Dual Drug-loaded Nanoparticles Research Articles

Folate functionalized multifunctional CuO@PHBV@PDA nanoplatform for pH-Responsive dual drug delivery and ROS-driven apoptosis in breast cancer

Current anticancer nanocarriers are still constrained by a disparity between their various functionalities and biocompatibility. Drug combinations delivered via cell-specific nanocarriers have the potential to improve therapeutic efficacy. Herein, we prepared a ROS-responsive CuO nanoparticle drug delivery system for treating breast cancer loaded with 5-Fluorouracil (5-FU) and paclitaxel (PTX), encased in a layer of PHBV/PDA and embellished with folate to yield 5-FU@PTX-CuO@PHBV@PDA/FA NPs. Excellent monodispersity, size stability, and biocompatibility were displayed by the resulting nanoplatform with a diameter of about 186.3 ± 7.2 nm. Synthesized nanoplatform was studied in NIH 3T3 and MCF-7 cells to determine their antitumor mechanism. Invitro pH-dependent drug release rate, drug encapsulation, loading efficiency, and hemocompatibility were all quantified via Ultraviolet–visible spectroscopy. Half-maximal inhibitory concentration values for dual drug-loaded CuO@PHBV@PDA/FA NPs and free drugs combination were 12.5 and 25 μg/mL, respectively, indicating considerably stronger antitumor activity of 5-FU@PTX-CuO@PHBV@PDA/FA NPs than free drugs combination. Apoptotic cell death, mitochondrial membrane potential loss, and ROS production were also examined in vitro. In contrary, dual drug-loaded nanoparticles exhibited concentration-dependent and synergistic cytotoxicity towards MCF-7 cells. Together, these findings suggest that the 5-FU@PTX-CuO@PHBV@PDA/FA nanoplatform may help to resolve the conflict between the multifunctionality and biocompatibility of nanocarriers.

Combinational strategy using albumin-based nanoparticles to enable synergetic anti-rheumatic efficacy and reduced hepatotoxicity

Methotrexate (MTX) is recognized as the golden standard for rheumatoid arthritis (RA) treatment. However, it can cause liver damage in long-term application. Although nanomedicines can target to inflamed sites, most of them tend to accumulate in liver. Glycyrrhizinic acid (GA) holds potential to reverse MTX-associated hepatotoxicity. The combination of GA and MTX might achieve a synergistic anti-inflammatory efficacy and reduced hepatotoxicity. As MTX and GA have totally different in vivo performance, it is necessary to co-encapsulate them in one carrier to coordinate their in vivo fates. Here, we co-delivered MTX and GA to arthritic joints using a human serum albumin-based nanoparticle (HSN). We found the dual drug-loaded albumin nanoparticles (HSN/MTX/GA) could preferentially distribute in inflamed joints, where GA can extend MTX retention by inhibiting the expression of efflux pumps for MTX, thereby exerting synergistic therapeutic effect. In liver tissues, GA was able to reverse the MTX-induced liver damage by activating anti-oxidant defense Nrf2/HO-1 and anti-apoptosis Bcl-2/Bax signaling. We offer a combinational strategy to effectively overcome the MTX-induced hepatotoxicity and enhance the anti-rheumatic efficacy simultaneously. Furthermore, we verified the underlying mechanism about how GA cooperated with MTX in vivo for the first time. Our findings can provide valuable insights for long-term treatment of RA.

Targeting Intracellular Bacteria with Dual Drug-loaded Lactoferrin Nanoparticles.

Treatment of microbial infections is becoming daunting because of widespread antimicrobial resistance. The treatment challenge is further exacerbated by the fact that certain infectious bacteria invade and localize within host cells, protecting the bacteria from antimicrobial treatments and the host's immune response. To survive in the intracellular niche, such bacteria deploy surface receptors similar to host cell receptors to sequester iron, an essential nutrient for their virulence, from host iron-binding proteins, in particular lactoferrin and transferrin. In this context, we aimed to target lactoferrin receptors expressed by macrophages and bacteria; as such, we prepared and characterized lactoferrin nanoparticles (Lf-NPs) loaded with a dual drug combination of antimicrobial natural alkaloids, berberine or sanguinarine, with vancomycin or imipenem. We observed increased uptake of drug-loaded Lf-NPs by differentiated THP-1 cells with up to 90% proportion of fluorescent cells, which decreased to about 60% in the presence of free lactoferrin, demonstrating the targeting ability of Lf-NPs. The encapsulated antibiotic drug cocktail efficiently cleared intracellular Staphylococcus aureus (Newman strain) compared to the free drug combinations. However, the encapsulated drugs and the free drugs alike exhibited a bacteriostatic effect against the hard-to-treat Mycobacterium abscessus (smooth variant). In conclusion, the results of this study demonstrate the potential of lactoferrin nanoparticles for the targeted delivery of antibiotic drug cocktails for the treatment of intracellular bacteria.

