Inhalable TPGS/DPPC Micelles Coloaded with Curcumin and Icariin for Targeted Lung Cancer Therapy
Abstract
Lung cancer, particularly NSCLC, poses a major therapeutic challenge due to drug resistance and the poor aqueous solubility of chemotherapeutic agents, limiting treatment efficacy. This study investigates inhalable micelles for the codelivery of curcumin (CUR) and icariin (ICA), two hydrophobic bioactive compounds with anticancer potential, as a targeted therapeutic approach for NSCLC. The optimized micellar formulation (9:1 TPGS/DPPC) yielded nanomicelles (∼18 nm) with high encapsulation efficiency (∼90%) and a zeta potential of −1.24 mV, demonstrating stability for pulmonary administration. In vitro cytotoxicity studies demonstrated enhanced anticancer activity of CUR- and ICA-loaded micelles against A549 lung cancer cells (IC50 = 3.0 μg/mL), lower than doxorubicin (30 μg/mL), suggesting enhanced cytotoxic potential. Additionally, DPPH assays confirmed that encapsulation preserved curcumin’s functionality. Aerosolization studies demonstrated a high fine particle fraction (67 ± 3%) and emitted fraction (95 ± 1.0%), confirming the micelles’ suitability for deep lung deposition and effective pulmonary drug delivery. These findings highlight the potential of CUR- and ICA-loaded micelles as an inhalable NSCLC treatment, requiring further preclinical investigation.
Introduction
Lung cancer remains the leading cause of cancer-related mortality, with over 1.8 million projected deaths worldwide in 2021. (1) Nonsmall cell lung cancer (NSCLC) accounts for approximately 80%–85% of all cases. (2) Standard treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, immunotherapy, and molecularly targeted therapy. (3) The development of biomarker-driven therapies in the past decade has facilitated personalized treatment strategies for NSCLC. (4) However, despite these advancements, fewer than 25% of patients experience durable therapeutic responses, with resistance often emerging due to tumor heterogeneity, adaptive mutations, and drug efflux mechanisms. (5) Developing localized drug delivery systems that enable efficient lung deposition and enhance drug retention in the respiratory tract remains essential for NSCLC therapy.
Natural bioactive compounds, including phytochemicals, have been explored for their potential role in cancer therapy due to their ability to interact with tumor microenvironments and support conventional treatments. (6−8) Building upon these encouraging outcomes, we aim to explore novel therapeutic approaches for NSCLC utilizing natural products.
Curcumin (CUR), a polyphenolic bioactive compound extracted from Curcuma longa, has demonstrated anticancer activity across multiple malignancies, including colorectal, pancreatic, breast, prostate, lung, and oral cancers. (9) Its pharmacological effects are primarily attributed to its ability to regulate apoptosis, cell cycle progression, and inflammatory signaling pathways. (10) Curcumin has demonstrated synergistic effects when combined with chemotherapeutic agents such as gemcitabine, platinum-based agents, and dasatinib, further enhancing its therapeutic potential. (11−13)
Icariin (ICA), a bioactive flavonoid glycoside isolated from Epimedium species, is widely used in traditional Chinese medicine. (14) Due to its hydrophobic nature, ICA is highly soluble in organic solvents but demonstrates limited aqueous solubility, restricting its direct clinical application. (15,16) It exhibits anticancer properties by modulating multiple pathways, including the induction of apoptosis, inhibition of cell cycle progression, and suppression of angiogenesis and metastasis. (17) Moreover, our previous findings indicate that ICA-loaded micelles can regulate macrophage polarization toward the M2 phenotype, a mechanism that holds significant implications for the tumor microenvironment and immune modulation in cancer therapy. (18,19)
Combination therapy involving multiple bioactive agents has been demonstrated to enhance therapeutic efficacy while reducing the risk of drug resistance in oncology. (20,21) The coadministration of CUR and ICA presents a promising strategy for NSCLC treatment by utilizing their complementary mechanisms of action, including apoptosis induction, cell cycle arrest, and modulation of oncogenic signaling pathways.
The clinical application of CUR and ICA is limited by their poor aqueous solubility, which hinders their formulation into inhalable systems and requires appropriate delivery strategies to improve dispersibility. Nanoparticle-based drug delivery platforms provide an effective approach to overcoming these limitations by improving solubility, prolonging systemic circulation, and enabling site-specific drug accumulation. (22−30) Various nanoparticle platforms including liposomes, (22) nanoemulsions, (23) solid lipid nanoparticles, (24) metal nanoparticles, (25) protein nanoparticles, (26) nanotubes, (27) nanofibers, (28) carbon dots, (29) and polymeric nanoparticle (30) are being explored for their ability to enhance solubility and provide controlled drug release. These systems can improve drug accumulation in tumor tissues while minimizing systemic side effects, making them promising candidates for the combined delivery of CUR and ICA in NSCLC therapy.
