The Cardioprotective Effect of Vitamin D in Breast Cancer Patients Receiving Adjuvant Doxorubicin Based Chemotherapy.

PURPOSE: The primary objective of this study was to investigate the potential protective effect of Vitamin D (Vit D) on DOX induced cardio toxicity (DIC) in early breast cancer patients receiving adjuvant DOX based chemotherapy (AC). The secondary objective was to investigate the anti-inflammatory effect of Vit D by measuring serum IL-6 and its correlation with cardio toxicity. METHODS: This study was carried out on 150 newly diagnosed women with breast cancer who were planned to receive four cycles of adjuvant AC chemotherapy regimen (60 mg/m2 DOX and 600 mg/m2 cyclophosphamide) every 21 days. Study patients were randomized 1:1 into a control group treated with AC and a Vit D group treated with AC plus 0.5 µg of Vit D (Bon One 0.5 µg) orally once daily during the whole treatment course. The cardio protective effect of Vit D was assessed by measuring serum levels of Lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and anti-inflammatory Interleukin 6 (IL-6) at baseline, and after 4 cycles of AC in all study patients. RESULTS: Vit D supplementation in Vit D group patients was associated with a significant decrease (P < 0.001) in serum levels of LDH, cTnT, and IL-6 compared to the control group . CONCLUSION: The present work provides a promising clinical evidence to support the cardio protective effects of Vit D against DIC through attenuating the evoked pro-inflammatory cytokines induced by DOX.

Omega 3 fatty acids effect on the vascular calcification biomarkers fetuin A and osteoprotegerin in hemodialysis patients.

Chronic renal failure patients on dialysis are at a high risk of death due to vascular calcification. This study aimed at investigating the effect of omega-3 fatty acids on the vascular calcification biomarkers fetuin-A and osteoprotegerin (OPG) in patients with chronic renal failure who are undergoing hemodialysis. This prospective, open-label, controlled, parallel study included 60 hemodialysis patients who were randomized to receive either omega-3 fatty acids capsule along with their standard care of treatment (omega-3 group) or their standard care of treatment only (control group). Serum levels of fetuin-A, OPG, calcium, phosphorus, hemoglobin, parathyroid hormone, blood urea nitrogen (BUN), albumin, serum creatinine (SCr), and serum triglycerides (TG) were measured at baseline and after six months of intervention and follow-up of both groups. Significantly increased levels of fetuin-A and OPG (p < 0.001) were observed in the omega-3 group six months after the intervention compared with the control group. Levels of TG, albumin, SCr, BUN, phosphorous, calcium, hemoglobin, and parathyroid hormone were not significantly different in the omega-3 group compared with the control group after six months of intervention. Our study concluded that omega-3 may have a clinically beneficial effect in decreasing cardiovascular events by increasing the levels of the protective vascular calcification inhibitors fetuin-A and osteoprotegerin in chronic renal failure patients who are undergoing hemodialysis.

Combinatorial antitumor effects of amino acids and epigenetic modulations in hepatocellular carcinoma cell lines.

Hepatocellular carcinoma (HCC) is a highly fatal form of liver cancer. Recently, the interest in using amino acids as therapeutic agents has noticeably grown. The present work aimed to evaluate the possible antiproliferative effects of selected amino acids supplementation or deprivation in human HCC cell lines and to investigate their effects on critical signaling molecules in HCC pathogenesis and the outcomes of their combination with the histone deacetylase inhibitor vorinostat. HepG2 and Huh7 cells were treated with different concentrations of L-leucine, L-glutamine, or L-methionine and cell viability was determined using MTT assay. Insulin-like growth factor 1 (IGF1), phosphorylated ribosomal protein S6 kinase (p70 S6K), p53, and cyclin D1 (CD1) protein levels were assayed using ELISA. Caspase-3 activity was assessed colorimetrically. L-leucine supplementation (0.8-102.4 mM) and L-glutamine supplementation (4-128 mM) showed dose-dependent antiproliferative effects in both cell lines but L-methionine supplementation (0.2-25.6 mM) only affected the viability of HepG2 cells. Glutamine or methionine deprivation suppressed the proliferation of HepG2 cells whereas leucine deprivation had no effect on cell viability in both cell lines. The combination between the effective antiproliferative changes in L-leucine, L-glutamine, and L-methionine concentrations greatly suppressed cell viability and increased the sensitivity to vorinostat in both cell lines. The growth inhibitory effects were paralleled with significant decreases in IGF-1, phospho p70 S6k, and CD1 levels and significant elevations in p53 and caspase-3 activity. Changes in amino acids concentrations could profoundly affect growth in HCC cell lines and their response to epigenetic therapy.