Synergic fabrication of dual drug-loaded polymeric nanoparticles system to improve the in vitro treatment of glioma metastasis specific targeting therapy

ABSTRACT Poor drug delivery to the tumour site and harmful drug effects on the nearby healthy tissue are the two main issues with chemotherapeutic treatments for glioma. This study tests the efficacy of a chitosan dual delivery system loaded with rutin and aucubin to treat glioma. It was shown in vitro that rutin/aucubin loaded chitosan nanoparticlesignificantly inhibited U87 cells and promoted apoptosis, and the combination therapy results were superior to those of each compound used alone. The rutin-aucubin combination decreased the glioma cell’s ability to migrate. The chitosan rutin-aucubin nanocomposites showed time dependent cell uptake in U87 cells when labelled with RBITC ANG. At a low dose of 0.156 μg/mL chitosan rutin-aucubin successfully inhibited tumour growth and adhesion and ~ 43% necrosis was observed in mitochondrial membrane potential (ΔΨm) assay. In conclusion, rutin and aucubin drugs were codelivered which inhibited tumour proliferation by inducing cellular apoptosis at a low dose. This showed the system’s potential to effectively enhance glioma therapy.

Dual drug-loaded cubosome nanoparticles for hepatocellular carcinoma: a design of experiment approach for optimization and in vitro evaluation

BackgroundLiver cancer, a formidable and complex disease, poses a significant global health threat, stemming from various causes, including chronic infections like hepatitis B and C, cirrhosis, and lifestyle factors. In liver cancer treatment, targeted delivery revolutionizes precision therapy, minimizing side effects by directing drugs specifically to cancer cells. This study aims to develop and statistically optimize cubosomal formulations containing piperine and quercetin with the goal of augmenting their activity against hepatocellular carcinoma.ResultsEmploying a central-composite design, we utilized Design-Expert® software to guide the experiment. The key formulation variables were the concentration of glyceryl monooleate (GMO) and Poloxamer-407, while the dependent responses were particle size (PS) and entrapment efficiency (EE%). The optimized cubosomal formulation was validated through the utilization of high-resolution transmission electron microscopy (HR-TEM), in vitro release studies, and an in vitro cell proliferation assay conducted on the HepG2 cell line. High-performance liquid chromatography was employed for the determination of piperine and quercetin in the optimized cubosomal nanoparticle. The optimized formulation had a composition of 2.5 (w/w%) GMO and 0.5 (w/w%) Poloxamer 407. The predicted values for PS and EE% were 102.34 and 75.11%, respectively. The cytotoxicity of the optimized cubosomal formulation exhibited enhanced efficacy on the HepG2 cancer cell line, even at lower concentrations, when compared to the standard. Notably, it demonstrated a superior cytotoxic effect on the liver cancer cell line.ConclusionThe findings of the study indicated that cubosomes exhibit promise as an effective carrier for delivering piperine and quercetin, addressing hepatocellular carcinoma effectively.Graphical abstract

A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.

Preparation and anti-triple-negative breast cancer cell effect of a nanoparticle for the codelivery of paclitaxel and gemcitabine