Polymeric micelles are nanosized core–shell structures formed through the self-assembly of amphiphilic macromolecules, such as block and graft copolymers. These micelles consist of a hydrophobic core and a hydrophilic shell, enabling the encapsulation of hydrophobic drugs within the core while the hydrophilic shell provides stability in aqueous environments. Measuring between 10 and 100 nm in size, polymeric micelles offer distinct advantages for drug delivery, including enhanced dispersibility, biocompatibility, increased solubility of water-insoluble drugs, and improved absorption by reducing degradation rates. (31)
D-α-tocopheryl polyethylene glycol succinate (TPGS)-based micellar formulations have emerged as a potential nanomedicine platform for drug delivery. TPGS is a pharmaceutical excipient composed of a hydrophobic vitamin E moiety and a hydrophilic polyethylene glycol (PEG) chain. This amphiphilic structure enhances the solubility of poorly water-soluble compounds such as CUR and ICA. Literature reports have documented TPGS-based micellar formulations loaded with anticancer agents like docetaxel, (32) paclitaxel conjugated with transferrin, (33) and formulations targeting the HER-2 receptor for drug delivery, (34) demonstrating the versatility of TPGS in nanomedicine.
Pulmonary drug delivery is a noninvasive approach that enables localized drug deposition while reducing systemic exposure. This strategy is particularly relevant for inhalable formulations of hydrophobic drugs like CUR and ICA, which require solubilization for effective nebulization. (35) Dipalmitoylphosphatidylcholine (DPPC), a major component of pulmonary surfactant, has been approved for inhalation in various formulations, including Survanta (as an active ingredient) and Inbrija (as an excipient). The use of DPPC in inhalable formulations enhances lung compatibility and can improve the delivery and absorption of therapeutic agents in the respiratory tract. (35)
Previous studies have demonstrated that CUR and ICA have anticancer activity. However, the synergistic effects of CUR and ICA in cancer therapy, particularly when utilizing nanoparticle-based pulmonary delivery systems, have not been thoroughly investigated. This study aims to develop and characterize CUR and ICA-loaded TPGS/DPPC micelles for pulmonary administration, evaluating their physicochemical properties, aerosol performance, and in vitro effects. The addition of DPPC, which resembles natural pulmonary surfactants, may enhance drug absorption in the respiratory tract, thereby optimizing therapeutic outcomes. (36) This study hypothesizes that CUR and ICA-loaded TPGS/DPPC micelles can be formulated for nebulizer-mediated pulmonary administration, facilitating lung deposition, improving cellular uptake, and enabling sustained therapeutic action against NSCLC.
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Materials
Curcumin (Alfa Aesar Co., Ltd., UK), icariin (Tokyo Chemical Industry Co., Ltd., Japan), 2,2-diphenyl-1-picrylhydrazyl (DPPH) (Alfa Aesar Co., Ltd., Japan), coumarin 6 (Sigma-Aldrich, USA), doxorubicin (DOX) (Sigma-Aldrich, USA), methanol (Sigma-Aldrich, USA), d-α-tocopheryl polyethylene glycol succinate (TPGS) (Sigma-Aldrich, USA), dipalmitoylphosphatidylcholine (DPPC) (Lipoid Co., Ltd., Germany), A549 cell lines (ATCC, USA), methanol, DMEM/F12, fetal bovine serum (FBS), PBS, TryLE Express Enzyme (1×), and MTT reagent were purchased from Merck Life Science UK Ltd. (UK). NucBlue Reagent (Hoechst 33342) was obtained from Life Technologies Limited (UK). CellMask Orange Actin Tracking Stain was purchased from Thermo Fisher Scientific (UK). Acetonitrile, HPLC-grade water, and dimethyl sulfoxide (DMSO) were purchased from Cambridge Bioscience (UK).
Chengwei Jiang, Rongjun Bai, and Satyanarayana Somavarapu, Inhalable TPGS/DPPC Micelles Coloaded with Curcumin and Icariin for Targeted Lung Cancer Therapy, ACS Omega Article ASAP, DOI: 10.1021/acsomega.5c00008
See also the interesting video on Vitamin E TPGS below and read more: here