–6 cm/s), and Mann-Nos_SMEDD (1.03±0.15 × 10–6 cm/s). (d) Efflux ratios of total Nos from Nos solution, Nos_SMEDD, and Mann-Nos_SMEDD. Efflux ratios were estimated by dividing the secretory apparent permeabilities by the corresponding absorptive apparent permeability for each formulation. Results are presented as means ± SD. Results are from triplicates of at least two experiments per group. Differences in means were analyzed by unpaired t-test; P<0.05 were considered significant (***P < 0.0001, vs Nos solution; ###P < 0.0001, vs Nos_SMEDD).
Fig 3.
Mannosylated microparticles have delayed absorption and higher bioavailability.
Fig shows pharmacokinetic profiles of intravenous Nos solution and oral formulations in Sprague-Dawley rats. Rats were fasted overnight and given a single intravenous bolus Nos (2 mg/kg), or 10mg/kg orally as Nos in corn oil, Nos_SMEDD, and Mann-Nos_SMEDD. Plasma samples were obtained and analyzed for the concentration of Nos as described in Materials and Methods. Data are presented as means ± SD of plasma concentration of Nos (μg/mL) with time (n = 3 per group).
Table 2.
Pharmacokinetic profiles of noscapine formulations in rats.
Fig 4.
Chemoresistant H1650 SP cells are sensitized to Cisplatin by Nos_SESDs and Mann-Nos_SESDs.
(a) H1650 SP cells showed higher spheroid formation potential compared to H1650 MP cells (***P<0.0001). (b-d) Anticancer effects of Noscapine (Nos) and Cisplatin (Cis) determined by cell viability studies in (b) H460, (c) H1650 MP, and (d) H1650 SP cells after 72 hr incubation; single and combination treatments of Cis, Nos, and Cis with fixed concentrations (5, 10, and 20 μM) of Nos after 72 hr incubation demonstrated no significant anticancer effects. (e) The marginal decreases in H1650 SP cell viability following treatment with Nos_SESDs and Mann-Nos_SESDs are significantly enhanced when giving in combination with Cis. Results were presented as cell viability (percent of control) against log concentration as triplicates of at least two different experiments.
Fig 5.
Mannosylated noscapine microparticles enhance cisplatin sensitivity in NSCLC.
Panel displays anti-tumor effects of Nos-SMEDD and Mann-Nos_SMEDD in nu/nu mice bearing orthotopic lung tumors, alone and in combination with Cisplatin. Fig 5a shows the effect of oral noscapine and the solid microparticle. Fig 5b shows the effect of mannosylation over the solid microparticle. Fig 5c shows dose sensitivity of noscapine. Fig 5d shows the effect of the mannosylated microparticle on cisplatin response,and Fig 5e shows potential toxicity of treatment with respect to mouse body weight. Results are presented at percent means ± SD normalized against untreated control group (n = 4 per group).Differences in means were analyzed by One-way analysis of variance (P<0.05), followed by Bonferroni post-test with 90% confidence intervals (P<0.1). Significance was reached at *P<0.1, **P<0.01, and ***P<0.001.