Amphiphilic polymers (HA-ANI) were prepared by grafting hyaluronic acid (HA) and 6-(2-nitroimidazole)hexylamine (ANI) and then self-assemble in water to form nanoparticles (NPs) that could be loaded with paclitaxel (PTX) and gemcitabine (GEM) by dialysis. Infrared spectroscopy and 1H-NMR indicated the successful synthesis of HA-ANI. Three different ratios of NPs were prepared by adjusting the ratios of hydrophilic and hydrophobic materials, and the particle size decreased as the ratio of hydrophilic materials increased. When HA:ANI = 2.0:1, the nanoparticles had the smallest size distribution, good stability and near spherical shape and had high drug loading and encapsulation rates. In vitro release experiments revealed that NADPH could accelerate the drug release from NPs. Cellular uptake rate reached 86.50% at 6 h. The toxic effect of dual drug-loaded nanoparticles (P/G NPs) on MDA-MB-231 cells at 48 h was stronger than that of the free drug. The AO/EB double-staining assay revealed that a large number of late apoptotic cells appeared in the P/G NPs group, and the degree of cell damage was significantly stronger than that of the free drug group. In the cell migration assay, the 24 h-cell migration rate of the P/G NPs group was 5.99%, which was much lower than that of the free group (13.87% and 17.00%). In conclusion, MDA-MB-231 cells could effectively take up P/G NPs, while the introduction of the nano-codelivery system could significantly enhance the toxicity of the drug to MDA-MB-231 cells as well as the migration inhibition effect.

Development and characterization of pH-responsive nanocarriers for chemo-photothermal combination therapy of acidic tumors.

The combination of photothermal therapy and chemotherapy has been considered a promising strategy for improving the excellent antitumor activities of these treatments. In this study, we developed a new simple type of pH-sensitive chemo-photothermal combination agent capable of repeated exposures to a near-infrared (NIR) laser and evaluated its anticancer efficacy in vitro and in vivo. Doxorubicin (Dox) and gold nanoclusters (GNCs) were successfully co-loaded into pH-sensitive nanoparticles (poly(ethylene glycol)-poly[(benzyl-l-aspartate)-co-(N-(3-aminopropyl)imidazole-L-aspartamide)] (PEG-PABI)), resulting in a particle size of approximately120 nm with a narrow size distribution. The dual drug-loaded nanoparticles (Dox/GNC-loaded PEG-PABI micelles (Dox/GNC-Ms)) showed consistent pH-sensitive properties and heat generation efficiency after repeated NIR laser exposure. In particular, GNC-M has improved photothermal stability while maintaining high photothermal conversion efficiency, addressing the shortcomings of previous gold nanoparticles. As the concentration of GNC-Ms, irradiation light exposure time, and light source intensity increased, the amount of heat generated and the anticancer effect increased. When Dox was encapsulated with GNCs (Dox/GNC-Ms), a faster drug release rate under acidic pH conditions and a strong synergistic effect against U87MG cells were observed. When the Dox/GNC-M system was extended to in vivo studies, it effectively increased the temperature of the tumor tissue under near-infrared irradiation and showed excellent anticancer efficacy. Therefore, the Dox/GNC-M system could be a simple but promising strategy for chemo-photothermal combination treatment capable of targeting acidic tumors.

PLGA Nanoparticles Containing VCAM-1 Inhibitor Succinobucol and Chemotherapeutic Doxorubicin as Therapy against Primary Tumors and Their Lung Metastases.

The treatment of malignant tumors is usually accompanied by poor prognosis due to metastasis of tumor cells. Hence, it is crucial to enhance anti-metastasis efficacy when anti-tumor treatments are conducted. It has been reported that the vascular cell adhesion molecule-1 (VCAM-1) is highly expressed on the surface of tumor cells and plays an essential role in the metastasis of tumor cells. Thus, reducing VCAM-1 expression offers hope for inhibiting the metastasis of tumor cells. Evidence has shown that succinobucol (Suc) can selectively and efficiently inhibit VCAM-1 expression. Inspired by these, we designed dual drug-loaded PLGA nanoparticles (Co-NPs) to co-deliver VCAM-1 inhibitor Suc and the chemotherapeutic doxorubicin (Dox) which could both effectively suppress primary melanoma and its lung metastases. Co-NPs were composed of PLGA encapsulated Suc and Dox as hydrophobic cores and DSPE-mPEG2000 as surface modification materials. With an appropriate particle size (122.4 nm) and a negatively charged surface (-6.77 mV) we could achieve prolonged blood circulation. The in vitro experiments showed that Co-NPs had potent cytotoxicity against B16F10 cells and could significantly inhibit VCAM-1 expression and migration of B16F10 cells. Additionally, the in vivo experiments showed that Co-NPs could efficiently suppress not only primary melanoma but also its lung metastases. In conclusion, PLGA nanoparticles containing VCAM-1 inhibitor Suc and chemotherapeutic Dox as therapy against primary tumors and their lung metastases provides a promising drug delivery strategy for the treatment of metastatic malignant tumors.

