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Stealth Liposomal Chemotherapeutic Agent for Triple Negative Breast Cancer with Improved Pharmacokinetics
Nagavendra Kommineni1, David Paul2,3, Raju Saka1
1Nanomedicine and Advanced Drug Delivery Lab, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India - 500037.
Abstract:
Triple-negative breast cancer is one of the most lethal cancers. Chemotherapeutics for targeting CDK4 and CDK6 like Palbociclib (PAB) in triple-negative breast cancer was widely explored. However, poor bioavailability and severe side effects profile limiting its clinical usage in the field of cancer chemotherapy. Herein, we set out to develop the stealth liposomes (LPS) of PAB by rotary thin film evaporation with a vesicle size of less than 100 nm. In vitro, drug release studies were performed and fitted into different release kinetic models. LPS were characterized by electron microscopic techniques for morphology. The engineered nanotherapeutics agents were further evaluated in 4T1 triple-negative breast cancer cell lines for its anti-cancer potential and cellular uptake. The hemolytic potential and pharmacokinetic (PK) behavior of developed LPS-PAB and PAB were analyzed by using robust UHPLC-QTOF-MS method. LPS-PAB demonstrates biphasic release profile with first-order release kinetics. Further, LPS-PAB has shown less IC50 value (1.99 µM) compared to PAB alone (3.24 µM). The designed nanoliposomes were tagged with fluorescent FITC dye to check rapid cellular uptake. Importantly, stealth LPS-PAB has shown a 1.75-fold reduction in hemolytic potential as compared to PAB plain drug at 100 µg/mL concentration. The PK results obtained was displayed 2.5-fold increase in Cmax, 1.45-fold increase in AUCtot, 1.8-fold increase in half-life and 1.3-fold increase in MRT with LPS-PAB when compared to orally administered PAB suspension. These findings suggest that novel LPS-PAB can be employed as an alternate therapeutic strategy to eradicate triple-negative breast cancer.
Insights
Stealth liposomes encapsulating Palbociclib (LPS-PAB) improve bioavailability and reduce toxicity for triple-negative breast cancer treatment. This novel nanotherapeutic enhances anti-cancer efficacy and offers a promising alternative to conventional chemotherapy.
Area of Science:
- Nanomedicine
- Pharmacology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is highly lethal.
- Palbociclib (PAB), a CDK4/6 inhibitor, shows promise for TNBC but suffers from poor bioavailability and side effects.
- Novel drug delivery systems are needed to improve PAB's therapeutic index.
Purpose of the Study:
- To develop stealth liposomes (LPS) of Palbociclib (LPS-PAB) for enhanced triple-negative breast cancer therapy.
- To characterize the physicochemical properties, drug release kinetics, and anti-cancer potential of LPS-PAB.
- To evaluate the safety and pharmacokinetic profile of LPS-PAB compared to free PAB.
Main Methods:
- Stealth liposomes (LPS) of PAB were prepared using rotary thin film evaporation.
- Physicochemical characterization included vesicle size analysis and electron microscopy.
- In vitro drug release, cytotoxicity assays (IC50), cellular uptake studies, hemolytic potential assessment, and pharmacokinetic analysis (UHPLC-QTOF-MS) were performed.
Main Results:
- LPS-PAB exhibited a biphasic release profile with first-order kinetics and a size <100 nm.
- LPS-PAB demonstrated superior anti-cancer activity with a lower IC50 (1.99 µM) than PAB (3.24 µM).
- LPS-PAB showed a 1.75-fold reduction in hemolytic potential and improved pharmacokinetic parameters (2.5-fold increase in Cmax, 1.45-fold increase in AUC, 1.8-fold increase in half-life, 1.3-fold increase in MRT) compared to PAB suspension.
Conclusions:
- Stealth liposomal encapsulation significantly enhances the anti-cancer efficacy and safety profile of Palbociclib for triple-negative breast cancer.
- LPS-PAB represents a promising nanotherapeutic strategy to overcome the limitations of conventional PAB chemotherapy.
- Further investigation is warranted to explore the clinical potential of LPS-PAB in treating triple-negative breast cancer.
