Co-drug Delivery Research Articles

Co-loading Radio-photosensitizer Agents on Polymer and Lipid-based Nanocarriers for Radio-photodynamic Therapy Purposes: Review.

Polymer and lipid-based nanocarriers are a state-of-art in nanomedicine and in co-drug delivery of drugs that could merges various diagnostic and treatment modalities such radiotherapy (RT), photodynamic therapy (PDT) and chemotherapy (CT) in cancer therapy. Among various shapes and nanostructures, polymer and lipid-based nanocarriers have the potential to carry two drugs in same time to cells. However, hydrophobic and hydrophilic drug can be loaded in between layers as well as in the core of these nanocarriers, simultaneously. This advantage of NPs can be employed in combination therapy. Radiosensitizer and photosensitizer agents play a critical role in radio-photodynamic therapy (RT-PDT) of cancer. Co-delivery of these agents to cancerous cells is advantageous to cancer therapy but still remain as a challenge of RT-PDT. However, in this review, we have highlighted the challenges of RT-PDT and role of polymer and lipid-based nanocarriers to codelivery of hydrophobic and hydrophilic agents as radio-photosensitizers. Hence, the different kinds of Poly (lactic-co-glycolic acid) nanoparticles (NPs) have been categorized. Then, the biophysical mechanism of radio- photosensitizer agents with co-loading on polymer and lipid-based nanocarriers in RT-PDT treatment of cancer has been outlined. Finally, attention has been drawn to polymer and lipid-based nanocarriers in codrugs delivery. Taken together, this work presents the latest updates on this area and highlighted the pros and cons of co-delivery for RT-PDT purposes.

A biocompatible drug controlled release system based on β-cyclodextrin crosslinked magnetic lactose/ZIF-8 metal-organic frameworks for cancer treatment

Natural saccharides (Chitosan, Lactose, alginate, and β-cyclodextrin) have recently attracted much attention from researchers as drug delivery systems for cancer therapy. In this regard, for the first time, we designed a new targeted carrier based on magnetic lactose-modified ZIF-8 metal-organic frameworks crosslinked with β-cyclodextrin (M-Lactose@ZIF-8-β-CD) for the pH-responsive controlled release of anticancer drugs, hydrophilic doxorubicin (DOX), and hydrophobic curcumin (CUR) to MCF-7 breast cancer cells. The encapsulation efficiency of M-Lactose@ZIF-8-β-CD was found to be 95.16 % for DOX and 65.01 % for CUR. The in vitro release studies showed a pH-responsive controlled release of DOX and CUR from M-Lactose@ZIF-8-β-CD at pH 5, which confirmed the performance of the prepared carrier in the cancerous microenvironments. The release mechanism of both drugs was well described by the Korsmeyer-Peppas and Fickian diffusion. In addition, in vitro cytotoxicity, hemolysis, and antioxidant investigations clearly showed that the prepared M-Lactose@ZIF-8-β-CD carriers had good biocompatibility, high blood compatibility, and excellent antioxidant activity due to the presence of natural saccharides in carriers. Based on these findings, the M-Lactose@ZIF-8-β-CD can be applied as a promising targeted co-drug delivery carrier for cancer therapy.

Preparation and characterization of multi-target nanoparticles for co-drug delivery

Self-assembly of various amphipathic copolymers is a simple method that allows the preparation of complex nanoparticles with several useful properties. Therefore, the aim of this research was to develop nanoparticles with better biocompatibility, biodegradability, and prolonged circulation time in the bloodstream to deliver drugs and genes into breast cancer tissues in a controlled and targeted manner. In this study, the copolymers PLA-chitosan- PEG -folic acid (COPA), PLA-chitosan- PEG -glucose (COPB), COPA & COPB (COPAB) and chitosan- PLA-PEG FA /Glu/VEGF/siRNA/PTX (NPsAB/siRNA/Paclitaxel) were synthesized, to control the release of paclitaxel (PTX) and siRNA and the circulation time of nanoparticles in blood. This was confirmed by 1H NMR and FTIR spectroscopy. The particle size, zeta potential and morphology of NPsAB /siRNA/PTX were studied by DLS and TEM, respectively. The results showed that the NPsAB/siRNA/PTX had spherical morphology with particle size and zeta potential about 200 nm and −7.8 mV, respectively. In vitro cytotoxicity assay results showed that the nanoparticles had good biocompatibility and low toxicity. Also demonstrated that NPsAB in the serum medium improved the efficiency of drug and siRNA delivery more than two-fold compared to COPA, COPB, and COPAB nanoparticles. Due to results the release pattern of siRNA and PTX from NPsAB nanoparticles under an acidic environment was significantly higher than that of their release rate in a neutral medium. Therefore, due to the acidity of tumor tissue, this property of NPsAB nanoparticles seems to be useful in the treatment of cancer.

