Hydrophobic Chemotherapeutic Agents Research Articles

Gastric cancer specific drug delivery with hydrophilic peptide probe conjugation.

Cancer-specific diagnosis is challenging. Phage display is an approach that could contribute to finding new specific biomarkers. In this study, we developed a new peptide probe specific for gastric cancer and validated it for gastric cancer-specific theranostics. We isolated linear peptides by screening a combinatorial phage library for a cancer stem cell marker, LGR5 protein. Among these, peptides with high selectivity against gastric cancer cells were selected and examined for therapeutic poteintial in vitro as well as in vivo. Through leucine-rich G protein-coupled receptor 5 (LGR5) protein-based phage display, we obtained a hydrophilic 7-mer peptide sequence (STCTRSR, named STC). Both the STC-peptide-conjugated fluorescent dye and chlorin e6 (Ce6) displayed a significantly higher intensity in gastric cancer cells compared to that in healthy cells. In mice with gastric cancer, the fluorescence in the tumors was 3.4× more intense when treated with the Ce6-STC conjugate compared to that with free Ce6 and conferred higher phototoxicity after single laser irradiation. Repeated photodynamic therapy could further reduce the tumor volume after treating these mice with the Ce6-STC conjugate. The treatment with the Ce6-STC conjugate exhibited a significantly lower fluorescence in the liver than that with free Ce6. In conclusion, we confirmed that the STC peptide is a gastric cancer-specific probe that could be useful in gastric cancer theranostics. In conclusion, considering its targeting ability and hydrophilicity, various hydrophobic chemotherapeutic agents could be revisited for gastric cancer treatment in combination with the probe described in this study.

Hydroxypropyl Beta Cyclodextrin as a Potential Surface Modifier for Paclitaxel Nanocrystals.

Paclitaxel (PTX) is a hydrophobic chemotherapeutic agent cytotoxic against many serious cancers. This study aimed at designing novel PTX nanocrystals (PTX-NCs) coated with the biocompatible and biodegradable hydroxypropyl-beta-cyclodextrin (HPβCD) polymer with specific characteristics through the formation of a non-inclusion complex. Briefly, PTX-NCs were prepared by the anti-solvent method followed by homogenization. Then, the surface of the prepared PTX-NCs was modified using the HPβCD coat (HPβCD-PTX-NCs). The prepared nanocrystals, both coated and uncoated, were characterized in terms of size, polydispersity index, charge, morphology, and stability. Moreover, the nanocrystals were investigated using powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), and Fourier transform infrared spectroscopy (FTIR). As well, the in vitro release of PTX from the nanocrystals was determined under conditions similar to the IV route of administration. Furthermore, the tendency of the nanocrystals to induce hemolysis was investigated. Results indicated that the size was about 241.4 and 310.5nm, the polydispersity index was 0.14 and 0.21, and the zeta potential was about - 22.6 and - 16.4mV for PTX-NCs and HPβCD-PTX-NCs, respectively. Additionally, the PXRD, FTIR, and DSC profiles can be explained by the NCs' integrity and coat formation. The SEM images showed that both PTX-NCs and HPβCD-PTX-NCs have rod-like structures. Moreover, HPβCD-PTX-NCs had significantly superior in vitro release than both PTX-NCs and PTX. Interestingly, the hemolytic assay showed that HPβCD-PTX-NCs had a more efficient and safer profile than PTX-NCs. This study emphasized that HPβCD could be an interesting candidate for the surface modification of PTX-NCs providing superior properties such as release and safety profiles.