Promoted Antitumor Activity of Myricetin against Lung Carcinoma Via Nanoencapsulated Phospholipid Complex in Respirable Microparticles.

PURPOSE: Myricetin (MYR) flavonoid is well-recognized for its antioxidant, anti-inflammatory and anti-tumor potential. Introducing nanomedicine was the ultimate resort to solve the imperfections of this nutraceutical, namely solubility, stability and delivery issues. The study, thus, aims at developing inhalable microparticles comprising MYR solid lipid nanoparticles (SLNs) for lung cancer therapy. METHODS: A two-step preparation procedure starting with complexation of MYR with the phospholipid Lipoid-S100, followed by nanoencapsulation in Gelucire-based, surfactant-free SLNs was developed. SLNs were characterized in terms of physicochemical properties, MYR loading, release behavior as well as anti-tumor potential and cellular uptake. Respirable microparticles were then obtained by spray drying SLNs with carbohydrate carriers. Their size, flowability and pulmonary deposition pattern were assessed. RESULTS: Optimized SLNs were 75.98 nm in diameter with a zeta-potential of -22.5 mV, and an encapsulation efficiency of 84.5%. Attempts to ameliorate drug loading implicate MYR-phospholipid complexation (MYR-PH-CPX) prior to its entrapment in SLNs, which ensured 5-fold increase in drug loading. Viability assays were modified to guarantee MYR chemical stability. Superior antitumor activity of MYR-phospholipid-complex and 3-fold reduction in IC50 were accomplished with MYR-SLNs. This could be related to enhanced cellular uptake revealed by confocal imaging and doubled fluorescence intensity. SLNs entrapping MYR-PH-CPX were spray-dried with carbohydrate carriers to produce respirable microparticles. The latter ensured MMAD of 2.39 µm and span index of 1.84, in addition to good flowability and > 80% release over 8 h. Deposition experiments revealed MMAD of 2.77 µm, FPF of 81.23 and EF of 93% indicating particle deposition in the targeted bronchial region. CONCLUSIONS: The study highlights the ability of phospholipid-complex on the nanoencapsulation, cellular uptake and antitumor activity of MYR. Formulation of respirable microparticles gives promises of efficacious therapy of lung carcinoma.

Synthesis of lactoferrin mesoporous silica nanoparticles for pemetrexed/ellagic acid synergistic breast cancer therapy.

Despite the clinical approval of few nanomedicines for cancer therapy, some drawbacks still impede their improved efficiency including low drug loading, off-target toxicity and development of multi-drug resistance. Herein, lactoferrin (Lf)-coupled mesoporous silica nanoparticles (MSNPs) were developed for combined delivery of the cytotoxic drug pemetrexed (PMT) and the phytomedicine ellagic acid (EA) for synergistic breast cancer therapy. While the hydrophobic EA was physically encapsulated within the pores of MSNPs via the adsorptive properties of MSNPs and the electrostatic interactions between the negatively charged EA and positively charged amino modified MSNs, the highly water soluble PMT was chemically anchored to the Lf shell through chemical conjugation to the surface of lactoferrin coated MSNPs by carbodiimide reaction to avoid pre-mature drug release and systemic toxicity. The dual drug-loaded Lf-MSNPs (284 nm) demonstrated a sequential faster release of EA followed by a sustained release of PMT. The dual drug-loaded Lf-MSNPs exhibited highest cytotoxicity against MCF-7 (Michigan Cancer Foundation-7) breast cancer cells as revealed by the lowest combination index (CI = 0.885) compared to free drugs. The combination index value (< 1) revealed synergy between both loaded drugs. Furthermore, high cellular uptake of the nanocarriers into MCF-7 breast cancer cells was observed via Lf-receptor mediated endocytosis. Altogether, the dual drug-loaded Lf-targeted MSNPs showed to be a promising carrier for breast cancer therapy through triggering different signaling pathways, and hence overcoming the multi-drug resistance and minimizing the systemic toxicity.