Bioengineered DNA-decorated UiO-66-based nanocarriers for combined administration of doxorubicin and sorafenib: Hepatocellular carcinoma treatment and chemotherapy

Natural biomaterials were used to decorate UiO-66-NH2 to develop a platform for co-drug delivery of doxorubicin and sorafenib as a cost-effective and easy way to use a drug delivery system (DDS). To properly characterize the modified MOFs, standard analytical methods were used. Then doxorubicin and sorafenib were loaded into and onto the porosity of the MOF, UiO-66-NH2. The surface morphological analysis, FESEM, and TEM images revealed the hexagonal structure of the UiO-66-NH2, demonstrating the successful synthesis of these green MOFs. Internalization and loading of doxorubicin on the MCF-7 cell line was investigated with two-dimensional fluorescence microscopy, which shows that drug internalizations on the cancerous cells were successful and promising. The drug payload of 49.5% and 31.2% for doxorubicin and sorafenib were attained, respectively. Study on the MCF-7 HT-29 and HEK-293 cell lines exhibited excellent cell viability when subjected to both low and high concentrations of 0.1 µg.mL−1 and 50 µg.mL−1, respectively. After 24 h of treatment, the relative cell viability of 85.1%, 88.1%, and 76.8% was achieved for the HT-29, HEK-293, and MCF-7 cell lines, respectively. In addition, after 48 h of treatment, the relative cell viability of 82.5%, 83.5%, and 68.5% was recorded, respectively. However, the percentage of cell viability was dramatically reduced by coating the nanocarrier with Ginkgo biloba leaf extract and E. Coli DNA (62.6%, 40.9%, and 45.1% for 24 h treatment and 62.1%, 38.5%, and 38.9% for 48 h treatment in HEK-293, HT-29, and MCF-7 cell lines, respectively).

Polymeric nanoparticles for drug delivery in glioblastoma: State of the art and future perspectives.

Glioblastoma (GBM) is an aggressive, fatal and malignant primary brain tumor. Despite the current standard treatment for glioblastoma patients including neurosurgical resection, followed by concomitant radiation and chemotherapy, the median survival rate is only about 15months. An unresolved challenge for current therapies is related to getting drugs through the blood-brain barrier (BBB), which hinders many chemotherapeutic agents from reaching tumors cells. Although a large amount of research has been done to circumvent the BBB and deliver drugs to the brain, with nanoparticles (NPs) taking the lead, the challenge is still high. In this regard, the BBB and how to transfer drug pathways through the BBB, especially using NPs, are introduced here. Afterwards, the latest advances in drug delivery, co-drug delivery, and combination modalities are described specifically for GBM treatments using natural and synthetic polymeric NPs and adjuvant therapies including hyperthermia, photodynamic therapy and also ketogenic regimens. In addition, receptor-mediated endocytosis agents that exist in endothelial capillary cells of the brain are explained. Lastly, future directions to finally deliver drugs through the BBB for GBM treatment are emphasized. It is the hope that this review can provide a number of practical pathways for the future development of BBB permeable nanochemotherapeutics against GBM.