In vivo study of miktoarm star copolymers as a promising nanocarrier to transfer hydrophobic chemotherapeutic agents to breast cancer tumor

In this project, in vitro and in vivo properties of drug loaded nanocarriers based on miktoarm star copolymer mPEG-Lys-PCL2 were evaluated. Miktoarm was synthesized using ring opening polymerization reaction. Then, quercetin which is a hydrophobic plant based flavonol, was loaded into star NCs using nanoprecipitation method. The structure and biocompatibility nanocarriers were determined using proton nuclear magnetic resonance, Fourier-transform infrared spectroscopy, dynamic light scattering, hemolysis assay and lethal dose test. According to biocompatibility tests, prepared nanocarrier was practically nontoxic. The drug loading and encapsulation efficiency of nanocarriers were high because of miktoarm has two hydrophobic arms and more spaces between layers in comparison with linear copolymer with the same material. The results of MTT assay proved that quercetin-loaded star nanocarriers possess acceptable toxicity on cancerous cells which is because of the ability of miktoarm to mimic phospholipid structure. Furthermore, in vivo results showed the quercetin-loaded star nanocarriers is more effective to inhibit tumor volume than the free Quer. Also, the survival rate of mice treated with quercetin loaded star nanocarriers enhanced so that all the treated mice survived more than 75 days, and 20% of them were alive even after 85 days of experiment.

Hypoxia-sensitive drug delivery to tumors

Achievement of a high dose of drug in the tumor while minimizing its systemic side effects is one of the important features of an improved drug delivery system. Thus, developing responsive carriers for site-specific delivery of chemotherapeutic agents has become a main goal of research efforts. One of the known hallmarks of cancerous tumors is hypoxia, which offers a target for selective drug delivery. The stimuli-sensitive micellar system developed by us, (PEG-azobenzene-PEI-DOPE (PAPD) has proven to be effective in vitro. The proposed construct developed, PAPD, contains an azobenzene group as a hypoxia-sensitive moiety that triggers the shedding of the PEG layer from the nanoparticle surface under conditions of hypoxia to improve cellular uptake. Using microfluidics, we show significantly improved cellular association and penetration under hypoxia in both single cells and in a 3D tumor model. Employing an in vivo model, we demonstrate slower tumor growth that did not induce systemic side effects, including weight loss in an experimental animal model, when compared to the free drug treatment. This complex-in-nature but simple-in-design system for the simultaneous delivery of siRNA to silence the P-glycoprotein and doxorubicin with active tumor targeting and proven therapeutic efficacy represents a universal platform for the delivery of other hydrophobic chemotherapeutic agents and siRNA molecules which can be further modified.

Efficient drug delivery and anticancer effect of micelles based on vitamin E succinate and chitosan derivatives

Nanocarriers have emerged as a promising cancer drug delivery strategy. Multi-drug resistance caused by overexpression of multiple-drug excretion transporters in tumor cells is the major obstacle to successful chemotherapy. Vitamin E derivatives have many essential functions for drug delivery applications, such as biological components that are hydrophobic, stable, water-soluble enhancing compounds, and anticancer activity. In addition, vitamin E derivatives are also effective mitocan which can overcome multi-drug resistance by binding to P glycoproteins. Here, we developed a carboxymethyl chitosan/vitamin E succinate nano-micellar system (O-CMCTS-VES). The synthesized polymers were characterized by Fourier Transform IR, and 1H NMR spectra. The mean sizes of O-CMCTS-VES and DOX-loaded nanoparticles were around 177 nm and 208 nm. The drug loading contents were 6.1%, 13.0% and 10.6% with the weight ratio of DOX to O-CMCTS-VES corresponding 1:10, 2:10 and 3:10, and the corresponding EEs were 64.3%, 74.5% and 39.7%. Cytotoxicity test, hemolysis test and histocompatibility test showed that it had good biocompatibility in vitro and in vivo. Drug release experiments implied good pH sensitivity and sustained-release effect. The DOX/O-CMCTS-VES nanoparticles can be efficiently taken up by HepG2 cancer cells and the tumor inhibition rate is up to 62.57%. In the in vivo study by using H22 cells implanted Balb/C mice, DOX/O-CMCTS-VES reduced the tumor volume and weight efficiently with a TIR of 35.58%. The newly developed polymeric micelles could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of solid tumors.

