Smart Nanocarriers Research Articles

Light‐Triggered Clustered Vesicles with Self‐Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor

Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light‐triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H2O2) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC‐PAMAM) are coassembled with reactive‐oxygen‐species‐responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light‐triggered thermal effect that is able to decompose H2O2 into O2, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen‐mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC‐PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light‐triggered vesicles with both self‐supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.

Engineering the Surface of Smart Nanocarriers Using a pH-/Thermal-/GSH-Responsive Polymer Zipper for Precise Tumor Targeting Therapy In Vivo.

Nanocarrier surface chemistry plays a vital role in mediating cell internalization and enhancing delivery efficiency during in vivo chemotherapy. Inspired by the ability of proteins to alter their conformation to mediate functions, a pH-/thermal-/glutathione-responsive polymer zipper consisting of cell-penetrating poly(disulfide)s and thermosensitive polymers bearing guanidinium/phosphate (Gu+ /pY- ) motifs to spatiotemporally tune the surface composition of nanocarriers for precise tumor targeting and efficient drug delivery is developed. Surface engineering allows the nanocarriers to remain undetected during blood circulation and favors passive accumulation at tumor sites, where the acidic microenvironment and photothermal heating break the pY- /Gu+ binding and rupture the zipper, thereby exposing the penetrating shell and causing enhanced cellular uptake via counterion-/thiol-/receptor-mediated endocytosis. The in vivo study demonstrates that by manipulating the surface states on command, the nanocarriers show longer blood circulation time, minimized uptake and drug leakage in normal organs, and enhanced accumulation and efficient drug release at tumor sites, greatly inhibiting tumor growth with only slight damage to normal tissues. If integrated with a photothermal dye approved by the U.S. Food and Drug Administration (FDA), polymer zipper would provide a versatile protocol for engineering nanomedicines with high selectivity and efficiency for clinical cancer treatment.

Sonochemical fabrication of folic acid functionalized multistimuli-responsive magnetic graphene oxide-based nanocapsules for targeted drug delivery

A novel folic acid (FA) functionalized multistimuli-responsive magnetic graphene oxide (GO)-based nanocapsules (FA-MRMGONCs) were designed as a targeted drug carrier. The FA-MRMGONCs were obtained successfully from thiolated GO (TGO) and FA functionalized thiolated chitosan (FA-CS-SH) via sonochemical approach. FA-MRMGONCs were endowed with photothermal properties from GO. The hydrosulfuryl groups (-SH) of TGO and FA-CS-SH would be cross-linked to form the disulfide bonds under sonication. The disulfide bonds could be broken under reductive trigger and showed excellent reductive responsiveness to control drugs release. The oleic acid modified Fe3O4 NPs (OA-Fe3O4 NPs) were encapsulated into the FA-MRMGONCs and endowed FA-MRMGONCs with favorable magnetic guide functionality. Moreover, FA-MRMGONCs showed attractive FA-receptor-mediated targeting ability to the FA-receptors (FRs) positive cells due to the immobilization of FA on FA-MRMGONCs. The novel FA-MRMGONCs could be a promising smart nanocarrier for targeted delivery and triggered release of hydrophobic drugs for the cancer therapy in biomedical applications.

K+ -Responsive Block Copolymer Micelles for Targeted Intracellular Drug Delivery.

In this work, a novel type of block copolymer micelles with K+ -responsive characteristics for targeted intracellular drug delivery is developed. The proposed smart micelles are prepared by self-assembly of poly(ethylene glycol)-b-poly(N-isopropylacry-lamide-co-benzo-18-crown-6-acrylamide) (PEG-b-P(NIPAM-co-B18C6Am)) block copolymers. Prednisolone acetate (PA) is successfully loaded into the micelles as the model drug, with loading content of 4.7 wt%. The PA-loaded micelles display a significantly boosted drug release in simulated intracellular fluid with a high K+ concentration of 150 × 10-3 m, as compared with that in simulated extracellular fluid. Moreover, the in vitro cell experiments indicate that the fluorescent molecules encapsulated in the micelles can be delivered and specifically released inside the HSC-T6 and HepG2 cells responding to the increase of K+ concentration in intracellular compartments, which confirms the successful endocytosis and efficient K+ -induced intracellular release. Such K+ -responsive block copolymer micelles are highly potential as new-generation of smart nanocarriers for targeted intracellular delivery of drugs.

Luminescent/magnetic PLGA-based hybrid nanocomposites: a smart nanocarrier system for targeted codelivery and dual-modality imaging in cancer theranostics.

Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI-PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor-specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability waŝ14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 μg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2-weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM-PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment.

Cyanine based Nanoprobes for Cancer Theranostics.

Cyanine dyes are greatly accredited in the development of non-invasive therapy that can "see" and "treat" tumor cells via imaging, photothermal and photodynamic treatment. However, these dyes suffer from poor pharmacokinetics inducing severe toxicity to normal cells, insufficient accumulation in tumor regions and rapid photobleaching when delivered in free forms. Nanoparticles engineered to encapsulate these compounds and delivering them into tumor regions have increased rapidly, however, so far, these nanoparticles (NPs) have not proved to be so effective to circumvent existing challenges. Newly designed multifunctional smart nanocarriers that can improve phototherapeutic properties of these dyes, co-encapsulate multiple potent therapeutic compounds, and simultaneously overcome limitations related to tumor recurrence, metastases, limited intracellular uptake, and tumor hypoxia have potential to revolutionize modern paradigm of cancer therapy. Such cyanine based multifunctional nanocarriers integrating imaging and therapy in a single platform can effectively produce better clinical outcomes in cancer treatment. This review briefly summarizes recent advancements of cyanine nanoprobes that are currently used as imaging/phototherapeutic agents in unimodal/bimodal/trimodal cancer theranostics. Finally, we conclude this review by addressing challenges of pre-existing therapeutic systems and designs adopted to overcome them with a brief insight assimilating future perspective of emerging cyanine-based NPs in cancer theranostics.

A pH-triggered charge reversal and self-fluorescent micelle as a smart nanocarrier for doxorubicin controlled release

A novel pH-sensitive charge reversal and self-fluorescent polymeric micelle is designed and synthesized successfully. The smart micelle is prepared based on MPEG-polyurethane multi-block copolymer, which is synthesized by polycondensation, with 1, 4-bis (hydroxyethyl) piperazine (HEP) and hydroxyl-sulfamethazine (Hydroxyl-SM) as pH-sensitive molecules and fluorescein isothiocyanate (FITC) as fluorescent segment. The resulting MPEG-polyurethane multi-block copolymer is examined by 1H–NMR, UV-vis spectra, fluorescence spectra and an acid-base titration. Moreover, the diameter, morphology and cytotoxicity of obtained polymer micelle are measured by dynamic light scattering (DLS), transmission electron microscopy (TEM) and MTT assay. The results indicate that the micelle has a small diameter of less than 200 nm and can remain unchanged within two weeks. Zeta-potential measurement shows that the negative charge of micelle can switch into positive charge as the pH value decreasing from 9.0 to 3.0. Subsequently, the fluorescence intensity decreases significantly with the reducing of pH values. The MTT assay shows the low cytotoxicity and good biocompatibility of the MPEG-polyurethane polymeric micelles. Finally, doxorubicin (DOX) is loaded into micelles to detect in vitro release behavior. The drug loaded micelles show a faster release behavior at pH 5.0 than that at pH 7.4. Therefore, the pH-sensitive charge reversal and self-fluorescent micelle can be a potential smart carrier for delivery and controlled release of protein drug.

Smart Asymmetric Vesicles with Triggered Availability of Inner Cell-Penetrating Shells for Specific Intracellular Drug Delivery.

Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nanocarriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVRG-b-poly(ε-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9% and 91%, respectively. Upon treatment with MMP-2 to cleave the stealthy PEG shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76% exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (∼10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.

Pancreatic Cancer Therapy Review: From Classic Therapeutic Agents to Modern Nanotechnologies.

Pancreatic cancer remains one of the most lethal cancers worldwide, with an extremely poor prognosis. This cancer is considered the 5th leading cause of cancer related death. The median survival after diagnosis is generally 2-8 months and five-year survival rate is less than 5%. In recent years, nanotechnology is emerging as a rising approach for drug delivery since it has opened up new landscapes in medicine through introduction of smart nanocarrier systems that can selectively deliver the therapeutic agent in a specific region and in appropriate levels, reducing the adverse side effects. This review covers the main delivery systems developed so far for anticancer drug delivery to the pancreas over a period of 20 years, from polymeric to lipidic-based nanosystems, with a particular emphasis on albumin as core material.