D-mannose functionalized MgAl-LDH/Fe-MOF nanocomposite as a new intelligent nanoplatform for MTX and DOX co-drug delivery

Commonly the directly administered chemotherapy drugs lack targeting in tumor treatment. Thus, trying to improve cancer treatment efficiency led us to design a new intelligent system for cancer treatment. Considering these, in the current work, at first, the 2-aminoterephthalic acid (NH2-BDC) intercalated layered double hydroxides (MgAl-(NH2-BDC) LDH) were synthesized simply. Afterward, the in situ growth of the iron-based metal-organic frameworks in the presence of MgAl-(NH2-BDC) LDH occurred (MgAl-LDH/Fe-MOF). In the end, the reaction of MgAl-LDH/Fe-MOF with D-mannose (D-Man) achieved the MgAl-LDH/Fe-MOF/D-Man ternary hybrid nanostructure. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis confirmed the formation of the monodisperse Fe-MOF with nanosize in the presence of MgAl-LDH. Importantly, methotrexate (MTX) and doxorubicin (DOX) entrapment efficiency reached respectively about 28 wt% and 21% for MgAl-LDH/Fe-MOF/D-Man. The in vitro drug release experiments revealed a higher drug release at pH 5.0 in comparison with pH 7.4 which revealed its promising potential for anticancer drug delivery applications. Bioassay results revealed that the co-drug-loaded MgAl-LDH/Fe-MOF/D-Man has higher cytotoxicity on MDA-MB 231 cells. At last, fluorescence microscopy and flow cytometric analysis confirmed the successful uptake of MgAl-LDH/Fe-MOF/D-Man into MDA-MB 231 cell lines, as well as its bioimaging potential. A survey in the published literature approved that this work is the first report on the evaluation of the MgAl-LDH/Fe-MOF/D-Man for targeted co-delivery of both MTX and DOX. Finally, results collectively demonstrate the importance of the biocompatible MgAl-LDH/Fe-MOF/D-Man as a hopeful candidate for biomedicinal applications from the targeted co-drug delivery and bioimaging potential viewpoints.

Doxorubicin and Imatinib co-drug delivery using non-covalently functionalized carbon nanotube: Molecular dynamics study

Multidrug resistance (MDR) is an obstacle to most anticancer treatments’ success. The drug’s efficiency in various kinds of cancer treatment decreases in the case of single drug usage. In this study, to overcome this issue, we determine the co-loading of anticancer drugs Doxorubicin and Imatinib by crude and functionalized carbon nanotubes coated with Chitosan and Polyethylene Glycol polymers in different states using molecular dynamics simulations. The effect of polymers and the number of polymer chains on their loading was also studied. The simulation results showed that increasing the number of polymer chains affects the loading of drugs. Also, the Chitosan polymer has a more significant effect on the loading process of these drugs compared to the polyethylene glycol polymer. The number of loaded molecules for each drug is investigated.

Supramolecular self-assemblies based on water-soluble pillar[6]arene and drug-drug conjugates for the combination of chemotherapy

Although some co-drug delivery systems have been reported to treat cancer, how to optimal design these nano-systems with enhanced therapeutic efficacy is still a major challenge. As for the nitrogen mustard drugs chlorambucil (Cb), the overexpressed glutathione (GSH) in cancer tissue is responsible for their detoxification and reduced bioavailability. In this paper, chlorambucil-oxoplatin (Cb-Pt) was prepared to fabricate water-soluble pillar[6]arene (WP[6]) based supramolecular drug-drug self-assemblies (SDSAs). Remarkably, after the transcytosis by cancer cells, SDSAs was reduced by GSH to re lease Cb and higher toxic cisplatin, accompanying with the declining GSH level and ascending ROS level. Moreover, in vitro and in vivo experiments demonstrated that SDSAs with oxidative stress amplification strategy exhibited excellent therapeutic effect. This strategy might be useful for the synergistic co-drug based chemotherapy field.

Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer

The use of magnetic nanoparticles (MNPs) in biomedical applications has been wildly opted due to their unique properties. Here, we designed MNPs loaded with erlotinib (ERL/SPION-Val-PEG) and conjugated them with anti-mucin16 (MUC16) aptamer to introduce new image-guided nanoparticles (NPs) for targeted drug delivery as well as non-invasive magnetic resonance imaging (MRI) contrast agents. Also, the combination of our nanosystem (NS) along with L-Asparaginase (L-ASPN) led to synergistic effects in terms of reducing cell viability in ovarian cancer cells, which could suggest a novel combination therapy. The mean size of our NS was about 63.4 ± 3.4 nm evaluated by DLS analysis and its morphology was confirmed using TEM. Moreover, the functional groups, as well as magnetic properties of our NS, were examined by FT-IR and VSM tests, respectively. The loading efficacy of erlotinib on MNPs was about 80% and its release reached 70.85% over 7 days in the pH value of 5.4. The MR images and flow cytometry results revealed that the cellular uptake of ERL/SPION-Val-PEG-MUC16 NPs in cells with MUC16 overexpression was considerably higher than unarmed NPs. In addition, T2-weight MR images of ovarian cancer-bearing mice indicated significant signal intensity changes at the tumour site 4 h after intravenous injection compared to the non-target MNPs. Our data suggest ERL/SPION-Val-PEG NPs as an image-guided co-drug delivery system for ovarian cancer.

Dual anticancer drug delivery of D-galactose-functionalized stimuli-responsive nanogels for targeted therapy of the liver hepatocellular carcinoma

In the current research work for the first time, we designed and fabricated a new double-responsive (pH and temperature) and photoluminescent nanogels capped with D-galactose (D-Gal) moieties (CQDs/β-CD/NIPAM@AA-Gal) in three steps and then evaluated its potential as a targeted drug carrier. The used common characterization techniques approved the success in fabrication of the CQDs/β-CD/NIPAM@AA-Gal nanogels. CQDs/β-CD/NIPAM@AA-Gal nanogels demonstrated homogeneous size distribution with an average hydrodynamic diameter of about 657 nm. About 47.8% and 72% of loading capacity respectively were observed respectively for methotrexate (MTX) and doxorubicin (DOX) anticancer drugs (MTX@DOX@CQDs/β-CD/NIPAM@AA-Gal). The controlled drug release ability of the MTX@DOX@CQDs/β-CD/NIPAM@AA-Gal was verified through a comparison of the drug release profiles at the simulated tumor and physiological conditions. In vitro cytotoxicity, 4′,6-diamidino-2-phenylindole (DAPI) staining, and cell cycle assays displayed the good biocompatibility of CQDs/β-CD/NIPAM@AA-Gal. Furthermore, fluorescent imaging approved its bioimaging potential. Overall summation of the achieved results proposes that the CQDs/β-CD/NIPAM@AA-Gal can be generally tested as a medical nanovehicle with a wide range of applicability potential for cancer cells monitoring and co-drug delivery.

Highly Soluble and Stable, High Release Rate Nanocellulose Codrug Delivery System of Curcumin and AuNPs for Dual Chemo-Photothermal Therapy.

As a natural antitumor drug, curcumin (CUR) has received increasing attention from researchers and patients due to its various medicinal properties. However, currently CUR is still restricted due to its low and stand-alone therapeutic effects that seriously limit its clinical application. Here, by using cellulose nanocrystals (CNCs) as a nanocarrier to load CUR and AuNPs simultaneously, we developed a hybrid nanoparticle as a codrug delivery system to enhance the low and stand-alone therapeutic effects of CUR. Aided with the encapsulation of β-cyclodextrin (βCD), both the solubility and the stability of CUR are greatly enhanced (solubility increased from 0.89 to 131.7 μg/mL). Owing to the unique rod-like morphology of CNCs, the system exhibits an outstanding loading capacity of 31.4 μg/mg. Under the heat effects of coloaded AuNPs, the system demonstrates a high release rate of 77.63%. Finally, with CNC as a bridge nanocarrier, all aforementioned functions were integrated into one hybrid nanoparticle. The all-in-one integration ensures CUR to have enhanced therapeutic effects and enables the delivery system to exhibit combined chemo-photothermal therapy outcomes. This work presents a significant step toward CUR's clinical application and provides a new strategy for effective and integrative treatment of tumor disease.