Folic Acid-Functionalized Nanomedicine: Folic Acid Conjugated Copolymer and Folate Receptor Interactions Disrupt Receptor Functionality Resulting in Dual Therapeutic Anti-Cancer Potential in Breast and Prostate Cancer

We have previously reported on a functionalized folic acid (FA) conjugated poly(styrene-alt-maleic anhydride) (SMA) via biological linker 2,4-diaminobutyric acid (DABA) (FA-DABA-SMA) copolymer. This biocompatible nanocopolymer self-assembles in a pH-dependent manner, providing stimuli responsiveness, active targeting, and extended release of hydrophobic chemotherapeutic agents and effectively penetrates the inner core of 3-dimensional cancer spheroid models. The empty FA-DABA-SMA decreased tumor spheroid volume, revealing a previously unknown mechanism of action. Here, we investigated the potential mechanism of the small (20 kDa) and large (350 kDa) FA-DABA-SMA empty copolymers affecting the folic acid receptor alpha (FRα) signaling properties in breast and prostate cancer cell lines. Microscopic imaging, immunocytochemistry, flow cytometry, Caspase 3/7 apoptosis assays, Incucyte live cell tracking, the scratch wound assay, the water-soluble tetrazolium salt-1 (WST-1) cell viability assay, morphologic changes, and Western blot for the expression levels of FRα on the cell surface were used on MDA MB-231 and MCF-7 breast and DU-145 prostate cancer cell lines. The findings indicate that FA-DABA-SMA increases FRα expression levels in breast MDA MB-231 cancer cells and then disrupts FR signaling by reducing HES1 and NOTCH1 protein expression levels. Also, FA-DABA-SMA induces apoptosis and further causes a change in the MDA MB-231 cells' morphology and significantly reduces their ability to migrate in a scratch wound assay. Collectively, these findings provide a novel insight into the functionalized FA-DABA-SMA copolymer. The 350 and 20 kDa copolymers actively target FRα to initialize internationalization. However, only the large size and sheet-shaped 350 kDa copolymers disrupt FRα signaling. The significance of these novel findings reveals that the copolymer's intracellular activity is critically dependent on the size and structural shape. This report offers novel therapeutic insight into a dual mechanism of the FA-DABA-SMA copolymer for its therapeutic potential to treat cancer.

Synthetic HDL Nanoparticles Delivering Docetaxel and CpG for Chemoimmunotherapy of Colon Adenocarcinoma.

Colon carcinomas comprise over two-thirds of all colorectal cancers with an overall 5-year survival rate of 64%, which rapidly decreases to 14% when the cancer becomes metastatic. Depending on the stage of colon carcinoma at diagnosis, patients can undergo surgery to attempt complete tumor resection or move directly to chemotherapy with one or a combination of drugs. As with most cancers, colon carcinomas do not always respond to chemotherapies, so targeted therapies and immunotherapies have been developed to aid chemotherapy. We report the development of a local combination therapy for colon carcinoma whereby chemo- and immunotherapeutic entities are delivered intratumorally to maximize efficacy and minimize off-target side effects. A hydrophobic chemotherapeutic agent, docetaxel (DTX), and cholesterol-modified Toll-like receptor 9 (TLR9) agonist CpG (cho-CpG) oligonucleotide are co-loaded in synthetic HDL (sHDL) nanodiscs. In vivo survival analysis of MC-38 tumor-bearing mice treated intratumorally with DTX-sHDL/CpG (median survival; MS = 43 days) showed significant improvement in overall survival compared to mice treated with single agents, free DTX (MS = 23 days, p < 0.0001) or DTX-sHDL (MS = 28 days, p < 0.0001). Two of seven mice treated with DTX-sHDL/CpG experienced complete tumor regression. None of the mice experienced any systemic toxicity as indicated by body weight maintenance and normal serum enzyme and protein levels. In summary, we have demonstrated that chemo- and immunotherapies can be co-loaded into sHDLs, delivered locally to the tumor, and can be used to improve survival outcomes significantly compared to chemotherapy alone.