Nanogels comprising reduction-cleavable polymers for glutathione-induced intracellular curcumin delivery

In this study, we prepared nanogels of a disulfide-cleavable polymer via polyionic complexation and genipin cross-linking and evaluated their reduction-triggered intracellular curcumin (Cur) delivery. These nanogels were stable at physiological conditions due to the formation of genipin cross-linking and helical PLL/PDC complexes and would swell/dissociate at acidic and reductive conditions due to the dissociation of PLL/PDC complexes and cleaving of disulfide bonds. The cellular uptake and intracellular release of Cur-loaded nanogels were demonstrated by tracking the fluorescent Cur and in vitro drug release studies, confirming the triggered release of Cur at acidic and reductive microenvironments in cells. The MTT, TUNEL staining, and Caspase-3 activity assays showed that the Cur-loaded nanogels exhibited higher cellular proliferation inhibition toward U-87 MG cells than free Cur, whereas the blank nanogels exhibited low cytoxicity. The results highlight the potential of functional nanogels prepared by polyionic complexation and cross-linking as a smart nanocarrier for drug delivery.

Synthesis of Norbornene Derived Helical Copolymer by Simple Molecular Marriage Approach to Produce Smart Nanocarrier

A novel library of norbornene derived helical copolymer has been synthesized through the coupling of two homopolymers via Molecular Marriage Approach. The helicity is governed by the non-covalent interactions like hydrogen bonding, π-π stacking and the influence of hydrophobic and hydrophilic motifs. The detailed characterization of the copolymer (Copoly 1) has been provided and the super structures are confirmed through dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The observed size of the aggregates was about 200 nm. The density functional theory (DFT) is favorably supported for the formation of proposed structure of Copoly 1. Circular dichroism (CD) measurement has confirmed the one handed helical structure of the copolymer. Reservoir capability of this pH responsive polymer (Copoly 1) to encapsulate anti-cancer drug doxorubicin (DOX) warrants its potential applications in the field of bio-medical sciences.

Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light.

Nanotechnology has begun to play a remarkable role in various fields of science and technology. In biomedical applications, nanoparticles have opened new horizons, especially for biosensing, targeted delivery of therapeutics, and so forth. Among drug delivery systems (DDSs), smart nanocarriers that respond to specific stimuli in their environment represent a growing field. Nanoplatforms that can be activated by an external application of light can be used for a wide variety of photoactivated therapies, especially light-triggered DDSs, relying on photoisomerization, photo-cross-linking/un-cross-linking, photoreduction, and so forth. In addition, light activation has potential in photodynamic therapy, photothermal therapy, radiotherapy, protected delivery of bioactive moieties, anticancer drug delivery systems, and theranostics (i.e., real-time monitoring and tracking combined with a therapeutic action to different diseases sites and organs). Combinations of these approaches can lead to enhanced and synergistic therapies, employing light as a trigger or for activation. Nonlinear light absorption mechanisms such as two-photon absorption and photon upconversion have been employed in the design of light-responsive DDSs. The integration of a light stimulus into dual/multiresponsive nanocarriers can provide spatiotemporal controlled delivery and release of therapeutic agents, targeted and controlled nanosystems, combined delivery of two or more agents, their on-demand release under specific conditions, and so forth. Overall, light-activated nanomedicines and DDSs are expected to provide more effective therapies against serious diseases such as cancers, inflammation, infections, and cardiovascular disease with reduced side effects and will open new doors toward the treatment of patients worldwide.

Ultrasonic nanotherapy of breast cancer using novel ultrasound-responsive alginate-shelled perfluorohexane nanodroplets: In vitro and in vivo evaluation

Development of a new class of multifunctional ultrasound-responsive smart nanocarriers that combine therapeutic properties with diagnostic imaging has gained great attention in recent years. Here, we describe the results of ultrasonic nanotherapy of breast cancer using novel alginate-stabilized perfluorohexane nanodroplets. Doxorubicin (Dox)-loaded multifunctional nanodroplets (Dox-NDs) were synthesized via nanoemulsion process and evaluated in vitro and in vivo with focus on cytotoxicity, hemolytic activity, biodistribution, biosafety, and antitumor activity. Echogenic property of nanodroplets was confirmed by B-mode ultrasound imaging. Tumor therapy using Dox-NDs combined with sonication (Dox-ND-US) resulted in strong in vivo antitumor activity characterized by tumor regression which could be because of on demand efficient ultrasound-aided drug release from nanodroplets in tumor tissue under the action of ultrasound. Dox concentration in tumor area for Dox-ND-US treated group reached 10.9μg/g after sonication for 4min (28kHz, 0.034W/cm2), which was 5.2-fold higher compared to non-sonicated Dox-NDs group. The cardiotoxicity of Dox-NDs was much lower than that of free Dox and no hemolytic activity was observed for Dox-NDs.Strong therapeutic effect of these multifunctional nanodroplets combined with their ultrasound-contrast property indicated that this drug delivery system has a great potential in smart cancer-therapy.