Carboxymethyl starch encapsulated 5-FU and DOX co-loaded layered double hydroxide for evaluation of its in vitro performance as a drug delivery agent

Achieving a new oral drug delivery system with controlled drug release behavior is valuable in cancer therapy. Therefore, for the first time, doxorubicin (DOX) and 5-fluorouracil (5-Fu) were simultaneously co-loaded on the as-synthesized layered double hydroxides LDH(MgAl). The resulted system was encapsulated with carboxymethyl starch to improve its efficiency for colon cancer therapy. Several characterization techniques were used to evaluate the successful synthesis of the CMS@LDH(MgAl)@DOX,5-Fu microspheres. The scanning electron microscopy result showed that the size of prepared microspheres is about 72 μm. Additionally, the presence of one broad peak at 2θ ~ 20 of the X-ray diffraction spectrum approved its amorph nature. The drug release study showed a controlled release profile with ~22% of DOX and 29% of 5-Fu. In addition, the cell viability test outcome confirmed the sustained drug release pattern from CMS@LDH(MgAl)@DOX,5-Fu against the colon cancer cell line. The results suggest that the prepared microspheres are capable to operate as an acceptable formulation for oral co-drug delivery.

Folic acid-modified photoluminescent dialdehyde carboxymethyl cellulose crosslinked bionanogels for pH-controlled and tumor-targeted co-drug delivery

This work aimed to fabricate a new photoluminescent bionanogel with both targeted anticancer drug delivery and bioimaging potentials. Briefly, at first photoluminescent carbon dots (CDs) were synthesized from the low-cost and more available black pepper with traditional medicinal properties. The as-synthesized dialdehyde carboxymethyl cellulose (DCMC) was used as a safe crosslinker for gelatin crosslinking in the presence of CDs (CDs/DCMC-Gel). Eventually, the residual amine functional groups of gelatin were used for the conjugation of CDs/DCMC-Gel with folic acid (FA) ((CDs/DCMC-Gel)-FA bionanogels). All employed physicochemical characterization methods approved the (CDs/DCMC-Gel)-FA bionanogels fabrication route. SEM analysis specified the spherical morphology with a diameter of ~70–90 nm for it. Curcumin (CUR) and doxorubicin (DOX) respectively were loaded with drug entrapment efficiency of about 44.0% and 41.4%. The release rate for both drugs in acidic conditions was higher than in physiological conditions. In vitro antitumor experiments; MTT, DAPI staining, cellular uptake, and cell cycle tests showed the superior anticancer effect of the CUR@DOX@(CDs/DCMC-Gel)-FA in comparison with free CUR@DOX. Moreover, the (CDs/DCMC-Gel)-FA acted as a hopeful bio-imaging tool. Taken together, the designed (CDs/DCMC-Gel)-FA could be proposed as a promising nanosystem for efficient chemotherapy.

Synthesis of folic acid-conjugated glycodendrimer with magnetic β-cyclodextrin core as a pH-responsive system for tumor-targeted co-delivery of doxorubicin and curcumin

One of the most important applications of nanotechnology in cancer treatment involves the design of magnetic nanocomposites for the targeted delivery of anticancer drugs to cancer cells. This study aims to develop a novel, appropriate, and efficient magnetic carrier having antioxidant properties for the controlled release of anticancer drugs, hydrophilic doxorubicin (DOX), and hydrophobic curcumin (CUR) to cancer cells using folic acid conjugated with magnetic glycodendrimer (Fe 3 O 4 -β-CD-CTD-FA). The synthesized carrier was characterized using DLS, EDX, XRD, BET, FT‐IR, Zeta potential, VSM, TEM, and SEM analysis. The TEM results showed that synthesized Fe 3 O 4 -β-CD-CTD-FA have a spherical-like core-shell structure with an average diameter of approximately 533 nm. The encapsulation efficiency (EE) of Fe 3 O 4 -β-CD-CTD-FA was found to be 98.96% for DOX and 70.91% for CUR. The release studies of DOX and CUR from Fe 3 O 4 -β-CD-CTD-FA showed that maximum release occurs at pH 5 which means it has a controlled pH-responsive behavior. In vitro cytotoxicity and confocal microscopy of the as-synthesized Fe 3 O 4 -β-CD-CTD-FA in MDA-MB-231 cells clearly showed that the prepared carrier had no significant cytotoxicity and could easily enter the cell. Furthermore, the in vitro antioxidant capacity of Fe 3 O 4 -β-CD-CTD-FA was evaluated by DPPH assay and the results exhibited that the synthesized carrier has excellent antioxidant activity (75.45%). Therefore, the obtained glycodendrimer in this study due to their target ability under a magnetic field, excellent biocompatibility, good colloidal stability, simple preparing method, and good antioxidant activity could be used as a promising targeted co-drug delivery system for cancer therapy. • Fe 3 O 4 -β-CD-CTD-FA nanocomposite with antioxidant properties successfully prepared. • The resulted nanocomposite was applied for co-delivery of DOX and CUR to breast cancer cells. • In vitro cytotoxicity and confocal microscopy illustrated that the nanocomposite had no significant cytotoxicity and could easily enter the cells.