Transferrin/α-tocopherol modified poly(amidoamine) dendrimers for improved tumor targeting and anticancer activity of paclitaxel.

Aim: Transferrin anchored, poly(ethylene glycol) (PEG) and α-tocopheryl succinate (α-TOS) conjugated generation 4 dendrimer has been prepared in order to develop a tumor targeted delivery system of a hydrophobic chemotherapeutic agent, paclitaxel (PTX). Materials & methods: The dendrimers were characterized physicochemically for size, ζand encapsulation ability. The cellular uptake, cytotoxicity potential and apoptosis of prepared nanoconstruct were evaluated in human cervical epithelial cells monolayer and 3D spheroids. Results &conclusion: G4-TOS-PEG-Tf demonstrated increased cellular uptake, cytotoxicity and apoptotic potential of PTX compared with free PTX and G4-TOS-PEG-PTX. G4-TOS-PEG-Tf-PTX inhibited growth of human cervical epithelial cells spheroids significantly. The newly developed dendrimers hold promise as an efficient delivery system for PTX or other hydrophobic chemotherapeutic agents for targeted delivery to tumors.

Self-assembled peptide nanoparticles responsive to multiple tumor microenvironment triggers provide highly efficient targeted delivery and release of antitumor drug

Stimuli-responsive drug delivery systems based on tumor microenvironment conditions show tremendous promise to enhance tumor-targeted delivery and drug release. Herein, a multifunctional peptide (P51) was developed for programmed delivery of the hydrophobic chemotherapeutic agent pirarubicin. P51 was prepared with a ligand-specific targeting for the cancer biomarker Arg-Gly-Asp (RGD), and three tumor microenvironment-sensitive release triggers, acid environment, reducing agent, and a specific enzyme. The peptides Cys-s-s-Cys (disulfide linkage) and Pro-Val-Gly-Leu-Ile-Gly correspond to the cleavage sites of a reducing agent (DTT) and an enzyme (MMP-2). The peptides act as a junction between Ser-Glu-Glu-Asp-Pro (a negatively charged sequence) and a 41-residue peptide containing an α-helix that has the capacity to encapsulate pirarubicin via electrostatic and hydrophobic interactions. These interactions can be disrupted by the acidic tumor microenvironment. Self-assembly of P51 and pirarubicin (P51-THP NPs) results into stable spherical nanoparticles in a single step. We have demonstrated that the acid environment, DTT, and MMP-2 stimulate the release of pirarubicin from P51-THP NPs and, more importantly, the efficiency of drug release is markedly increased when all three release triggers are present. In addition, more effective tumor targeting, antitumor effect, and reduced systemic toxicity of P51-THP NPs have been confirmed by in vitro and in vivo results.

Co-delivery of paclitaxel and curcumin to foliate positive cancer cells using Pluronic-coated iron oxide nanoparticles

Active targeting of folic acid and passive targeting of magnetic nanoparticles to bring about co-delivery of hydrophobic chemotherapeutic agents were the focus of this work. Co-precipitation in alkaline environment was employed for synthesizing Fe3O4 nanoparticles and stabilized by oleic acid. Aqueous dispersibility of oleic acid coated nanoparticles was brought about by folic acid modified Pluronic F127 and Pluronic F127 mixture. Folic acid is used as a targeting agent which was joined to Pluronic F127 via diethylene glycol bis(3-aminopropyl) ether spacer. The nanocomposite was used to delivery hydrophobic anticancer drugs, paclitaxel, and curcumin. Successful modification at each step was confirmed by FTIR and NMR. Quantitative analysis of attached folic acid indicated a total of 84.34% amount of conjugation. Nanoparticles characterization revealed the hydrodynamic size of and nanocomposite to be 94.2 nm nanometres. Furthermore, transmission electron micrograph reveals the size of the nanoparticle to be 12.5 nm hence also shows the superparamagnetic activity. Drug encapsulation efficiency of 34.7% and 59.5% was noted for paclitaxel and curcumin, respectively. Cytotoxic property of drug-loaded nanocomposites was increased in case of folic acid functionalized nanoparticles and further increased in the presence of an external magnetic field. Cellular uptake increased in the folic acid conjugated sample. Further many folds in the presence of an external magnetic field.Graphic abstract