Boronic-targeted albumin-shell oily-core nanocapsules for synergistic aromatase inhibitor/herbal breast cancer therapy.

Multi-modality strategies of albumin-mediated drug accumulation in tumor, boronate-based active tumor targeting and synergistic cancer therapy were combined together for effective treatment of breast cancer. Herein we report the development of albumin-shell oily-core nanocapsules (NCs), loaded with novel combination of hydrophobic drugs, exemestane (EXE) and hesperetin (HES), for targeted breast cancer therapy. This protein-lipid nanohybrid carrier was successfully fabricated using a simple protein-coating method based on the electrostatic adsorption of negatively charged albumin shell onto the oily core containing cationic surfactant. While EXE was directly encapsulated into the oily core, HES was pre-formulated in the form of phospholipid complex before solubilization in oily phase. In addition to albumin-mediated binding to albondin and SPARC, phenylboronic acid was chemically coupled to the albumin shell to confer additional tumor targeting. The targeted nanocarrier (TNC) demonstrated enhanced internalization into MCF-7 breast cancer cells resulting in synergistic cytotoxic activity with a combination index (CI) of 0.662 and dose reduction index (DRI) of 8.22 and 1.84 for EXE and HES, respectively. In vivo, TNC displayed superior anti-cancer activity in tumor-bearing mice compared to their non-targeted counterparts and the free drug combination. A significant reduction of both tumor volume (7-folds) and Ki67 expression (3-folds) was obtained by the targeted nanocarriers compared to positive control. Overall, the boronic-targeted albumin NCs offer a promising platform for hydrophobic drug combination against cancer therapy.

Multicompartmental lipid-protein nanohybrids for combined tretinoin/herbal lung cancer therapy.

Aim: Multicompartmental lipid-protein nanohybrids (MLPNs) were developed for combined delivery of the anticancer drugs tretinoin (TRE) and genistein (GEN) as synergistic therapy of lung cancer. Materials & methods: The GEN-loaded lipid core was first prepared and then coated with TRE-loaded zein shell via nanoprecipitation. Results: TRE/GEN-MLPNs demonstrated a size of 154.5 nm. In situ ion pair formation between anionic TRE and the cationic stearyl amine improved the drug encapsulation with enhanced stability of MLPNs. TRE/GEN-coloaded MLPNs were more cytotoxic against A549 cancer cells compared with combined free GEN/TRE. In vivo, lung cancer bearing mice treated with TRE/GEN-MLPNs displayed higher apoptotic caspase activation compared with mice-treated free combined GEN/TRE. Conclusion: TRE/GEN-MLPNs might serve as a promising parenteral nanovehicles for lung cancer therapy.

Dual-Targeted Lactoferrin Shell-Oily Core Nanocapsules for Synergistic Targeted/Herbal Therapy of Hepatocellular Carcinoma.

Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice (P < 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.

Combining hydrophilic chemotherapy and hydrophobic phytotherapy via tumor-targeted albumin-QDs nano-hybrids: covalent coupling and phospholipid complexation approaches.

BACKGROUND: The rationale of this study is to combine the merits of both albumin nanoparticles and quantum dots (QDs) in improved drug tumor accumulation and strong fluorescence imaging capability into one carrier. However, premature drug release from protein nanoparticles and high toxicity of QDs due to heavy metal leakage are among challenging hurdles. Following this platform, we developed cancer nano-theranostics by coupling biocompatible albumin backbone to CdTe QDs and mannose moieties to enhance tumor targeting and reduce QDs toxicity. The chemotherapeutic water soluble drug pemetrexed (PMT) was conjugated via tumor-cleavable bond to the albumin backbone for tumor site-specific release. In combination, the herbal hydrophobic drug resveratrol (RSV) was preformulated as phospholipid complex which enabled its physical encapsulation into albumin nanoparticles. RESULTS: Albumin-QDs theranostics showed enhanced cytotoxicity and internalization into breast cancer cells that could be traced by virtue of their high fluorescence quantum yield and excellent imaging capacity. In vivo, the nanocarriers demonstrated superior anti-tumor effects including reduced tumor volume, increased apoptosis, and inhibited angiogenesis in addition to non-immunogenic response. Moreover, in vivo bioimaging test demonstrated excellent tumor-specific accumulation of targeted nanocarriers via QDs-mediated fluorescence. CONCLUSION: Mannose-grafted strategy and QD-fluorescence capability were beneficial to deliver albumin nanocarriers to tumor tissues and then to release the anticancer drugs for killing cancer cells as well as enabling tumor imaging facility. Overall, we believe albumin-QDs nanoplatform could be a potential nano-theranostic for bioimaging and targeted breast cancer therapy.

