Wbselen and gemcitabine synergistically inhibited the viability of JF305 and MiaPaCa-2 human pancreatic cancer cells

Gemcitabine (GEM) is a cell-cycle specific inhibitor of DNA synthesis and repair, and has been applied as the first-line therapy for patients with locally advanced or metastatic pancreatic cancers. However, the median survival time is only 5.65 mon when GEM was administrated as a monothearpy. Therefore, novel therapeutic agents and/or combinations with GEM are needed for the treatment of pancreatic cancer. In this study, we aim to evaluate the efficacy of treatment with wbselen (WB), GEM, and combination treatment with GEM and WB in two pancreatic cancer cell lines, JF305 and MiaPaCa-2 cells. The combination index (CI) and the dose-reduction index (DRI) of combined treatment with different dose and time regimes were analyzed based on median-effect theory. Compared with single treatment with GEM, combination treatment displayed decreased response time and IC50, and increased maximum inhibition. Among the different combination regimes, the most significant synergistic effect was achieved when the dose ratios of WB to GEM was 2:1 in JF305 cells and 1:1 in MiaPaCa-2 cells after 48 h of drug treatment. When combinations of WB and GEM were used in these two cell lines, the dose of GEM was significantly reduced while the total drug concentration increased, especially after 48 h of drug treatments. Our results indicated that the combination treatment with WB and GEM had synergistic effect against pancreatic cancer in vitro.     

Combination of siRNA-directed Kras oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer

The synergetic inhibitory effects on human pancreatic cancer by nanoparticle-mediated siRNA and arsenic therapy were investigated both in vitro and in vivo. Poly(ethylene glycol)-block-poly(l-lysine) were prepared to form siRNA-complexed polyplex and poly(ethylene glycol)-block-poly(dl-lactide) were prepared to form arsenic-encapsulated vesicle, respectively. Down-regulation of the mutant Kras gene by siRNA caused defective abilities of proliferation, clonal formation, migration, and invasion of pancreatic cancer cells, as well as cell cycle arrest at the G0/G1 phase, which substantially enhanced the apoptosis-inducing effect of arsenic administration. Consequently, co-administration of the two nanomedicines encapsulating siRNA or arsenic showed ideal tumor growth inhibition both in vitro and in vivo as a result of synergistic effect of the siRNA-directed Kras oncogene silencing and arsenic-induced cell apoptosis. These results suggest that the combination of mutant Kras gene silencing and arsenic therapy using nanoparticle-mediated delivery strategy is promising for pancreatic cancer treatment.From the Clinical EditorTreatment of pancreatic cancer remains a major challenge. These authors demonstrate a method that combines a siRNA-based Kras silencing with arsenic delivery to pancreatic cancer cells using nanoparticles, resulting in enhanced apoptosis induction in the treated cells.     

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells

Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy, and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free GEM and PT core and the macromolecular system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.     

Targeted delivery of a combination therapy consisting of combretastatin A4 and low-dose doxorubicin against tumor neovasculature

The present study demonstrates the applicability of a novel strategy that employs targeted delivery of combined treatment against tumor neovasculature. Briefly, a ligand of integrins, cyclic arginine-glycine-aspartic acid-tyrosine-lysine pentapeptide (cRGDyK), was conjugated to the PEG end of polyethylene glycol-b-poly lactic acid (PEG-b-PLA), and doxorubicin was chemically linked to the PLA end of PEG-b-PLA. The targeted dual-drug micelle system was prepared by mixing combretastatin A4 (an antivascular agent), PEG-b-PLA, and the above two conjugates using a solution-casting method. The targeted micelles significantly enhanced cellular uptake of the drug by B16-F10 cells and human umbilical vein endothelial cells through a receptor-mediated endocytosis. The cRGDyK-modified dual-drug system achieved an optimal antitumor effect, lifespan increase, antineovasculature, antiproliferation, and apoptosis induction, revealing the advantage of active targeting and the modified combination therapy. In conclusion, the integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment. FROM THE CLINICAL EDITOR: A ligand of integrins was conjugated to PEG-b-PLA, and doxorubicin was chemically linked to the PLA. Efficiency was demonstrated in a cancer model. The integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment.     

Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy

Combination therapy for the treatment of cancer is becoming more popular because it generates synergistic anticancer effects, reduces individual drug-related toxicity and suppresses multi-drug resistance through different mechanisms of action. In recent years, nanotechnology-based combination drug delivery to tumor tissues has emerged as an effective strategy by overcoming many biological, biophysical and biomedical barriers that the body stages against successful delivery of anticancer drugs. The sustained, controlled and targeted delivery of chemotherapeutic drugs in a combination approach enhanced therapeutic anticancer effects with reduced drug-associated side effects. In this article, we have reviewed the scope of various nanotechnology-based combination drug delivery approaches and also summarized the current perspective and challenges facing the successful treatment of cancer.     

Tumor-targeted/reduction-triggered composite multifunctional nanoparticles for breast cancer chemo-photothermal combinational therapy

Breast cancer has become the most commonly diagnosed cancer type in the world. A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for breast cancer therapy. However, the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Therefore, to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect, a multifunctional nanoparticle system (PCRHNs) is developed, which is grafted onto the prussian blue nanoparticles (PB NPs) by reduction-responsive camptothecin (CPT) prodrug copolymer, and then modified with tumor-targeting peptide cyclo(Asp-d-Phe-Lys-Arg-Gly) (cRGD) and hyaluronic acid (HA). PCRHNs exhibited nano-sized structure with good monodispersity, high load efficiency of CPT, triggered CPT release in response to reduction environment, and excellent photothermal conversion under laser irradiation. Furthermore, PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT. In vivo studies indicate that PCRHNs exhibited excellent biocompatibility, prolonged blood circulation, enhanced tumor accumulation, allow tumor-specific chemo-photothermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity. Moreover, hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT. Collectively, PCRHNs may be a promising therapeutic way for breast cancer therapy.     

Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.     

Elaborately engineering of a dual-drug co-assembled nanomedicine for boosting immunogenic cell death and enhancing triple negative breast cancer treatment

Pure drug-assembled nanosystem provides a facile and promising solution for simple manufacturing of nanodrugs, whereas a lack of understanding of the underlying assembly mechanism and the inefficient and uncontrollable drug release still limits the development and application of this technology. Here, a simple and practical nanoassembly of DOX and DiR is constructed on basis of their co-assembly characteristics. Multiple interaction forces are found to drive the co-assembly process. Moreover, DOX release from the nanoassembly can be well controlled by the acidic tumor microenvironment and laser irradiation, resulting in favorable delivery efficiency of DiR and DOX in vitro and in vivo. As expected, the nanoassembly with high therapeutic safety completely eradicated the mice triple negative breast cancer cells (4T1) on BALB/c mice, owing to synergistic chemo-photothermal therapy. More interestingly, DiR and DOX synergistically induce immunogenic cell death (ICD) of tumor cells after treatment, enabling the mice to acquire immune memory against tumor growth and recurrence. Such a facile nanoassembly technique provides a novel multimodal cancer treatment platform of chemotherapy/phototherapy/immunotherapy.     

Combination prostate cancer therapy: Prostate-specific membranes antigen targeted,pH-sensitive nanoparticles loaded with doxorubicin and tanshinone

Prostate cancer is the second most frequently diagnosed cancer in the men population. Combination anticancer therapy using doxorubicin (DOX) and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, maximize the treatment effect, and overcome multi-drug resistance. The purpose of this study is to construct a drug delivery system for the co-delivery of DOX and tanshinones (TAN). Lipid nanoparticles loaded with DOX and TAN (N-DOX/TAN) were prepared by emulsification and solvent-diffusion method. PSMA targeted nanoparticles loaded with DOX and TAN (P-N-DOX/TAN) were synthesized by conjugating a PSMA targeted ligand to N-DOX/TAN. We evaluate the performance of this system in vitro and in vivo. P-N-DOX/TAN has a size of 139.7 ± 4.1 nm and a zeta potential of 11.2 ± 1.6 mV. The drug release of DOX and TAN from P-N-DOX/TAN was much faster than that of N-DOX/TAN. N-DOX/TAN presented more inhibition effect on tumor growth than N-DOX and N-TAN, which is consistent with the synergistic results and successfully highlighting the advantages of combing the DOX and TAN in one system. P-N-DOX/TAN achieved higher uptake by LNCaP cells (58.9 ± 1.9%), highest tumor tissue distribution, and the most significant tumor inhibition efficiency. The novel nanomedicine offers great promise for the dual drug delivery to prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.     