Hydrophilic Small Molecules That Harness Transthyretin To Enhance the Safety and Efficacy of Targeted Chemotherapeutic Agents.

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of targeted chemotherapeutic agents while maintaining their hydrophilicity and small size will represent a significant advance toward effective and safe cancer treatment. Here, we present a new approach for enhancing the safety and efficacy of targeted chemotherapeutic agents. By endowing hydrophobic chemotherapeutic agents with a targeting moiety and a hydrophilic small molecule that binds reversibly to the serum protein transthyretin, we generated small hydrophilic drug conjugates that displayed enhanced circulation half-life in rodents and selectivity to cancer cells. To the best of our knowledge, this is the first demonstration of a successful approach that maintains the small size and hydrophilicity of targeted anticancer agents containing hydrophobic payloads while at the same time extending their circulation half-life. This was demonstrated by the superior in vivo efficacy and lower toxicity of our conjugates in xenograft mouse models of metastatic prostate cancer.

Dual functional immunostimulatory polymeric prodrug carrier with pendent indoximod for enhanced cancer immunochemotherapy

Immunotherapy based on checkpoint blockade has been regarded as one of the most promising approaches towards many types of cancers. However, low response rate hinders its application due to insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. To achieve an overall enhanced therapeutic outcome, we developed a dual-functional immuno-stimulatory polymeric prodrug carrier modified with pendent indoximod, an indoleamine 2,3-dioxygenase (IDO) inhibitor that can be used to reverse immune suppression, for co-delivery of Doxorubicin (Dox), a hydrophobic anticancer agent that can promote immunogenic cell death (ICD) and elicit antitumor immunity. The resulted carrier denoted as POEG-b-PVBIND, consisting of poly (oligo (ethylene glycol) methacrylate) (POEG) hydrophilic blocks and indoximod conjugated hydrophobic blocks, is rationally designed to improve immunotherapy by synergistically modulating the tumor microenvironment (TME). Our data showed that Dox-triggered ICD promoted intra-tumoral infiltration of CD8+ T cells and IFN-γ-production by CD8+ T cells. Meanwhile, cleaved indoximod significantly increased CD8+ T cell infiltration while reducing the immunosuppressive T regulatory cells (Tregs). More importantly, Dox/POEG-b-PVBIND micelles led to significantly improved tumor regression in an orthotopic murine breast cancer model compared to both Dox-loaded POEG-b-PVB micelles (a control inert carrier) and POEG-b-PVBIND micelles alone, confirming combination effect of indoximod and Dox in improving the overall antitumor activity. Statement of SignificanceIndoleamine 2,3-dioxygenase (IDO) is an enzyme that can induce immune suppressive microenvironment in tumors. As a well-studied IDO inhibitor, indoximod (IND) represents a promising agent for cancer immunotherapy and could be particularly useful in combination with other chemotherapeutic agents. However, three major problems hinder its application: (1) IND is barely soluble in water; (2) IND delivery efficiency is limited (3) simultaneous delivery of two agents into tumor site is still challenging. Currently, most reports largely focus on improving the pharmacokinetic profile of IND alone via different formulations such as IND prodrug and IND nanocrystal. However, there is limited information about IND based co-delivery systems, especially for delivering hydrophobic chemotherapeutic agents. Here, we developed a new dual-functional polymeric prodrug carrier modified with a number of pendent IND units (denoted as POEG-b-PVBIND). POEG-b-PVBIND shows immunostimulatory and antitumor activities by itself. More importantly, POEG-b-PVBIND polymer is able to self-assemble into nano-sized micelles that are highly effective in formulating and codelivering other hydrophobic agents including doxorubicin (Dox), sunitinib (Sun), and daunorubicin (Dau), which can elicit antitumor immunity via promoting immunogenic cell death (ICD). We have shown that our new combination therapy led to a significantly improved antitumor activity in an aggressive murine breast cancer model (4T1.2).