Upregulation of cystathionine-γ-lyase/hydrogen sulfide pathway underlies the celecoxib counteraction of cyclosporine-induced hypertension and renal insult in rats.

We recently reported that celecoxib, a selective cyclooxygenase-2 (COX2) inhibitor, counteracts the adverse circulatory and renal actions of cyclosporine (CSA). Despite the seemingly advantageous nature of this interaction particularly in clinical settings that necessitate the combined use of the two drugs such as immune-related arthritis, the underlying mechanism remains elusive. This prompted us to test the hypothesis that the facilitation of the cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) signaling accounts for such favorable effects of celecoxib on CSA nephrotoxicity. The data showed that the 10-day co-treatment of rats with celecoxib (10 mg/kg/day) ameliorated the hypertensive and biochemical and renal structural damages caused by CSA (20 mg/kg/day). Celecoxib also reversed the CSA-evoked (i) reductions in the tubular and glomerular protein expression of CSE and levels of H2S, prostaglandin E2 (PGE2), and total antioxidant capacity (TAC), and (ii) increases in inflammatory (tumor necrosis factor-α, TNF-α), fibrotic (transforming growth factor-ß1, TGF-ß1) and apoptotic (caspase-3) cytokines. These celecoxib effects disappeared when rats were treated concomitantly with the CSE inhibitor DL-propargylglycine (DL-PAG), indicating the importance of the CSE-derived H2S in mediating the renoprotective action of celecoxib. This view is bolstered by the observation that the beneficial hemodynamic and renal actions of celecoxib were replicated after supplementation of rats with sodium sulfide (Na2S, H2S donor). Together, the increased abundance of renal CSE and H2S and subsequent dampening down of inflammatory, fibrotic, oxidant, and apoptotic pathways play pivotal roles in the capacity of celecoxib to compromise the troublesome hypertensive and nephrotoxic insults caused by CSA in rats.

Liquid crystalline assembly for potential combinatorial chemo-herbal drug delivery to lung cancer cells.

BACKGROUND: Lung cancer is the most common cancer and the leading cause of total deaths worldwide. Its classified into two major types including non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC) based on the origin of abnormal lung cells as well as the smoking status of the patient. NSCLC is the most common and aggressive type of lung cancer representing 80%-85% of all cases. PURPOSE: The aim of the study was to present lyotropic liquid crystalline nanoparticles (LCNPs) as promising carriers for co-delivery of the chemotherapeutic agent, pemetrexed (PMX) and the herbal drug, resveratrol (RSV) for effective lung cancer management. METHODS: The proposed PMX-RSV-LCNPs were prepared by hydrotrope method. Hydrophobic ion pairing with cetyl trimethyl ammonium bromide (CTAB) was implemented to increase the encapsulation efficiency of the hydrophilic PMX up to 95%±3.01%. RESULTS: The tailored PMX-RSV-LCNPs exhibited a particle size of 173±0.26 nm and biphasic release pattern with a relatively initial burst release within first 3-4 hour followed by sustained release up to 24 hours. Moreover, PMX-RSV-LCNPs manifested superior concentration and time dependent cytotoxicity profile against A549 lung cancer cells with IC50 4.0628 µg/mL. Besides, the enhanced cellular uptake profile based on bioadhesive properties of glyceryl monoolein (GMO) as well as energy independent (cholesterol dependent) pattern. In-vivo evaluations against urethane induced lung cancer bearing mice demonstrated the potentiality of PMX-RSV-LCNPs in tumor growth inhibition via inhibition of angiogenesis and induction of apoptosis. The results were supported by histopathological analysis and immunohistochemical Ki67 staining. Moreover, PMX-RSV-LCNPs displayed a promising safety profile via attenuating nephro- and hepatotoxicity. CONCLUSION: PMX-RSV-LCNPs elaborated in the current study hold a great promise for lung cancer treatment.

