Smart Nanocarriers Research Articles

Efficient Design to Monitor the Site‐specific Sustained Release of a Non‐Emissive Anticancer Drug

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.

Singlet Oxygen-Responsive Polymeric Nanomedicine for Light-Controlled Drug Release and Image-Guided Photodynamic-Chemo Combination Therapy.

Coencapsulation of chemotherapeutic agents and photosensitizers into nanocarriers can help to achieve a combination of chemotherapy and photodynamic therapy for superior antitumor effects. However, precise on-demand drug release remains a major challenge. In addition, the loaded photosensitizers usually tend to aggregate, which can significantly weaken their fluorescent signals and photodynamic activities. To address these issues, herein, a smart nanocarrier termed as singlet oxygen-responsive nanoparticle (SOR-NP) was constructed by introducing singlet oxygen (1O2)-sensitive aminoacrylate linkers into amphiphilic mPEG-b-PCL copolymers. Boron dipyrromethene (BDP) and paclitaxel (PTX) as model therapeutic agents were coloaded into an 1O2-responsive nanocarrier for realizing light-controlled drug release and combination cancer treatment. This polymeric nanocarrier could substantially relieve the aggregation of encapsulated BDP due to the presence of a long hydrophobic chain. Therefore, the formed SOR-NPBDP/PTX nanodrug could generate bright fluorescent signals and high levels of 1O2, which could mediate cell death via PDT and rupture aminoacrylate linker simultaneously, leading to collapse of SOR-NPBDP/PTX and subsequent PTX release. The light-triggered drug release and combined anticancer effects of SOR-NPBDP/PTX were validated in HepG2 and MCF-7 cancer cells and H22 tumor-bearing mice. This study provides a promising strategy for tumor-specific drug release and selective photodynamic-chemo combination treatment.

Enzyme-responsive smart nanocarriers for targeted chemotherapy: an overview.

Nanocarriers play pivotal roles in the field of biomedical applications, particularly in anticancer therapy. One of the prominent strategies for the transport of anticancer drugs with site-specific release and improved therapeutic efficacy is the use of an enzyme-responsive drug delivery system. There is an emerging class of cancer therapeutics engineered to control the release of a drug via enzymatic degradation. Enzymes, being an essential component of bio-nanotechnology toolbox, hold exceptional biorecognition abilities as well as outstanding catalytic properties. Often, abnormal enzyme expression observed in cancer offers many opportunities in designing nanocarriers modified with enzyme-labile linkage. Through altered physical or chemical characteristics of these nanocarriers or cleavage of the drug in response to thebio-action of enzyme, anon-demand drug release can be obtained. In this review, several classes of enzymes performing critical roles in cancer such as hydrolases, lipases, and oxidoreductases are summarized. Insights on various approaches that interfere with the mechanism of these enzymes have also been included. Finally, various smart nanocarriers such as mesoporous silica nanoparticles, gold nanoparticles, carbon-nanotubes, micelles, liposomes, and dendrimers serving as excellent platforms for enzyme-responsive formulationshave been discussed.

DNA Based and Stimuli-Responsive Smart Nanocarrier for Diagnosis and Treatment of Cancer: Applications and Challenges.

Simple SummaryDNA based and stimuli-responsive smart nano-carrier system can efficiently deliver encapsulated cargos in response to various driving thresholds. The conditional release of encapsulated carriers via modifications in the dynamic structure of DNA in response to tumor microenvironment has led to the specific delivery of active agents to the tumors. Therefore, specific drug delivery enhances the therapeutic efficacy and decreases the side effects on the neighboring healthy cells. Despite the great potential for pharmacological applications of the DNA-assisted and pH-sensitive smart nano-carriers, some challenges should be addressed before clinical transition. Since the therapeutic efficacies of DNA based smart nano-carriers have only been investigated in a proof-of-concept manner, the detailed in vivo parameters of the nano-carriers must be investigated and elucidated, including colloidal stability, circulating half-life, immunogenicity, dose-dependent cytotoxicity, pharmacokinetics, and clearance mechanisms.The rapid development of multidrug co-delivery and nano-medicines has made spontaneous progress in tumor treatment and diagnosis. DNA is a unique biological molecule that can be tailored and molded into various nanostructures. The addition of ligands or stimuli-responsive elements enables DNA nanostructures to mediate highly targeted drug delivery to the cancer cells. Smart DNA nanostructures, owing to their various shapes, sizes, geometry, sequences, and characteristics, have various modes of cellular internalization and final disposition. On the other hand, functionalized DNA nanocarriers have specific receptor-mediated uptake, and most of these ligand anchored nanostructures able to escape lysosomal degradation. DNA-based and stimuli responsive nano-carrier systems are the latest advancement in cancer targeting. The data exploration from various studies demonstrated that the DNA nanostructure and stimuli responsive drug delivery systems are perfect tools to overcome the problems existing in the cancer treatment including toxicity and compromised drug efficacy. In this light, the review summarized the insights about various types of DNA nanostructures and stimuli responsive nanocarrier systems applications for diagnosis and treatment of cancer.