Linear-like polypeptide-based micelle with pH-sensitive detachable PEG to deliver dimeric camptothecin for cancer therapy

Nano drug delivery systems have made significant progress in delivering anticancer drugs camptothecin (CPT). However, many challenges for CPT delivery remain, including low drug loading efficiency, premature drug leakage, and poor cellular internalization. Herein, we report a novel dual-sensitive polypeptide-based micelle with remarkably high drug loading of CPT for cancer therapy. This self-assembled micelle possesses the following essential components for CPT: (1) pH-sensitive PEG (OHC-PEG-CHO) for prolonging blood circulation and allowing biocompatibility by shielding the cationic micelles, which can be detached under the tumor acidic microenvironment and facilitates the cellular uptake; (2) polypeptide polylysine-polyphenylalanine (PKF) synthesized via ring-opening polymerization for micelle formation and CPT analogue loading; (3) dimeric CPT (DCPT) with redox-sensitive linker for increasing CPT loading and ensuring drug release at tumor sites. Interestingly, the linear-like morphology of PEG-PKF/DCPT micelles was able to enhance their cellular internalization when compared with the spherical blank PKF micelles. Also, the anticancer efficacy of DCPT against lung cancer cells was significantly improved by the micelle formation. In conclusion, this work provides a promising strategy facilitating the safety and effective application of CPT in cancer therapy.     

Tailored core‒shell dual metal–organic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare. Because of the heterogeneity of tumor, single therapy presents great limitations while synergistic therapy is arousing much attention, which shows desperate need of intelligent carrier for co-delivery. A core‒shell dual metal–organic frameworks (MOFs) system was delicately designed in this study, which not only possessed the unique properties of both materials, but also provided two individual specific functional zones for co-drug delivery. Photosensitizer indocyanine green (ICG) and chemotherapeutic agent doxorubicin (DOX) were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform. Except for efficient drug delivery, the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy. The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared (NIR) light irradiation. The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles, with a significantly higher inhibition rate. It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.     

Ascorbyl palmitate-incorporated paclitaxel-loaded composite nanoparticles for synergistic anti-tumoral therapy

A co-loaded drug delivery system based on ascorbyl palmitate that can transport various functional drugs to their targets within a tumor represents an attractive strategy for increasing the efficiency of anticancer treatment. In this study, we developed a dual drug delivery system to encapsulate ascorbyl palmitate (AP) and paclitaxel (PTX) for synergistic cancer therapy. AP, which is a vitamin C derivative, and PTX were incorporated into solid lipid nanoparticles (AP/PTX-SLNs), which were used to treat murine B16F10 melanoma that had metastasized to the lungs of mice. These nanoparticles were spherical with an average size of 223?nm as measured by transmission electron microscope and dynamic light scattering. In vitro cytotoxicity assays indicated that the AP/PTX-SLNs with an AP/PTX mass ratio of 2/1 provided the optimal synergistic anticancer efficacy. In vivo, AP/PTX-SLNs were revealed to be much more effective in suppressing tumor growth in B16F10-bearing mice and in eliminating cancer cells in the lungs than single drug (AP or PTX)-loaded SLNs via a synergistic effect through reducing the Bcl-2/Bax ratio. Furthermore, no marked side effects were observed during the treatment with the AP/PTX-SLNs, indicating that the co-delivery system with ascorbyl palmitate holds promising clinical potential in cancer therapy.     