Lactoferrin-tagged quantum dots-based theranostic nanocapsules for combined COX-2 inhibitor/herbal therapy of breast cancer.

AIM: Herein, tumor-targeted quantum dots (QDs)-based theranostic nanocapsules (NCs) coloaded with celecoxib and honokiol were developed. Materials & methodology: The anionic CD44-targeting chondroitin sulfate and cationic low density lipoprotein (LDL)-targeting lactoferrin (LF) were sequentially assembled onto the surface of the positively charged oily core. As an imaging probe, highly fluorescent mercaptopropionic acid-capped cadmium telluride QDs were coupled to LF. RESULTS: In vitro, fluorescence of QDs was quenched (OFF state) due to combined electron/energy transfer-mediated processes involving LF. After intracellular uptake of NCs, fluorescence was restored (ON state), thus enabled tracing their internalization. The NCs demonstrated enhanced cytotoxicity against breast cancer cells as well as superior in vivo antitumor efficacy. CONCLUSION: We propose these multifunctional nanotheranostics for imaging and targeted therapy of breast cancer.

Decorating protein nanospheres with lactoferrin enhances oral COX-2 inhibitor/herbal therapy of hepatocellular carcinoma.

AIM: Lactoferrin (LF)-targeted gliadin nanoparticles (GL-NPs) were developed for targeted oral therapy of hepatocellular carcinoma. MATERIALS & METHODS: Celecoxib and diosmin were incorporated in the hydrophobic matrix of GL-NPs whose surface was decorated with LF by electrostatic interaction for binding to asialoglycoprotein receptors overexpressed by liver cancer cells. RESULTS: Targeted GL-NPs showed enhanced cytotoxic activity and increased cellular uptake in liver tumor cells compared with nontargeted NPs. Moreover, they demonstrated superior in vivo antitumor effects including reduction in the expression levels of tumor biomarkers and induction of caspase-mediated apoptosis. Ex vivo imaging of isolated organs exhibited extensive accumulation of NPs in livers more than other organs. CONCLUSION: LF-targeted GL-NPs could be considered as an efficient nanoplatform for targeted oral drug delivery for liver cancer therapy.

Dual-targeted nano-in-nano albumin carriers enhance the efficacy of combined chemo/herbal therapy of lung cancer.

AIM: A Nano-in-Nano approach was exploited to facilitate incorporation of the chemotherapeutic drug etoposide (ETP) as nanosuspension, synergistically with berberine (BER) into hydrophilic albumin nanoparticles (HSA NPs). METHODS: For maximal tumor targeting, HSA was modified with mannose and phenyl-boronic acid. Furthermore, different crosslinkers were investigated for sustained release of water soluble BER from HSA NPs. RESULTS: The elaborated dual-targeted HSA NPs (216.2 nm) were spherical with high BER and ETP entrapment efficiency (69.5 and 87.6%, respectively) and loading (10.52 and 14.04%, respectively). The NPs exhibited sequential release pattern for both ETP and BER (51.55 and 34.33% over 72 h, respectively). Phenyl-boronic acid/mannose-HSA NPs demonstrated powerful cytotoxicity against A549 lung cancer cells (IC50: 12.4 µg/ml) correlated to enhanced cellular internalization. Dual-targeted NPs displayed 9.77-fold higher caspase-3 level and 3.5-fold lower VEGF level than positive control mice. CONCLUSION: Dual-targeted Nano-in-Nano albumin carriers could be beneficial for parenteral ETP/BER delivery to lung cancer.

Lactoferrin-decorated vs PEGylated zein nanospheres for combined aromatase inhibitor and herbal therapy of breast cancer.