A biophysical study on the mechanism of interactions of DOX or PTX with \u03b1-lactalbumin as a delivery carrier

Doxorubicin and paclitaxel, two hydrophobic chemotherapeutic agents, are used in cancer therapies. Presence of hydrophobic patches and a flexible fold could probably make α-Lactalbumin a suitable carrier for hydrophobic drugs. In the present study, a variety of thermodynamic, spectroscopic, computational, and cellular techniques were applied to assess α-lactalbumin potential as a carrier for doxorubicin and paclitaxel. According to isothermal titration calorimetry data, the interaction between α-lactalbumin and doxorubicin or paclitaxel is spontaneous and the K (M−1) value for the interaction of α-lactalbumin and paclitaxel is higher than that for doxorubicin. Differential scanning calorimetry and anisotropy results indicated formation of α-lactalbumin complexes with doxorubicin or paclitaxel. Furthermore, molecular docking and dynamic studies revealed that TRPs are not involved in α-Lac’s interaction with Doxorubicin while TRP 60 interacts with paclitaxel. Based on Pace analysis to determine protein thermal stability, doxorubicin and paclitaxel induced higher and lower thermal stability in α-lactalbumin, respectively. Besides, fluorescence lifetime measurements reflected that the interaction between α-lactalbumin with doxorubicin or paclitaxel was of static nature. Therefore, the authors hypothesized that α-lactalbumin could serve as a carrier for doxorubicin and paclitaxel by reducing cytotoxicity and apoptosis which was demonstrated during our in vitro cell studies.

Cholesterol-grafted chitosan micelles as a nanocarrier system for drug-siRNA co-delivery to the lung cancer cells

Combined delivery of a therapeutic small interfering RNA (siRNA) and a chemotherapeutic agent to cancer cells is promising as anticancer therapy, which could offer enhanced cell killing potential and low side effect. However, simultaneous delivery to tumor is challenging. In our study, cholesterol-modified low molecular weight chitosan (MW ~ 15 kDa) was employed as a self-assembled delivery system for both siRNA and a hydrophobic chemotherapeutic agent, curcumin to cancer cells. The siRNA/curcumin loaded nanoparticles (C-CCM/siRNA) were physico-chemically characterized for particle size (165 ± 2.6 nm) and zeta potential (+24.8 ± 2.2 mV). The ability of CCM to condense siRNA was determined by ethidium bromide exclusion and gel retardation assay using electrophoresis. The result demonstrated that the condensation of C-CCM with siRNA was optimum at minimum N/P ratio of 40. C-CCM/siRNA was stable at 4 °C for a period of >1 month. C-CCM/siRNA was taken up efficiently by human lung carcinoma cells, A549 in a time-dependent manner. The cellular internalization of C-CCM/siRNA was observed via clathrin-mediated endocytosis as determined by using specific endocytosis inhibitors. The study demonstrated the feasibility of the use of cholesterol conjugated chitosan as a co-delivery system for both siRNA and a hydrophobic drug for combination cancer therapy.

A targeted nanoplatform co-delivering chemotherapeutic and antiangiogenic drugs as a tool to reverse multidrug resistance in breast cancer

Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis. Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Statement of SignificanceHerein, we successfully developed a novel amphiphilic nanomaterial, LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]–reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.