Remodeling of imbalanced extracellular matrix homeostasis for reversal of pancreatic fibrosis

Pancreatic fibrosis is mainly manifested by imbalance in extracellular matrix (ECM) homeostasis due to excessive deposition of collagen in pancreas by activated pancreatic stellate cells (PSCs). Recently, some drugs have exhibited therapeutic potentials for the treatment of pancreatic fibrosis; however, currently, no effective clinical strategy is available to remodel imbalanced ECM homeostasis because of inferior targeting abilities of drugs and collagen barriers that hinder the efficient delivery of drugs. Herein, we design and prepare collagen-binding peptide (CBP) and collagenase I co-decorated dual drug-loaded lipid nanoparticles (named AT-CC) for pancreatic fibrosis therapy. Specifically, AT-CC can target fibrotic pancreas via the CBP and degrade excess collagen by the grafted collagenase I, thereby effectively delivering all-trans-retinoic acid (ATRA) and ammonium tetrathiomolybdate (TM) into pancreas. The released ATRA can reduce collagen overproduction by inhibiting the activation of PSCs. Moreover, the released TM can restrain lysyloxidase activation, consequently reducing collagen cross-linking. The combination of ATRA and TM represses collagen synthesis and reduces collagen cross linkages to restore ECM homeostasis. The results of this research suggest that AT-CC is a safe and efficient collagen-targeted degradation drug-delivery system for reversing pancreatic fibrosis. Furthermore, the strategy proposed herein will offer an innovative platform for the treatment of chronic pancreatitis.

Carboplatin and decitabine loaded lipid-coated albumin nanoparticles for an efficient treatment of platinum-resistant ovarian cancer

Carboplatin is extensively used in the first-line treatment of ovarian cancer. Although the majority of patients respond to platinum-based therapy, platinum resistance limits the efficiency of treatment in the clinical setting. During treatment, DNA methylation leads to epigenetic silencing of tumor suppressor genes and cancer cells lose their sensitivity to platinum-based compounds. The therapeutic utilization of decitabine, which is an epigenetic demethylating agent, in combination with carboplatin is considered as a novel method for overcoming drug resistance in ovarian cancer. In this study, we developed a pH-responsive lipid-coated nanoparticular system that was co-loaded with carboplatin and decitabine to modulate the platinum resistance. The nanoparticles exhibited a core-shell structure of 350 ± 12 nm particle size, −57 ± 2 mV surface charge. The cytotoxicity studies demonstrated that cytotoxic effect of carboplatin was achieved at significantly lower doses in platinum-sensitive and platinum-resistant ovarian cancer cells. In addition, confirmation of apoptosis by caspase and PARP cleavage in both cells strongly supported the efficacy of the nanoparticular system. Notably, dual drug-loaded nanoparticles led to MLH1 re-expression in resistant ovarian cancer cells, which may be attributed to improved drug sensitivity in cells. Overall, the developed nanoformulation has great potential for the treatment of platinum-sensitive as well as platinum-resistant ovarian cancer.

Phenylboronic Acid-Functionalized Copolypeptides: Facile Synthesis and Responsive Dual Anticancer Drug Release.

The incorporation of a phenylboronic acid group has appeared as an attractive strategy to build smart drug delivery systems. Here, we report novel synthesis of phenylboronic acid-functionalized copolypeptides based on an l-boronophenylalanine N-carboxyanhydride (BPA-NCA) monomer and their application for robust co-encapsulation and responsive release of dual anticancer drugs. By employing different poly(ethylene glycol) (PEG) initiators and copolymerizing with varying NCA monomers, linear and star PEG-poly(l-boronophenylalanine) copolymers (PEG-PBPA, star-PEG-PBPA), PEG-poly(l-tyrosine-co-l-boronophenylalanine) [PEG-P(Tyr-co-BPA)], PEG-poly(l-lysine-co-l-boronophenylalanine) [PEG-P(Lys-co-BPA)], and PEG-poly(β-benzyl-l-aspartate-co-l-boronophenylalanine) [PEG-P(BLA-co-BPA)] were obtained with controlled compositions. Interestingly, PEG-PBPA self-assembled into uniform micellar nanoparticles that mediated robust co-encapsulation and hydrogen peroxide (H2O2) and acid-responsive release of dual antitumor drugs, curcumin (Cur) and sorafenib tosylate (Sor). These dual drug-loaded nanoparticles (PBN-Cur/Sor) exhibited a greatly enhanced anticancer effect toward U87 MG-luciferase glioblastoma cells. The facile synthesis of phenylboronic acid-functionalized copolypeptides from BPA coupled with their robust drug loading and responsive drug release behaviors make them interesting for construction of smart cancer nanomedicines.