OBJECTIVES: Herein, we propose combined aromatase inhibitor and herbal therapy of breast cancer as a synergistic therapeutic modality. METHODS: Zein nanospheres were prepared by phase separation for co-delivery of exemestane and luteolin. To enhance their tumor-targeting capability, the nanospheres were coated with PEGylated phospholipids and lactoferrin for passive and active targeting, respectively. RESULTS: The developed nanospheres demonstrated a small particle size and controlled drug release. In addition, the nanospheres revealed high serum stability, acceptable hemocompatibility, and good physical stability. Moreover, a 5-fold scale-up of zein nanospheres could be enabled followed by spray-drying using 2.5% mannitol as a drying adjuvant. PEGylated and lactoferrin-targeted nanospheres showed enhanced cytotoxicity against MCF-7 and 4T1 breast cancer cells with higher selectivity to cancer cells rather than normal fibroblasts. The in-vivo pharmacokinetics and anti-tumor efficacy confirmed the superiority of zein nanospheres particularly after PEGylation compared to free drug(s). The enhanced anti-cancer activity of nanocarriers was revealed as prolonged circulation half-life, lower % change in tumor volume, reduced expression of aromatase, Cyclin D1 and VEGF markers as well as amplified apoptosis and necrosis. CONCLUSION: Overall, combined delivery of aromatase inhibitors and herbal drugs via tumor-targeted zein nanospheres could serve as a promising strategy for breast cancer therapy.

Dual-targeted casein micelles as green nanomedicine for synergistic phytotherapy of hepatocellular carcinoma.

In recent years, green nanomedicines have made transformative difference in cancer therapy researches. Herein, we propose dual-functionalized spray-dried casein micelles (CAS-MCs) for combined delivery of two phytochemicals; berberine (BRB) and diosmin (DSN) as targeted therapy of hepatocellular carcinoma (HCC). The nanomicelles enabled parenteral delivery of the poorly soluble DSN via its encapsulation within their hydrophobic core. Moreover, sustained release of the water soluble BRB was attained by hydrophobic ion pairing with sodium deoxycholate followed by genipin crosslinking of CAS-MCs. Dual-active targeting of MCs, via conjugating both lactobionic acid (LA) and folic acid (FA), resulted in superior cytotoxicity and higher cellular uptake against HepG2 cells compared to single-targeted and non-targeted CAS-MCs. The dual-targeted DSN/BRB-loaded CAS-MCs demonstrated superior in vivo anti-tumor efficacy in HCC bearing mice as revealed by down regulation of cell necrosis markers (NF-κB and TNF-α), inflammatory marker COX2, inhibition of angiogenesis and induction of apoptosis. Histopathological analysis and immunohistochemical Ki67 staining confirmed the superiority of the dual-targeted micelles. Ex-vivo imaging showed preferential liver-specific accumulation of dual-targeted CAS-MCs. Overall, this approach combined the benefits of traditional herbal medicine with nanotechnology via LA/FA-CAS-MCs loaded with BRB and DSN as a promising nanoplatform for targeted HCC therapy.

Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy.

Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200 nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over-expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112 µm) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy.

Inhalable multi-compartmental phospholipid enveloped lipid core nanocomposites for localized mTOR inhibitor/herbal combined therapy of lung carcinoma.

Pulmonary delivery of drug nanocarriers can overcome the shortcomings of systemic cancer therapy via the enhanced permeability and retention (EPR) based-nanomedicine. Herein, inhalable multi-compartmental nanocomposites with the capability for both localized and modulated release of the hydrophobic mTOR inhibitor, rapamycin (RAP) and the hydrophilic herbal drug, berberine (BER) have been developed for lung cancer therapy. Two types of multi-compartmental nanocarriers were fabricated by enveloping BER hydrophobic ion pair-lipid nanocore within a shell of RAP-phospholipid complex bilayer to reduce the delivery gap between the two drugs. To further enhance their tumor targeting, the nanocarriers were layer-by-layer coated by cationic lactoferrin and anionic hyaluronate resulting in enhanced internalization and cytotoxicity against lung cancer cells. The inhalable nanocomposites fabricated by spray-drying of multi-compartmental nanocarriers exhibited favorable aerosolization efficiency (MMAD of 3.28 µm and FPF of 55.5%). The powerful anti-cancer efficacy of inhalable nanocomposites in lung cancer bearing mice compared to the inhaled free drugs was revealed by remarkable decrease in lung weight, and reduction in both number and diameters of lung adenomatous foci and angiogenic markers compared to positive control. Overall, localized delivery of RAP and BER to tumor cells via inhalable multi-compartmental nanocomposites holds great promise in management of lung cancer.