Superior anti-neoplastic activities of triacontanol-PEG conjugate: synthesis, characterization and biological evaluations

Triacontanol (TA, C30H62O), abundantly present in plant cuticle waxes and bee waxes, has been found to display promising anti-neoplastic potentials. As a long chain fatty alcohol, TA possesses limited aqueous solubility, which hinders its medicinal application. To overcome its solubility barrier, a polymer prodrug was synthesized through attaching TA to poly ethylene glycol (PEG), using succinic acid as a linker with bifunctional amide and ester bonds. Anti-neoplastic effects of PEG-TA were assessed in LoVo and MCF7 cells, anti-proliferative and apoptosis-inducing activities were subsequently confirmed in mouse xenograft model. Encouragingly, PEG-TA possessed selective anti-cancer ability. It did not exhibit significant cytotoxicity on normal cells. Mechanistic examination revealed inhibition of NF-κB nuclear translocation, suppression on matrix degradation enzyme and down-regulation of angiogenic signaling might contribute to its anti-malignant effects. Pharmacokinetics clearly indicated PEGylated TA (named as mPEG2K-SA-TA) substantially enhanced TA delivery with increased plasma exposure (19,791 vs. 336.25 ng·mL−1·h−1, p < .001), mean residence time (8.46 vs. 2.95 h, p < .001) and elimination half-life (7.78 vs. 2.57 h, p < .001) compared to those of original TA. Moreover, mPEG2K-SA-TA appeared to be safe in preliminary toxicological assessment. PEGylated TA also emerged as a functional carrier to deliver hydrophobic chemotherapeutic agents, since it readily self-assembled to micelles in aqueous solution with a low critical micelle concentration (CMC, 19.1 µg·mL−1). Conclusively, PEG-TA conjugate displayed superior anti-neoplastic activities and low toxicity, as well as facilitated the delivery of other hydrophobic agents, which appeared to be an innovative strategy for cancer therapy.

Development and characterization of docetaxel-loaded lecithin-stabilized micellar drug delivery system (LsbMDDs) for improving the therapeutic efficacy and reducing systemic toxicity

In the present study, we attempted to develop a lecithin-stabilized micellar drug delivery system (LsbMDDs) for loading docetaxel (DTX) to enhance its therapeutic efficacy and minimize systemic toxicity. A novel DTX-loaded LsbMDDs was optimally prepared by a thin-film hydration method and then hydrated with a lecithin nanosuspension while being subjected to ultrasonication. Physical characteristics of the optimized DTX-loaded LsbMDDs formulations were examined and found to have a mean size of <200 nm, an encapsulation efficiency of >90%, and drug loading of >6% with stability at room temperature and at 4 °C being longer than 2 and 7 days, respectively. The in vitro release of DTX from the DTX-loaded LsbMDDs was slower than that from the generic product of DTX (Tynen®). A cell viability assay demonstrated that the LsbMDDs showed better cytotoxicity than Tynen® against CT26 cancer cells. The in vivo antitumor efficacy of the DTX-loaded LsbMDDs was observed to be better than that of Tynen® in a CT26 tumor-bearing mice model. A high-dose regimen of the DTX-loaded LsbMDDs formulation showed greater inhibition of DU145 tumor growth than did Tynen®, but with less to similar systemic toxicity. An in vivo study also showed that a greater amount of drug was able to accumulate in the tumor site with the DTX-loaded LsbMDDs, and its maximal tolerable doses for single and repeated injections were 2–2.5-fold higher than those of Tynen®. In conclusion, the LsbMDDs could be a promising high drug-loaded nanocarrier for delivering hydrophobic chemotherapeutic agents that can enhance the efficacy of chemotherapy and reduce systemic toxicity.

