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.

Self-targeted hyaluronic acid-b-poly (ß-amino ester) pH-switchable polymersome for guided doxorubicin delivery to metastatic breast cancer.

In this study, a targeted pH-sensitive polymersome incorporating doxorubicin (DOX) was manufactured implementing diblock copolymer of hyaluronic acid-b-pPoly (ß-amino ester) (HA-PBAE). The hydrophilic DOX was loaded into the aqueous compartment of HA-PBAE polymersomal structure during nanoprecipitation process with 60 % ± 3.0 entrapment efficiency (EE%) and 5.3 % ± 0.2 loading content (LC%) while demonstrating spherical morphology with size of 196 ± 3.8 nm and PDI of 0.3. The prepared platform (DOX-HA-PBAE) illustrated accelerated DOX release in acidic pH 5.4, and showed significantly higher cytotoxicity and cellular internalization in comparison with free DOX against 4T1 cell line (CD44 positive cell). In contrast, no significant growth inhibition was observed in CHO cell line (CD44 negative cell). Furthermore, DOX-HA-PBAE platform displayed higher therapeutic efficacy, favorable tumor accumulation and lower systemic toxicity in comparison with free DOX based on obtained experimental data in ectopic 4T1 tumor model in BALB/c Female mice in terms of tumor growth rate, survival rate, body weight loss, ex vivo biodistribution and pathological evaluations. The obtained results demonstrated that DOX-HA-PBAE polymersomes have potential to be used in metastatic breast cancer therapy with promising characteristics in terms of tumor growth suppression and safety profile.

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.

A multi-storey DNA nanostructure containing doxorubicin and AS1411 aptamer for targeting breast cancer cells.

Herein, we presented a novel DOX-loaded multi-storey DNA nanostructure, including AS1411 aptamer as a targeting agent for treatment of target cells (MCF-7 and 4T1). Gel retardation test and fluorometric analysis were used to examine the construction of DNA nanostructure and loading of DOX in the complex. At pH 5.5 and 7.4, the release patterns of DOX from the prepared formulation were studied. Cell viability test was conducted to analyse the cell cytotoxicity ability of the DOX loaded multi-storey DNA nanostructure compared to free DOX in 4T1, MCF-7 (target) and CHO cells (non-target). Flow cytometry analysis was used to examine the DOX-loaded DNA nanostructure internalisation. Finally, the developed DOX-loaded multi-storey DNA nanostructure was tested in vivo to see if it could prevent tumour growth. The drug was released from the nanocomplex in a pH-related process (higher release in acidic pH compared to neutral pH). According to MTT assay, DOX-loaded DNA nanostructure damaged nucleolin positive cells while not significantly affecting nucleolin negative cells. The formulation was efficaciously internalised into target cells (4T1 and MCF-7), but not into non-target ones. Moreover, DOX-loaded DNA nanostructure can restrict tumour growth, increase survival rate, and accumulate significantly more in the tumour site than free DOX.

Theranostic nanobubbles towards smart nanomedicines.

Targeted therapy and early accurate detection of malignant lesions are essential for the effectiveness of treatment and prognosis in cancer patients. The development of gaseous system as a versatile platform for the fabricated nanobubbles, has attracted much interest in improving the efficacy of ultrasound therapeutic, diagnostic, and theranostic platforms. Nano-sized bubble, as an ultrasound contrast agent, with spherical gas-filled structures exhibited contrast enhancement capability due to their inherent EPR effect. Additionally, nanobubbles exhibited good stability with extended retention time in the blood stream. The current review summarized various nanobubbles and discussed about the crucial parameters affecting the stability of ultrafine bubbles. Furthermore, therapeutic and theranostic gaseous systems for fighting against cancer were described.

Fabrication of versatile targeted lipopolymersomes for improved camptothecin efficacy against colon adenocarcinoma in vitro and in vivo.

BACKGROUND: Hybrid vesicular systems (lipopolymersomes) are promising platforms for minimizing the liposomes and polymersomes disadvantages in terms of chemotherapeutic transportation. In this regard, lipopolymersome has been designed to integrate the advantage of both polymersomes and liposomes to enable better structural integrity of the bilayer after encapsulation of hydrophobic drugs while maintaining the soft nature of liposomes, superior serum stability, and high encapsulation efficiency of cargos in the bilayer segment. RESEARCH DESIGN AND METHODS: In the present study, we reported preparation and characterization of five camptothecin (CPT)-loaded lipopolymersomal formulations composed of poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) and dipalmitoylphosphatidylcholine (DPPC) at different molar ratios using film rehydration method. Afterward, the preferred formulation was tagged with AS1411 DNA aptamer in order to evaluate the therapeutic index using nucleolin-positive colon cancer cell lines (HT29 and C26). RESULTS: The obtained data indicated that the prepared CPT-loaded lipopolymersome at a PEG-PLA: DPPC ratio of 75:25 exhibited superior stability and high loading capacity compared to other systems. Moreover, high cytotoxicity of the aptamer-targeted lipopolymersome and increased tumor accumulation were observed in comparison with non-targeted one. CONCLUSIONS: The designed polymer-rich lipopolymersomal platform offers bright future for the development of potent nanomedicine against cancer.

Marriage of phospholipid and block copolymer in lipopolymersome hybrid structure for efficient tumor accumulation.