Co-encapsulation of l-asparaginase and etoposide in dextran nanoparticles for synergistic effect in chronic myeloid leukemia cells

Co-encapsulation of multiple therapeutic drugs in a single nanocarrier has the potential to enable synergistic interactions, increase drug efficacy, and reduce side effects. The enzyme l-asparaginase and the small molecule drug etoposide have a known synergistic effect against selected cancer types. However, both drugs differ significantly in size, molecular weight, and solubility, which often results in challenges when a simultaneous delivery is required. In this study, we present the co-encapsulation of a large hydrophilic enzyme l-asparaginase and the small hydrophobic drug etoposide into a biodegradable, biocompatible, and acid-responsive dextran-based nanoparticle system. These dual drug-loaded nanoparticles show an excellent cellular uptake in chronic myeloid leukemia (CML) K562 cells and a stepwise release of the cytotoxic payloads in a pH-dependent manner. In activity tests, the dual drug-loaded formulation has shown a significant effect on cell viability (down to 31%) compared to those incubated only with l-asparaginase (92%) or etoposide (82%) at a particle concentration of 125 μg∙mL−1. These results show that the simultaneous co-delivery of these two drugs in K562 cells leads to synergistic cytotoxicity, indicating a great potential for the treatment of CML.

Dual Hyaluronic Acid and Folic Acid Targeting pH-Sensitive Multifunctional 2DG@DCA@MgO-Nano-Core-Shell-Radiosensitizer for Breast Cancer Therapy.

Simple SummaryIn this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This comprises hyaluronic acid (HA) and folic acid (FA) conjugated to 2-deoxy glucose (2DG) and a shell linked to a dichloroacetate (DCA) and magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective breast cancer (BC) treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were comprehensively examined. Mechanistically, we identified multiple component signal pathways as important regulators of BC metabolism and mediators for the inhibitory effects exerted by DDM. Nanoparticles exhibited sustained DDM release properties in bio-relevant media, which was responsive to acidic pH providing edibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays indicated that the functionalized DDM significantly suppressed cancer cell growth and boosted radiotherapy (RT) efficacy via inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. Accordingly, the inhibition of glycolysis/OXPHOS by DDM and RT treatment may result in cancer metabolic reprogramming via a novel PI3K/AKT/mTOR/P53NF-κB/VEGF pathway in BC cells. Therefore, the dual targeting of glycolysis/OXPHOS pathways is suggested as a promising antitumor strategy.Globally, breast cancer (BC) poses a serious public health risk. The disease exhibits a complex heterogeneous etiology and is associated with a glycolytic and oxidative phosphorylation (OXPHOS) metabolic reprogramming phenotype, which fuels proliferation and progression. Due to the late manifestation of symptoms, rigorous treatment regimens are required following diagnosis. Existing treatments are limited by a lack of specificity, systemic toxicity, temporary remission, and radio-resistance in BC. In this study, we have developed CD44 and folate receptor-targeting multi-functional dual drug-loaded nanoparticles. This composed of hyaluronic acid (HA) and folic acid (FA) conjugated to a 2-deoxy glucose (2DG) shell linked to a layer of dichloroacetate (DCA) and a magnesium oxide (MgO) core (2DG@DCA@MgO; DDM) to enhance the localized chemo-radiotherapy for effective BC treatment. The physicochemical properties of nanoparticles including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy were thoroughly examined. Mechanistically, we identified multiple component signaling pathways as important regulators of BC metabolism and mediators for the inhibitory effects elicited by DDM. Nanoparticles exhibited sustained DDM release properties in a bio-relevant media, which was responsive to the acidic pH enabling eligibility to the control of drug release from nanoparticles. DDM-loaded and HA–FA-functionalized nanoparticles exhibited increased selectivity and uptake by BC cells. Cell-based assays revealed that the functionalized DDM significantly suppressed cancer cell growth and improved radiotherapy (RT) through inducing cell cycle arrest, enhancing apoptosis, and modulating glycolytic and OXPHOS pathways. By highlighting DDM mechanisms as an antitumor and radio-sensitizing reagent, our data suggest that glycolytic and OXPHOS pathway modulation occurs via the PI3K/AKT/mTOR/NF-κB/VEGFlow and P53high signaling pathway. In conclusion, the multi-functionalized DDM opposed tumor-associated metabolic reprogramming via multiple signaling pathways in BC cells as a promising targeted metabolic approach.

Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.

Pharmaco-Technical Evaluation of Statistically Formulated and Optimized Dual Drug-Loaded Silica Nanoparticles for Improved Antifungal Efficacy and Wound Healing.

The current research aimed at designing mesoporous silica nanoparticles (MSNs) for a controlled coadministration of salicylic acid (SA) and ketoconazole (KCZ) to effectively treat highly resistant fungal infections. The sol–gel method was used to formulate MSNs, which were further optimized using central composite rotatable design (CCRD) by investigating mathematical impact of independent formulation variables such as pH, stirring time, and stirring speed on dependent variables entrapment efficiency (EE) and drug release. The selected optimized MSNs and pure drugs were subjected to comparative in vitro/in vivo antifungal studies, skin irritation, cytotoxicity, and histopathological evaluations. The obtained negatively charged (−23.1), free flowing spherical, highly porous structured MSNs having a size distribution of 300–500 nm were suggestive of high storage stability and improved cell proliferation due to enhanced oxygen supply to cells. The physico-chemical evaluation of SA/KCZ-loaded MSNs performed through powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA) indicates absolute lack of any interaction between formulation components and successful encapsulation of both drugs in MSNs. The EESA, EEKCZ, SA release, and KCZ release varied significantly from 34 to 89%, 36 to 85%, 39 to 88%, and 43 to 90%, respectively, indicating the quadratic impact of formulation variables on obtained MSNs. For MSNs, the skin tolerability and cell viability percentage rate were also having an extraordinary advantage over suspension of pure drugs. The optimized SA/KCZ-loaded MSNs demonstrated comparatively enhanced in vitro/in vivo antifungal activities and rapid wound healing efficacy in histopathological evaluation without any skin irritation impact, suggesting the MSNs potential for the simultaneous codelivery of antifungal and keratolyic agents in sustained release fashion.

Precise engineering of dual drug-loaded polymeric nanoparticles system to improve the treatment of glioma-specific targeting therapy

We have fabricated a novel method to achieve therapy- triggered changes in tumor cells by using promising effects concerning dual chemotherapeutic drugs. Dual-drug conveyance of Salinomycin (SAL) and Doxorubicin (DOX) exhibits a great anti-tumor ability, as SAL improves the impact of DOX management of glioma cells by supplying stability of the microenvironment. Nevertheless, encapsulations of SAL and DOX fanatical by (lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG)- based nanoparticles (NPs) is incompetents due to inappropriateness between the dual drug SAL and DOX polymeric framework. At the present, we show DOX and SAL can be formulated with dioleoylphosphatide acid (DOPA) through the hydrophobic covering of drug centers. In PEG-PLGA NPs, the DOPA- enclosed DOX can be co-incorporating in addition to SAL to encourage superior cancer activities. The DOX revealed seductively that the SAL encapsulations in PEG-PLGA NPs (SAL-DOX NPs) were improved. The transmission microscopy (TEM) studied the morphology of SAL NPs, DOX NPs, SAL-DOX NPs, and nanoparticle size. SAL-DOX NPs also induced major apoptosis in vitro human glioma cells such as LN229 and U251. Different biochemical trials such as AO-EB, Hoechst staining, and annexin V-FITC have confirmed morphological observations and apoptosis. The findings indicate that the SAL-DOX NPs is one of the promising caregivers of therapeutic candidates for human glioma cancer worth further study.

Aminocellulose - grafted polycaprolactone-coated core-shell nanoparticles alleviate the severity of ulcerative colitis: a novel adjuvant therapeutic approach.