Promising effects of nanomedicine in cancer drug delivery

Successful ushering of nanomedicine has shown immense potential in advancing cancer treatment regimens. The unique characteristics of nanoparticles such as their optimal size, shape, efficient surface to volume ratio, surfaces that can be optimally tailored make them very attractive delivery candidates for highly hydrophobic chemotherapeutic agents. Moreover, their inherent capacity to encapsulate these drugs and enhance their solubility profiles offers them unique advantages over conventional treatments. Surface modification with targeting ligands, increased intracellular uptake and prolonged circulation profiles in vivo establish their overall superiority over other treatment regimens. This article attempts to highlight some of these salient features of nanoparticles as drug delivery agents, which makes them more attractive in terms of providing promising opportunities in targeted drug delivery.

Albumin nanoparticles with synergistic antitumor efficacy against metastatic lung cancers

Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect. Albumin nanoparticles gradually released drugs over a period of 24h without burst effect. To confirm the synergistic effect of two drugs, in vitro cytotoxicity assay was performed using B16F10 melanoma cells. The cytotoxic effect on B16F10 melanoma cells was highest when co-treated with both curcumin and doxorubicin compared to single treatment of either curcumin and doxorubicin. The combined index calculated by medium-effect equation was 0.6069, indicating a synergistic effect. Results of confocal laser scanning microscopy and fluorescence-activated cell sorting corresponded to results from an in vitro cytotoxicity assay, indicating synergistic cytotoxicity induced by both drugs. A C57BL/6 mouse model induced by B16F10 lung metastasis was used to study in vivo therapeutic effects. When curcumin and doxorubicin were simultaneously treated, the metastatic melanoma mass in the lungs macroscopically decreased compared to curcumin or doxorubicin alone. Albumin nanoparticles encapsulating two anticancer drugs were shown to have an effective therapeutic result and would be an excellent way to treat resistant lung cancers.

D-α-Tocopheryl Succinate/Phosphatidyl Ethanolamine Conjugated Amphiphilic Polymer-Based Nanomicellar System for the Efficient Delivery of Curcumin and To Overcome Multiple Drug Resistance in Cancer.

Nanomedicines have emerged as a promising treatment strategy for cancer. Multiple drug resistance due to overexpression of various drug efflux transporters and upregulation of apoptotic inhibitory pathways in cancer cells are major barriers that limit the success of chemotherapy. Here, we developed a d-α-tocopherol (α-TOS)/lipid-based copolymeric nanomicellar system (VPM) by conjugating phosphatidyl ethanolamine (PE) and α-TOS with poly(ethylene glycol) (PEG) via an amino acid linkage. The synthesized polymers were characterized by Fourier transform IR, gas-phase chromatography, and 1H and 13C NMR spectroscopy. VPM exhibited mean hydrodynamic diameter of 141.0 ± 0.94 nm with low critical micelles concentrations (CMC) of 15 μM compared to plain PEG-PE micelles (PPM) with size of 23.9 ± 0.34 nm and CMC 20 μM. The bigger hydrophobic compartment in VPM resulted in improved loading of a potent chemotherapeutic drug, curcumin (Cur), and increased encapsulation efficiency (EE) (% drug loading 98.3 ± 1.92, and 85.3 ± 3.29; EE 14.8 ± 0.16 and 12.8 ± 0.09 for VPM and PPM, respectively). Curcumin loaded Vitamin E based micelles exhibited higher cytotoxicity compared to Curcumin loaded PEG-PE micelles in tested cancer cell lines. C-VPM demonstrated ∼3.2 and ∼2.7-fold higher ability to reverse multiple drug resistance compared to PPM and verapamil (concentration used 30 μM), respectively. In the in vivo study by using B16F10 implanted C57Bl6/J mice, C-VPM reduced the tumor volume and weight more efficiently than C-PPM by inducing apoptosis as analyzed by TUNEL assay on tumor cryosections. The newly developed polymeric micelles, VPM with improved drug loadability and ability to reverse the drug resistance could successfully be utilized as a nanocarrier system for hydrophobic chemotherapeutic agents for the treatment of drug-resistant solid tumors.