Design,preparation and pharmacodynamics of ICG-Fe(Ⅲ) based HCPT nanocrystals against cancer

The use of nanocrystal technology to manufacture drug delivery systems intended to enhance therapeutic efficacy has attracted the attention of the pharmaceutical industry. However, the clinical application of nanocrystal drugs for injection is restricted by Ostwald ripening and the large-scale use of stabilizers such as polysorbate and lecithin, which have potential toxicity risks including hemolysis and allergies. Here, we designed an amorphous nanocrystal drug complex (IHNC), which is stabilizer-free and composed of indocyanine green (ICG) framework loading with a chemotherapeutic agent of 10-hydroxycamptothecin (HCPT). Considering the possibility of industrial manufacturing, IHNC was simply prepared with the assistance of ferric ion (III) via supramolecular assembly strategy. The theoretical result of Materials Studio simulation indicated that the prepared ICG-Fe(III) framework showed a stable spherical structure with the appropriate cavity for encapsulating the two drugs of HCPT and ICG with equal mass ratio. The IHNC was stable at physiological pH, with excellent PTT/PDT efficacy, and in vivo probing characteristics. The nanoscale size and reductive stimuli-responsiveness can be conducive to drug accumulation into the tumor site and rapid unloading of cargo. Moreover, such combination therapy showed synergistic photo/chemotherapy effect against 4T1 breast cancer and its tumor inhibition rate even up to 79.4%. These findings demonstrated that the nanocrystal drug delivery strategy could avoid the use of stabilizers and provide a new strategy for drug delivery for combination therapy.     

Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment

Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard, we have synthesized Pem-PEG-Gem, wherein pemetrexed (Pem) and gemcitabine (Gem) are conjugated to a heterobifunctional polyethylene glycol (PEG) polymer for the effective treatment of Non-Small Cell Lung Cancer (NSCLC). Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.     

Remodeling “cold” tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona

There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8⁺ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).KEY WORDS: Tumor immune microenvironment, Tumor-associated macrophage, Epigenetic therapy, Immune checkpoint, Angiogenesis, Panobinostat, JQ1, Liposome     

Targeted delivery and stimulus-responsive release of anticancer drugs for efficient chemotherapy

Chemotherapy is currently an irreplaceable strategy for cancer treatment. Doxorubicin hydrochloride (DOX) is a clinical first-line drug for cancer chemotherapy. While its efficacy for cancer treatment is greatly compromised due to invalid enrichment or serious side effects. To increase the content of intracellular targets and boost the antitumor effect of DOX, a novel biotinylated hyaluronic acid-guided dual-functionalized CaCO₃-based drug delivery system (DOX@BHNP) with target specificity and acid-triggered drug-releasing capability was synthesized. The ability of the drug delivery system on enriching DOX in mitochondria and nucleus, which further cause significant tumor inhibition, were investigated to provide a more comprehensive understanding of this CaCO₃-based drug delivery system. After targeted endocytosis by tumor cells, DOX could release faster in the weakly acidic lysosome, and further enrich in mitochondria and nucleus, which cause mitochondrial destruction and nuclear DNA leakage, and result in cell cycle arrest and cell apoptosis. Virtually, an effective tumor inhibition was observed in vitro and in vivo. More importantly, the batch-to-batch variation of DOX loading level in the DOX@BHNP system is negligible, and no obvious histological changes in the main organs were observed, indicating the promising application of this functionalized drug delivery system in cancer treatment.     