Despite the noticeable advantages of the liposomes and polymersomes, they also revealed some drawbacks that could be minimized by preparing hybrid vesicular systems and integrating the advantage of both vehicles into one system named lipopolymersome. Lipopolymesome incorporates the biodegradability, stability, adjustability and chemical flexibility of polymersomes with the elasticity, soft nature and biocompatibility of liposomes. In the current study, wereported the development of five nanoscale lipopolymersomal hybrid vesicular systems consisting different molar ratios of dipalmitoylphosphatidylcholine (DPPC) and poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) (PEG-PLA: DPPC ratio of 100:0, 50:50: 25:75, 75:25 and 0:100). Rhod-6G-loaded hybrid vesicles were prepared via film rehydration. Then, the efficacy of five formulations were evaluated in terms of loading capacity, release pattern, cellular uptake, andin vivobiodistribution in ectopic tumor model in mice. The obtained results demonstrated that the self-assembly, loading capacity, cargo release and stability of hybrid nanoscale lipopolymersomes can be tuned by incorporation of amphiphilic lipid-polymers at various ratios. In this regard, the prepared hybrid nanovesicles consisting of DPPC-PEG-PLA (25:75) exhibited great potential through superior loading capacity, stability and tumor accumulation compared with other systems. It could be concluded that the prepared lipopolymersome offers important opportunities for the development of novel hybrid carriers for efficient transportation of therapeutics into tumor site.

Targeted MMP-2 responsive chimeric polymersomes for therapy against colorectal cancer.

In the current study, polyethylene glycol (PEG) was linked to polylactide (PLA) through the synthetic peptide PVGLIG which can be selectively cleaved by the tumor-associated matrix metalloproteinase 2 (MMP-2) enzyme. The synthesized chimeric triblock polymer of PEG-b-PVGLIG-PLA was implemented to form nanoscale self-assemble chimeric polymersomes. The hydrophobic SN38 was loaded into polymersomes with 70.3% ± 3.0% encapsulation efficiency demonstrating monodispersed spherical morphologies with 172 ±â€¯30 nm dimension. The prepared chimeric polymersomal formulation provided controlled release of SN38 at physiological condition while illustrating seven-folds higher release rate when exposed to MMP-2 enzyme. At the next stage, AS1411 aptamer was conjugated onto the surface of MMP-2 responsive polymersomal formulation in order to provide guided drug delivery against nucleolin positive cells. In vitro cellular toxicity assay against C26 cell line (nucleolin positive) demonstrated significantly higher toxicity of targeted formulation in comparison with non-targeted one in low SN38 concentrations (0.15-1.25 µg/mL). In vivo study in mice bearing subcutaneous C26 tumor showed higher therapeutic index for MMP-2 responsive chimeric polymersomal formulation of SN38 in comparison with non-responsive one. On the other hand, AS1411 aptamer-targeted MMP-2 responsive chimeric polymersomal formulation exhibited highest therapeutic index compared to other groups. It could be concluded that the targeted chimeric polymersomes bearing both cleavable peptide sequence between their blocks and targeting ligand on their surface, provide favorable characteristics as an ideal delivery system against cancer.

Hybrid nanoreservoirs based on dextran-capped dendritic mesoporous silica nanoparticles for CD133-targeted drug delivery.

In this study, the chemical features of dendritic mesoporous silica nanoparticles (DMSNs) provided the opportunity to design a nanostructure with the capability to intelligently transport the payload to the tumor cells. In this regard, doxorubicin (DOX)-encapsulated DMSNs was electrostatically surface-coated with polycarboxylic acid dextran (PCAD) to provide biocompatible dextran-capped DMSNs (PCAD-DMSN@DOX) with controlled pH-dependent drug release. Moreover, a RNA aptamer against a cancer stem cell (CSC) marker, CD133 was covalently attached to the carboxyl groups of DEX to produce a CD133-PCAD-DMSN@DOX. Then, the fabricated nanosystem was utilized to efficiently deliver DOX to CD133+ colorectal cancer cells (HT29). The in vitro evaluation in terms of cellular uptake and cytotoxicity demonstrated that the CD133-PCAD-DMSN@DOX specifically targets HT29 as a CD133 overexpressed cancer cells confirmed by flow cytometry and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. The potentially promising intelligent-targeted platform suggests that targeted dextran-capped DMSNs may find impressive application in cancer therapy.

Enzyme responsive drug delivery systems in cancer treatment.

Recent technological approaches in drug delivery have attracted scientist interest for improving therapeutic index of medicines and drug compliance. One of the powerful strategies to control the transportation of drugs is implementation of intelligent stimuli-responsive drug delivery system (DDS). In this regard, tumor tissues with unique characteristics including leaky vasculature and diverse enzyme expression profiles facilitate the development of efficient enzyme-responsive nanoscale delivery systems. Based on the stimuli nature (physical, chemical and biological), these systems can be categorized into three groups according to the nature of trigger initiating the drug release. Enzymes are substantial constituents of the biotechnology toolbox offering promising capabilities and ideal characteristics to accelerate chemical reactions. Nanoparticles which have the ability to trigger their cargo release in the presence of specific enzymes are fabricated implementing fascinating physico-chemical properties of different materials in a nanoscale dimension. In order to reduce the adverse effects of the therapeutic agents, nanocarriers can be utilized and modified with enzyme-labile linkages to provide on-demand enzyme-responsive drug release. In the current review, we give an overview of drug delivery systems which can deliver drugs to the tumor microenvironment and initiate the drug release in response to specific enzymes highly expressed in particular tumor tissues. This strategy offers a versatile platform for intelligent drug release at the site of action.