Three‐Dimensional Visualization of Subcellular Dynamics of Cancer Cell Destruction on Therapeutic Nanodrug Treatment

Multi-Modal Targeting Strategy for Breast Cancer In article number 2000145 by Sreejith Raveendran, D. Sakthi Kumar and co-workers, a multi-modal targeting strategy for breast cancer using combinatorial nanodrug complex is studied and ultra-structural visualization of subcellular targeting and multiple parallel damage caused to breast cancer cells are demonstrated using serial-block-face scanning electron microscopy. Mechanistic and conformational understanding of specific subcellular connections of novel smart nanocarriers with various intrinsic receptors are critical for the design and delivery of novel cancer therapeutics.

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Dynamic enzymatic synthesis of γ-cyclodextrin using a photoremovable hydrazone template

Nanocarriers based on block copolymers of l-proline and lactide: The effect of core crosslinking versus its pH-sensitivity on their cellular uptake

Although doxorubicin (DOX) is an effective drug with cytotoxicity against a variety of different tumors, it also induces undesired side-effects to the healthy tissues. Therefore, the smart nanocarrier-based systems are the solution for this problem due to the entrapment of the drug in the stimuli-responsive, polymeric core. This allows to decrease the toxicity of the DOX and allows for the delivery of DOX precisely to the tumor sites. Herein, we present such a smart nanoparticle platform composed of stimuli-responsive copolymers of l,l-lactide/d,d-lactide with l-proline, which were successfully synthesized through the combination of ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. These copolymers were used for the preparation of enantiomeric and stereocomplexed nanoparticles (NPs) with a mean diameter of about 160–210 nm that were used as a reservoir of the anticancer drug. The drug release results showed that (co)polymeric NPs possess an excellent pH-sensitive behavior under the acidic tumor microenvironment, however, it was less pronounced for NPs cross-linked by stereocomplexation between poly(l-lactide) (PLLA) and poly(d-lactide) PDLA chains. Additionally, the DOX-loaded NPs were effective against AGS, HeLa, and Lovo cells, nevertheless, their cytotoxicity strongly depends on the building blocks of the nanocarrier. Interestingly, the l-proline functionality enhances the cellular uptake of enantiomeric NPs, nonetheless, the high stability of NPs due to the supramolecular crosslinking of PLA macromolecules prevails over this effect and stereocomplexed NPs were better internalized by the cancer cells. These advantageous features indicate that stereocomplexed (sc), (co)polymeric NPs are promising candidates as a smart and versatile nanocarrier platform for the treatment of different types of tumors.

Synthesis of pH responsive, photocrosslinked gelatin-based hydrogel system for control release of ceftriaxone

Stimuli-responsive or smart nanocarriers are emerging class of materials used for drug delivery and tissue engineering applications. The objective of this study was to develop environment friendly, economic and smart gelatin based hydrogel for controlled delivery of ceftriaxone. Gelatin was modified with furfuryl amine and converted to hydrogel via photo oxidation reaction, initiated with visible light in the presence of crosslinking agent (eosin Y and riboflavin) to enhance the mechanical properties and increase structural integrity of the hydrogel. The conjugated gelatin-furfuryl amine (GFA) was characterized by 1H NMR and FTIR techniques. An antimicrobial drug (ceftriaxone) was encapsulated in hydrogels systems (HG-E and HG-R) and its encapsulation efficiency was found as 88 % and 74 %, respectively. The in-vitro swelling property and release profile of the drug reveals that the behavior of hydrogel was pH dependent for both the hydrogels systems. Antibacterial study performed on HG-R hydrogel system via disc diffusion method revealed a greater zone of inhibition for Staphylococcus aureus. Findings of the presented work revealed the formation of an excellent, smart hydrogel system using Eosin-Y as cross-linker having greater encapsulation efficiency that can potentially be used for drug delivery application of ceftriaxone to enhance its therapeutic effects.

