10 research outputs found
Enhancing delivery and cytotoxicity of resveratrol through a dual nanoencapsulation approach
Despite the known anticancer potential of resveratrol, its clinical applications are often hindered by physicochemical limitations such as poor solubility and stability. The encapsulation of resveratrol in formulations such as polymeric nanoparticles and liposomes has shown limited success. This study aimed to develop and optimize a novel drug carrier by co-encapsulating pristine resveratrol alongside cyclodextrinâresveratrol inclusion complexes in the lipophilic and hydrophilic compartments of liposomes, respectively by using a novel dual carrier approach. The particle size, polydispersity index and zeta potential of the final formulation were 131 ± 1.30 nm, 0.089 ± 0.005 and â2.64 ± 0.51 mV, respectively. Compared to free resveratrol and conventional liposomal formulations with drug release profile of 40â60%, our novel nanoformulations showed complete (100%) drug release in 24 h. The formulation was stable for 14 days at 4 °C. We also studied the in vitro cytotoxicity of resveratrol encapsulated liposomes in HT-29 colon cancer cell lines. The cytotoxicity profile of our liposomes was observed to be dose dependent and enhanced in comparison to free resveratrol (in DMSO). Our study demonstrates that co-encapsulation of pristine resveratrol along with its cyclodextrin complex in liposomal formulations is a plausible option for the enhanced delivery of the hydrophobic chemotherapeutic agent
Combating Acute Myeloid Leukemia via Sphingosine Kinase 1 Inhibitor-Nanomedicine Combination Therapy with Cytarabine or Venetoclax
MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AMLâs heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1â0.5 ”M) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the ChouâTalalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5â250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML
Targeting Acute Myeloid Leukemia Using Sphingosine Kinase 1 Inhibitor-Loaded Liposomes
Acute myeloid leukemia (AML) kills
75% of patients and represents
a major clinical challenge with a need to improve on current treatment
approaches. Targeting sphingosine kinase 1 with a novel ATP-competitive-inhibitor,
MP-A08, induces cell death in AML. However, limitations in MP-A08âs
âdrug-like propertiesâ (solubility, biodistribution,
and potency) hinder its pathway to the clinic. This study demonstrates
a liposome-based delivery system of MP-A08 that exhibits enhanced
MP-A08 potency against AML cells. MP-A08-liposomes increased MP-A08
efficacy against patient AML cells (>140-fold) and significantly
prolonged
overall survival of mice with human AML disease (P = 0.03). The significant antileukemic property of MP-A08-liposomes
could be attributed to its enhanced specificity, bioaccessibility,
and delivery to the bone marrow, as demonstrated in the pharmacokinetic
and biodistribution studies. Our findings indicate that MP-A08-liposomes
have potential as a novel treatment for AML