Augmentation of Therapeutic Efficacy in Drug-Resistant Tumor Models Using Ceramide Coadministration in Temporal-Controlled Polymer-Blend Nanoparticle Delivery Systems

The development of multidrug resistance (MDR) is a major hindrance to cancer eradication as it renders tumors unresponsive to most chemotherapeutic treatments and is associated with cancer resurgence. This study describes a novel mechanism to overcome MDR through a polymer-blend nanoparticle platform that delivers a combination therapy of C6-ceramide (CER), a synthetic analog of an endogenously occurring apoptotic modulator, together with the chemotherapeutic drug paclitaxel (PTX), in a single formulation. The PTX/CER combination therapy circumvents another cellular mechanism whereby MDR develops, by lowering the threshold for apoptotic signaling. In vivo studies in a resistant subcutaneous SKOV3 human ovarian and in an orthotopic MCF7 human breast adenocarcinoma xenograft showed that the PTX and CER nanoparticle combination therapy reduced the final tumor volume at least twofold over treatment with the standard PTX therapy alone. The study also revealed that the cotherapy accomplished this enhanced efficacy by generating an enhancement in apoptotic signaling in both tumor types. Additionally, acute evaluation of safety with the combination therapy did not show significant changes in body weight, white blood cell counts, or liver enzyme levels. The temporal-controlled nanoparticle delivery system presented in this study allows for a simultaneous delivery of PTX + CER in breast and ovarian tumor model drug, leading to a modulation of the apoptotic threshold. This strategy has tremendous potential for effective treatment of refractory disease in cancer patients.     

Assessment of Three-Drug Combination Pharmacodynamic Interactions in Pancreatic Cancer Cells

The pharmacodynamic interactions among trifluoperazine (TFP), gemcitabine (GEM), and paclitaxel (PTX) were assessed in pancreatic cancer cells (PANC-1). The phenothiazine TFP was chosen for its potential activity on cancer stem cells, while GEM and PTX cause apoptosis. Effects of each drug alone and in various combinations on cell growth inhibition of PANC-1 cells were studied in vitro to determine the drug-specific parameters and assess the nature of drug interactions. Joint inhibition (JI) and competitive inhibition (CI) equations were applied with a ψ interaction term. TFP fully inhibited growth of cells (I_max?=?1) with an IC₅₀?=?9887 nM. Near-maximum inhibition was achieved for GEM (I_max?=?0.825) and PTX (I_max=?0.844) with an IC₅₀?=?17.4 nM for GEM and IC₅₀?=?7.08 nM for PTX. Estimates of an interaction term ψ revealed that the combination of TFP-GEM was apparently synergistic; close to additivity, the combination TFP-PTX was antagonistic. The interaction of GEM-PTX was additive, and TFP-GEM-PTX was synergistic but close to additive. The combination of TFP IC₆₀–GEM IC₆₀–PTX IC₆₀ seemed optimal in producing inhibition of PANC-1 cells with an inhibitory effect of 82.1–90.2%. The addition of ψ terms to traditional interaction equations allows assessment of the degree of perturbation of assumed mechanisms.     

Dual-Targeting Nanoparticles: Codelivery of Curcumin and 5-Fluorouracil for Synergistic Treatment of Hepatocarcinoma

Chemotherapy has been the standard for cancer therapy, but the nonspecific cytotoxicity of chemotherapeutic agents and drug resistance of tumor cells has limited its efficacy. However, multidrug combination therapy and targeting therapy have resulted in enhanced anticancer effects and have become increasingly important strategies in clinical applications. In this study, a biotin-/lactobionic acid–modified poly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly(ethylene glycol) (BLPP) copolymer was synthesized, and curcumin- and 5-fluorouracil-loaded nanoparticles (BLPPNPs/C + F) were prepared to enhance the treatment of hepatocellular carcinoma. Blank BLPPNPs were shown to have great biocompatibility via both in vitro and in vivo studies. Good targeting of tumor cells of BLPPNPs was confirmed by flow cytometry, fluorescence microscopy, and biodistribution. The synergistic anticancer effects of BLPPNPs/C + F were demonstrated by cytotoxicity and animal studies, while western blotting was used to further verify the synergistic effect of curcumin and 5-fluorouracil. The dual-targeting and drug-loaded codelivery nanosystem demonstrated higher cellular uptake and stronger cytotoxicity for tumor cells. Therefore, these dual-targeting NPs are a promising codelivery carrier that could be made available for cellular targeting of anticancer drugs to achieve better intracellular delivery and synergistic anticancer efficacy.