Ulcerative colitis (UC) is an idiopathic inflammatory condition of colorectal regions. Existing therapies for UC face grave lacunae including off-target and other harmful side effects, extensive first-pass metabolism, rapid clearance, limited or poor drug absorption and various other limitations, resulting in lower bioavailability. These conditions demand advanced delivery strategies to inflammatory colonic conditions so that drugs can counter stomach acid, avail protective strategies at this pH and selectively deliver drugs to the colon. Therefore, this approach was undertaken to develop and characterize nanoparticles for the delivery of drugs glycyrrhizic acid as well as budesonide in UC. Biocompatible and biodegradable aminocellulose-conjugated polycaprolactone containing budesonide was covered onto gelatinous nanoparticles (NPs) loaded with GA. Nanoparticles were prepared by the solvent evaporation technique, which showed particle size of ∼230 nm, spherical shape, almost smooth morphological characters under transmission, scanning and atomic force microscopy. These NPs also improved disease activities like occult blood in the stool, length of the colon and fecal properties. The nanoparticle therapy appreciably decreased colonic mast cellular infiltration, significantly maintained mucin protection, ameliorated histological features of the colon. Furthermore, markers of inflammation such as iNOS, COX-2, IL1-β, TNF-α, NO, and MPO were also appreciably ameliorated with the therapy of dual drug-loaded nanoparticles. Overall, these results establish that dual drug-loaded core-shell NPs exhibit superior therapeutic properties over the free or naïve forms of GA and budesonide in acute colon inflammation and present advantages that may be assigned to their ability to significantly inhibit colon inflammatory conditions.

Dual drug delivery of trapoxin A and methotrexate from biocompatible PLGA-PEG polymeric nanoparticles enhanced antitumor activity in breast cancer cell line

Nanoparticle (NP) mediated systems have been considered for chemotherapeutical delivery because of their ability to control drug release and reduce side effects These systems can also be used to deliver two or more drugs at the same time and prevent the growth of resistant cancer cells. Trapoxin A (TPX) and methotrexate (MTX) have shown promising results in treatment or controlling the progression of cancer. The present study examines the synergistic anticancer efficiency of TPX and MTX co-loaded PLGA-PEG NPs against MCF-7 breast cancer cells. The resultant drug-loaded PLGA-PEG NPs displayed a spherical morphology with the uniform nanosize distribution. Besides, the possible mechanisms for the inhibition of cell growth, distribution of cell cycle, and induction of apoptotic cell death were analyzed by DAPI staining, cell cycle analysis, and qRT-PCR. Interestingly, the obvious synergistic anticancer effects and the activation of the mitochondrial apoptosis pathway were observed on the breast cancer cell line MCF-7 by treating with TPX/MTX-co-loaded PLGA-PEG NPs. Also, it was revealed that the dual drug-loaded NPs could considerably change the expression levels of cyclin D1, and Bcl-2 compared to the free combination of the drugs as well as the single drug-loaded NPs. Taken together, this work revealed that TPX/MTX co-loaded PLGA-PEG NP based combination therapy might have an important potential to increase the efficiency of breast cancer therapy.

Design and fabrication of cell-targeted, dual drug-loaded nanoparticles with pH-controlled drug release and near-infrared light-induced photothermal effects

Multi-functional nanoparticles with targeting and chemo-photothermal features are attractive materials for the development of therapeutics. In this study, thermal- and pH-sensitive nanoparticles loaded with two drugs were fabricated for controlled drug release. For synthesis of nanoparticles, we first prepared a PAMAM dendrimer cluster, which could provide large core space, and then sequentially loaded indocyanine green (ICG, a photothermal agent) and doxorubicin (DOX, a chemotherapeutic agent) premixed with polyacrylic acid (PAA) to the dendrimer cluster through ionic interactions. This self-assembling strategy yielded a high drug-loading content for both DOX (19.1 ± 0.4%) and ICG (54 ± 1%). Subsequently, PEG and Herceptin were covalently attached to nanoparticles to promote their bio-recognition by HER2-overexpressing cancer cells. DOX was released by changing pH from 7.4 to 5; DOX release was markedly enhanced by NIR (808 nm) laser irradiation. Conjugation with Herceptin could enhance specific attachment and accumulation of nanoparticles in tumor cells. Under NIR laser irradiation, ICG served as a remote-controlled trigger to generate considerable heat that caused severe physical damage and extensive cell apoptosis. Furthermore, after NIR laser irradiation, drug delivery and penetration of the nanoparticles into tumor spheroids were enhanced, indicating the potential therapeutic application of the newly developed nanoparticles.