Targeting Tumor Cells with Nanoparticles for Enhanced Co-Drug Delivery in Cancer Treatment.

Gastric cancer (GC) is a fatal malignant tumor, and effective therapies to attenuate its progression are lacking. Nanoparticle (NP)-based solutions may enable the design of novel treatments to eliminate GC. Refined, receptor-targetable NPs can selectively target cancer cells and improve the cellular uptake of drugs. To overcome the current limitations and enhance the therapeutic effects, epigallocatechin-3-gallate (EGCG) and low-concentration doxorubicin (DX) were encapsulated in fucoidan and d-alpha-tocopherylpoly (ethylene glycol) succinate-conjugated hyaluronic acid-based NPs for targeting P-selectin-and cluster of differentiation (CD)44-expressing gastric tumors. The EGCG/DX-loaded NPs bound to GC cells and released bioactive combination drugs, demonstrating better anti-cancer effects than the EGCG/DX combination solution. In vivo assays in an orthotopic gastric tumor mouse model showed that the EGCG/DX-loaded NPs significantly increased the activity of gastric tumors without inducing organ injury. Overall, our EGCG/DX-NP system exerted a beneficial effect on GC treatment and may facilitate the development of nanomedicine-based combination chemotherapy against GC in the future.

Preparation and evaluation of gemcitabin and cisplatin-entrapped Folate-PEGylated liposomes as targeting co-drug delivery system in cancer therapy

In this research, we reported the preparation and properties of lipid-loaded nanoparticle modified with polyethylene glycol (PEG) and folic acid (FA) as a co-drug delivery system for controlling the release of cisplatin (Cis) and gemcitabine (Gem). Then, LIP-PEG-FA-Cis-Gem nano-complex was characterized by FT-IR, DLS, TEM, SEM, and XRD. The results suggest that these nano-complexes have spherical morphology with appropriate size and surface charge. The drug entrapment efficiencies were calculated about 22.96% (Cis) and 25% (Gem). In vitro drug release profile and then the therapeutic efficiency of LIP-PEG-FA-Cis-Gem nano-complex was also investigated on A549, MCF-7 and normal MRC5 cell lines. The cell viability value was observed 10.39 ± 4.88% (A549), 7.56 ± 4.87% (MCF7), and 23.2 ± 6.29% (MRC5) after 48 h of treatment with 8 μM concentration. Additionally, apoptosis amounts have indicated 83.0 ± 0.70% and 82.5 ± 0.21% for A549 and MCF7 cell lines after 48 h posttreatment, respectively. Moreover, the apoptotic P21 and P53 gene expression were observed 13.85 ± 0.73 and 17.16 ± 2.12 folds for A549, 6.78 ± 0.84 and 13.08 ± 0.84 folds for MCF7 after 48 h of incubation with LIP-PEG-FA-Cis-Gem IC50 concentrations, respectively. Therefore, our synthetic nano-liposome can be an excellent candidate for co-delivery of Gem & Cis agents to folat receptor-expressing tumors and the inhibition of cancer cells.

Development and investigation of dual potent anticancer drug-loaded nanoparticles for the treatment of lung cancer therapy

