Nucleolin-targeted doxorubicin and ICG co-loaded theranostic lipopolymersome for photothermal-chemotherapy of melanoma in vitro and in vivo.

Combination therapy using chemo-photothermal therapy (chemo-PTT) shows great efficacy toward tumor ablation in preclinical studies. Besides, lipopolymersomes as a hybrid nanocarriers, integrate advantages of liposomes and polymersomes in a single platform in order to provide tremendous biocompatibility, biodegradability, noteworthy loading efficacy for both hydrophobic and hydrophilic drugs with adjustable drug release and high stability. In this study, a multipurpose lipopolymersome was fabricated for guided chemotherapy-PTT and CT-scan imaging of melanoma. A lipopolymerosomal hybrid nanovesicle consisting of equal molar ratio of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) diblock copolymer (molar ratio 1:1) was fabricated. The nanoparticulate system was prepared through film rehydration technique for encapsulation of doxorubicin (DOX) and indocyanine green (ICG) to form DOX-ICG-LP platform. At the next stage, AS1411 DNA aptamer was conjugated to the surface of lipopolymersome (Apt-DOX-ICG-LP) for selective delivery. The sizes of DOX-ICG-LP and Apt-DOX-ICG-LP were obtained through DLS analysis (61.0 ±â€¯6 and 74 ±â€¯5, respectively). Near Infrared-responsive release pattern of the prepared lipopolymersome was verified in vitro. The formulated platform showed efficient photothermal conversion, and superior stability with acceptable encapsulation efficiency. Consistent with the in vitro studies, NIR-responsive lipopolymersome exhibited significantly higher cellular toxicity for Chemo-PTT versus single anti-cancer treatment. Moreover, superlative tumor shrinkage with favorable survival profile were attained in B16F10 tumor-bearing mice received Apt-DOX-ICG-LP and irradiated with 808 nm laser compared to those treated with either DOX-ICG-LP or Apt-DOX-ICG-LP without laser irradiation. The diagnostic capability of Apt-DOX-ICG-LP was addressed using in vivo NIR imaging, 6 and 24 h post-intravenous administration. The results indicated desirable feature of an established targeted theranostic capability of Apt-DOX-ICG-LP for both diagnostics and dual chemo-PTT of melanoma.

Synthesis of folate targeted theranostic cubosomal platform for co-delivery of bismuth oxide and doxorubicin to melanoma in vitro and in vivo.

Liquid crystalline nanoparticles (LCNPs) have gained much attention in cancer nanomedicines due to their unique features such as high surface area, storage stability, and sustained-release profile. In the current study, a novel LCNP for co-encapsulation of Bi2O3 and hydrophilic doxorubicin (DOX) was fabricated and functionalized with folic acid (FA) to achieve efficient tumor targeting toward CT-scan imaging and chemotherapy of melanoma in vitro and in vivo. LCNPs Bi2O3 NPs were prepared using glycerol monooleate-pluronic F-127 (GMO/PF127/water). Firstly, GMO/water were homogenized to prepare LC gel. Then, the stabilizer aqueous solution (PF127/Bi2O3/DOX) was added to the prepared LC gel and homogenized using homogenization and ultrasonication. The formulated NPs exhibited superior stability with encapsulation efficiency. High cytotoxicity and cellular internalization of the FA-Bi2O3-DOX-NPs were observed in comparison with Bi2O3-DOX-NPs and the free DOX in folate-receptor (FR) overexpressing cells (B16F10) in vitro. Moreover, ideal tumor suppression with increased survival rate were observed in tumorized mice treated with FA-Bi2O3-DOX-NPs compared to those treated with non-targeted one. On the other hand, the CT-imaging ability of the Bi2O3-DOX-NPs was tested inB16F10 tumor-bearing mice. The obtained data indicated a high potential of the developed targeted theranostic FA-Bi2O3-DOX-NPs for diagnostics and treatment of melanoma.

Surface engineering of hollow gold nanoparticle with mesenchymal stem cell membrane and MUC-1 aptamer for targeted theranostic application against metastatic breast cancer.

Mesenchymal stem cell membrane (MSCM)-coated biomimetic doxorubicin-loaded hollow gold nanoparticles were fabricated and decorated with MUC1 aptamer in order to provide smart theranostic platform. The prepared targeted nanoscale biomimetic platform was extensively characterized and evaluated in terms of selective delivery of DOX and CT-scan imaging. The fabricated system illustrated spherical morphology with 118 nm in diameter. Doxorubicin was loaded into the hollow gold nanoparticles through physical absorption technique with encapsulation efficiency and loading content of 77%±10 and 31%±4, respectively. The in vitro release profile demonstrated that the designed platform could respond to acidic environment, pH 5.5 and release 50% of the encapsulated doxorubicin during 48 h, while 14% of the encapsulated doxorubicin was released in physiological condition, pH 7.4 up to 48 h. The in vitro cytotoxicity experiments on 4T1 as MUC1 positive cell line illustrated that the targeted formulation could significantly increase mortality at 0.468 and 0.23 µg/ml of equivalent DOX concentration compared to non-targeted formulation while this cytotoxicity was not observed in CHO as MUC1 negative cell line. Furthermore, in vivo experiments showed high tumor accumulation of the targeted formulation even 24 h after intravenous injection which induced effective tumor growth suppression against 4T1 tumor bearing mice. On the other hand, existence of hollow gold in this platform provided CT scan imaging capability of the tumor tissue in 4T1 tumor bearing mice up to 24 h post-administration. The obtained results indicated that the designed paradigm are promising and safe theranostic system for fighting against metastatic breast cancer.