Bypassing multidrug resistant ovarian cancer using ultrasound responsive doxorubicin/curcumin co-deliver alginate nanodroplets

Ultrasound-responsive perfluorocarbon nanoemulsions are a class of new multifunctional smart nanocarriers which combine diagnostic properties with therapeutic properties and release their drug payload in a controlled manner in response to ultrasound. Therefore, combination therapy using chemotherapeutic and chemosensitizing agents co-entrapped in these nanocarriers seems beneficial for cancer treatment. In the present study, multifunctional smart alginate/perfluorohexane nanodroplets were developed for co-delivery of doxorubicin and curcumin (a strong chemosensitizer). The nanodroplets with the average particle size of 55.1nm were synthesized via nanoemulsion process. The entrapment efficiency of doxorubicin was 92.3%. To improve curcumin entrapment into the alginate shell, Span 60 was added to the formulation as a co-surfactant and finally curcumin entrapment of about 40% was achieved. Ultrasound-mediated drug release kinetic was evaluated at two different frequencies of 28kHz (low frequency) and 1MHz (high frequency). Low frequency ultrasound resulted in higher triggered drug release from nanodroplets. The nanodroplets showed strong ultrasound contrast via droplet to bubble transition as confirmed via B-mode ultrasound imaging.Enhanced cytotoxicity in adriamycin-resistant A2780 ovarian cancer cells was observed for Dox-Cur-NDs compared to Dox-NDs because of the synergistic effects of doxorubicin and curcumin. However, ultrasound irradiation significantly increased the cytotoxicity of Dox-Cur-NDs. Finally, in vivo ovarian cancer treatment using Dox/Cur-NDs combined with ultrasound irradiation resulted in efficient tumor regression. According to the present study, nanotherapy of multidrug resistant human ovarian cancer using ultrasound responsive doxorubicin/curcumin co-loaded alginate-shelled nanodroplets combined with ultrasound irradiation could be a promising modality for the future of cancer treatment.

Investigation on a smart nanocarrier with a mesoporous magnetic core and thermo-responsive shell for co-delivery of doxorubicin and curcumin: a new approach towards combination therapy of cancer

A novel and smart MIO-P(NIPAM-MAm) nanocomposite has been prepared for combinational delivery of Dox and Cur for cancer treatment.

Mesoporous silica nanoparticles with lactose-mediated targeting effect to deliver platinum(iv) prodrug for liver cancer therapy.

Chemotherapy is the most common therapeutic strategy for the treatment of unresectable hepatocellular carcinoma. However, the therapeutic efficacy is limited by the low delivery efficiency of chemotherapeutics and severe toxicity towards healthy tissues. To address these challenges, active-targeting mesoporous silica nanoparticles conjugating a platinum(iv) prodrug were developed as a therapy for liver cancer for the first time. Taking advantage of liver-targeting lactobionic acid (LA), the smart nano-carriers not only enhanced the circulation time, but also effectively concentrated at the liver tumor site. Moreover, the conjugated platinum(iv) could be reduced in the reductive tumor environment for the fast release of active platinum(ii). The novel targeting and self-responsive drug-loading system offers new prospects for liver cancer chemotherapy.

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC–MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.

Biocompatible magnetic tris(2-aminoethyl)amine functionalized nanocrystalline cellulose as a novel nanocarrier for anticancer drug delivery of methotrexate

A smart, pH-responsive and biocompatible nanocarrier, aimed to achieve an efficient targeted drug delivery system, was facilely synthesized.

Structure-Dependent and Glutathione-Responsive Biodegradable Dendritic Mesoporous Organosilica Nanoparticles for Safe Protein Delivery

The design of smart nanocarriers that could recognize and differentiate cancer cells and normal cells is of great importance in drug delivery. Here we report the first example of cancer cell-specific degradable dendritic mesoporous organosilica nanoparticles (DDMONs). A unique pore structure-dependent glutathione (GSH)-responsive degradation behavior is revealed: the degradation rates of two nanoparticles with different pore sizes are similar in normal cells (“leveling effect”), while large-pore DDMONs show a faster degradation rate than small-pore nanoparticles in cancer cells with relatively high intracellular GSH levels (“differentiating effect”). The cancer cell-specific degradability and concomitant cargo release lead to efficient protein delivery toward cancer cells but reduced cytotoxicity toward normal cells.

Smart nanocarriers for drug delivery: controllable LSPR tuning

Smart nanocarriers for drug delivery: controllable LSPR tuning