Combinations of two potent chemotherapeutic drugs are often used to treat early stage lung cancer. To enhance the efficiency of the treatment, a combinational co-drug delivery system of gemcitabine (GEM) and 5-fluorouracil (5FU) is used owing to its great antitumor ability, as GEM and 5FU improve the anticancer ability of lung cells by stabilizing the tumor microenvironment. Nevertheless, encapsulation of GEM and 5FU potential anticancer drugs by co-loaded poly(lactic-co-glycolic acid) (PLGA)- Polyethylene glycol (PEG) nanoparticles (NPs) is not effective because of the incompatibility of the dual drug GEM and 5FU polymeric biodegradable system. Transmission electron microscopy was used to examine the morphology of GEM NPs, 5FU NPs, and GEM-5FU NPs, along with their nanoparticle morphology and size. GEM-5FU NPs also induced apoptosis in vitro in human lung cells such as A549 and HEL-299. Morphological changes and cell deaths were the result of different biochemical staining techniques such as acridine orange-ethidium bromide (AO-EB) and Hoechst staining. In addition, the mechanistic investigation of cell death was confirmed by Annexin V-Fluorescein isothiocyanate (FITC) using flow cytometry. Taken together, this dual co-drug delivery method revealed that GEM-5FU NPs might have a remarkable potential to enhance the efficacy of lung cancer therapy.

Strategy for Traceless Codrug Delivery with Platinum(IV) Prodrug Complexes Using Self-Immolative Linkers.

A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the p-aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.

Intercalation of curcumin into liposomal chemotherapeutic agent augments apoptosis in breast cancer cells.

Resistance to common chemotherapeutic agents is a frequent phenomenon in late-stage breast cancers. An ideal system capable of the co-delivery of hydrophobic and hydrophilic chemotherapeutic agents can regulate the dosage and co-localization of pharmaceutical compounds and thereby improve the anticancer efficacy. Here, for the first time, we have intercalated curcumin (Cur) into a double-layered membrane of cisplatin (Cis) liposomes to obtain a dosage controlled co-delivery formulation, capable of inducing apoptosis in breast cancer cells. The concentrations of Cur and Cis in nanoliposome (Cur-Cis@NLP) were optimized by response surface methodology (RSM); RSM optimization showed 99.81 and 23.86% entrapment efficiency for Cur and Cis, respectively. TEM analysis demonstrated the fabrication of nanoparticles with average diameter of 100 nm. The anticancer and apoptotic effects of Cur-Cis@NLPs were also evaluated using MTT assay, fluorescent staining and flow cytometry assays. Cytotoxicity assessments of various Cur-Cis@NLPs concentrations demonstrated a concentration-dependent manner. In comparison to free and liposomal Cis, Cur-Cis@NLP reduced breast cancer cells' viability (82.5%) in a significant manner at a final concentration of 32 μg.mL-1 and 20 μg.mL-1 of Cur and Cis, respectively. Combination index values calculation of Cur-Cis@NLP showed an overall CI value <1, indicating synergetic effect of the designed co-delivery system. Additionally, flow cytometry assay demonstrated Cur-Cis@NLPs triggered apoptosis about 10-folds higher than liposomal Cis. This co-drug delivery system has a potential for the encapsulation and release of both hydrophobic and hydrophilic drugs, while taking the advantages of the reduced cytotoxic effect along with achieving high potency.

Self-assembled peptide nanoparticles with endosome escaping permits for co-drug delivery

The diagnosis and treatment of major diseases, especially tumors, was the key to improving the cure rate and survival rate of patients. Therefore, one of the main goals of modern medicine was to develop effective, non-toxic treatments. This paper successfully established dipeptide nanoparticles/clofarabine/aptamer AS1411/influenza hemagglutinin peptide/siRNA/doxorubicin (DNPs/Clolar/AS1411/HA/RNA/DOX) multi-functional nanoparticles for specific delivery, cancer treatment and bioimaging. It was an ideal choice for multi-drug synergy treatment. First, non-toxic DNPs formed by self-assembly of dipeptides with safe and biocompatible effect. Second, from the perspective of the multi-functional nanoparticles for nano-drug tumors imaging monitoring, AS1411 and HA were used as cell permits for enhancing the specificity of cell drug delivery ability and improving the endosomal escape, respectively. Third, the multi-functional nanoparticles with Clolar, siRNA and DOX, three drug synergistic treatments were used to improve the therapeutic effect of tumors. Both cell experiments and vivo experiments demonstrated that the synergistic treatment of the multi-drugs was superior to the effect of single-drug therapy. Thus, the proposed multi-functional nanoparticles have initiated new ideas for these hybrid anticancer drugs based on peptide self-assembled nanocarriers and its widely applications in biomedicine.