Synthesis of manganese-incorporated polycaplactone-poly (glyceryl methacrylate) theranostic smart hybrid polymersomes for efficient colon adenocarcinoma treatment.

In the current study, a multifunctional nanoscale vesicular system (polymersome) with the ability to accumulate in the site of action, control drug release and integrate diagnostic and therapeutic functions was developed. The theranostic polymersome was engineered as a promising dual-functional nanoplatform, which can be used for tumor therapy and magnetic resonance imaging (MRI). In this regard, the amphiphilic diblock copolymer of poly(ε-caprolactone)-block-poly(glyceryl methacrylate)[(PCL-b-PGMA)] was synthesized by combined ring-opening polymerization (ROP), and reversible addition-fragmentation chain-transfer (RAFT) polymerization techniques followed by hydrolysis of the pendant oxiran rings to hydroxyl groups. Because of the amphiphilic properties and desirable hydrophobic/hydrophilic balance of the synthesized copolymer, it could self-assemble to form a polymersomal structure in an aqueous environment (with diameters about 100-145 nm). The hydrophilic anticancer drug, doxorubicin (DOX) and hydrophobic paramagnetic Mn (phenanthroline)2 complex, being well-represented on T1-weighted magnetic resonance imaging (MRI), were encapsulated in the hydrophilic core (33%±2.3 efficiency) and hydrophobic bilayer membrane (100 %efficient) of a polymersome system, respectively to provide PCL-PGMA@Mn(phen)2/DOX NPs. It was found that adding aptamer AS1411 to NPs surfaces enhanced their specificity and selectivity towards colorectal cancer cells expressing nucleolin (HT29 and C26). In vivo evaluation after intravenous administration of the prepared platform was performed using subcutaneous C26 tumor-bearing Balb/C mice. The obtained results demonstrated that the prepared targeted platform provided a reduced systemic toxicity in terms of body weight loss and mortality while showing efficient tumor regression. Furthermore, the prepared theranostic platform afforded MRI imaging capability for tumor monitoring. It could be concluded that the biocompatible PCL-PGMA magnetic DOX-loaded polymersomes could serve as a versatile multifunctional system for simultaneous tumor imaging and therapy.

Combination therapy using Smac peptide and doxorubicin-encapsulated MUC 1-targeted polymeric nanoparticles to sensitize cancer cells to chemotherapy: An in vitro and in vivo study.

Targeting inhibitors of apoptosis proteins (IAPs) family comprising high level expression in many cancer cells, could sensitize tumor cells to conventional chemotherapies. In the present study, we designed both doxorubicin and SmacN6 (an antagonist of the IAPs) encapsulated polymeric nanoparticles (NPs) and investigated their synergistic effect of combination therapy in vitro and in vivo. According to the results, NPs-SmacN6 significantly enhanced the cytotoxicity effect of NPs-DOX and reduced its IC50 in MCF-7, 4T1 and C26 cancer cells. Western blot analysis confirmed mechanism of cell apoptosis via caspase activation through intrinsic and also extrinsic pathways. Moreover, 5TR1 aptamer-modified NPs could effectively deliver DOXor SmacN6 to C26 cancer cells (MUC1 positive) in comparison with the non-targeted one (p < 0.001). However, they could not be efficiently internalized into CHO cells (MUC1 negative), showing less cytotoxicity in this cell line. In vivo experiments in BALB/c mice bearing C26 tumor indicated that Apt-NPs-DOX in combination with Apt-NPs-SmacN6 had significant tumor growth inhibition in comparison with mice receiving either free DOX or Apt-NPs-DOX with p < 0.0001 and p < 0.05, respectively. Our results revealed that combination therapy of DOX and SmacN6 via Apt-modified nanoparticles can lead to improvement of therapeutic index of DOX in MUC1 positive cancer cells.

A novel colorimetric triple-helix molecular switch aptasensor for ultrasensitive detection of tetracycline.

Detection methods of antibiotic residues in blood serum and animal derived foods are of great interest. In this study a colorimetric aptasensor was designed for sensitive, selective and fast detection of tetracycline based on triple-helix molecular switch (THMS) and gold nanoparticles (AuNPs). As a biosensor, THMS shows distinct advantages including high stability, sensitivity and preserving the selectivity and affinity of the original aptamer. In the absence of tetracycline, THMS is stable, leading to the aggregation of AuNPs by salt and an obvious color change from red to blue. In the presence of tetracycline, aptamer binds to its target, signal transduction probe (STP) leaves the THMS and adsorbs on the surface of AuNPs. So the well-dispersed AuNPs remain stable against salt-induced aggregation with a red color. The presented aptasensor showed high selectivity toward tetracyclines with a limit of detection as low as 266 pM for tetracycline. The designed aptasensor was successfully applied to detect tetracycline in serum and milk.