Metal-organic framework nanohybrid carrier for precise pesticide delivery and pest management

Smart core–shell nanocarriers can release pesticides in response to stimuli from the microenvironment associated with pests and the physiological behaviors of protected crops. In this work, a smart nanocarrier (MIL-101(Fe)@silica) with dual functions of site-specific delivery and plant nutrition was fabricated to deliver chlorantraniliprole (CAP) for sustainable pest management. The results showed that the developed CAP@MIL-101(Fe)@silica with a size of approximately 270 nm had a stable core–shell nanostructure with a highly crystallized regular octahedron. The photostability of the drug loaded in the carrier under UV-light irradiation was 16.5 times higher than that of technical CAP. The introduction of the silica shell prevented the premature escape of CAP from the MIL-101(Fe) core in the environment and endowed the developed nanohybrid carrier with base-triggered release properties. In a laboratory bioassay, CAP@MIL-101(Fe)@silica had favorable insecticidal activity (LC50 = 0.389 mg/L) in controlling Plutella xylostella larvae. After fourteen days of spraying in the greenhouse experiment, the mortality of the CAP@MIL-101(Fe)@silica treatment (86%) against P. xylostella larvae was significantly higher than that of the CAP suspension concentration treatment (36.7%). In addition, MIL-101(Fe)@silica was safe for crops and could enhance the crop fresh weight and dry weight by 18.6–19.6% and 4.8–17.7%, respectively. Therefore, MIL-101(Fe)@silica could be used as a biocompatible carrier for site-specific pesticide delivery and simultaneously as a fertilizer for crop growth, which would be a novel route for the development of a precise pesticide delivery nanoplatform.

Three‐Dimensional Visualization of Subcellular Dynamics of Cancer Cell Destruction on Therapeutic Nanodrug Treatment

Ultrastructural visualization of targeted nanoparticles against its interactions with subcellular organelles through electron microscopy and its 3D rendering is always challenging. Mechanistic and conformational understandings of specific subcellular connections of novel smart nanocarriers with various intrinsic receptors of breast cancer cells are critical for the design and delivery of novel cancer therapeutics. Toxicological effects of gold nanocages, passivated with extremophilic polysaccharide, Mauran functionalized with 4‐hydroxytamoxifen and monoclonal antibody Pr1E11 result in downright decimation of subcellular organelles in breast cancer MCF7 cells resulting in parallel type I and type II cell deaths. Herein, the deleterious repercussions of the therapeutic gold nanocages (TANs) on the subcellular organelles of MCF7 cells are studied. Confocal and transmission electron microscopic images reveal significant localization of the TANs within the mitochondria, lysosomes, and autophagosomes leading to their destruction in a span of 96 h from their incubation. The 3D electron density maps of these subcellular organelles computed using images recorded by scanning block‐face electron and transmission electron microscopes reveal a previously unknown systemic degradation process of mitochondria and the structure of autolysosome. Together, this data fortifies the benefit of subcellular cancer targeting and multiple parallel damage explained through advanced electron microscopic visualization.

Superparamagnetic iron oxide–gold nanoparticles conjugated with porous coordination cages: Towards controlled drug release for non-invasive neuroregeneration

This paper reports a smart intracellular nanocarrier for sustainable and controlled drug release in non-invasive neuroregeneration. The nanocarrier is composed by superparamagnetic iron oxide-gold (SPIO-Au) core-shell nanoparticles (NPs) conjugated with porous coordination cages (PCCs) through the thiol-containing molecules as bridges. The negatively charged PCC-2 and positively charged PCC-3 are compared for intracellular targeting. Both types result in intracellular targeting via direct penetration across cellular membranes. However, the pyrene (Py)-PEG-SH bridge enabled functionalization of SPIO-Au NPs with PCC-3 exhibits higher interaction with PC-12 neuron-like cells, compared with the rhodamine B (RhB)-PEG-SH bridge enabled case and the stand-alone SPIO-Au NPs. With neglectable toxicities to PC-12 cells, the proposed SPIO-Au-RhB(Py)-PCC-2(3) nanocarriers exhibit effective drug loading capacity of retinoic acid (RA) at 13.505 μg/mg of RA/NPs within 24 h. A controlled release of RA is achieved by using a low-intensity 525 nm LED light (100% compared to 40% for control group within 96 h).

PEGylated Nanographene Oxide in Combination with Near-Infrared Laser Irradiation as a Smart Nanocarrier in Colon Cancer Targeted Therapy.

Anti-cancer therapies that integrate smart nanomaterials are the focus of cancer research in recent years. Here, we present our results with PEGylated nanographene oxide particles (nGO-PEG) and have studied their combined effect with near-infrared (NIR) irradiation on low and high invasive colorectal carcinoma cells. The aim is to develop nGO-PEG as a smart nanocarrier for colon cancer-targeted therapy. For this purpose, nGO-PEG nanoparticles’ size, zeta potential, surface morphology, dispersion stability, aggregation, and sterility were determined and compared with pristine nGO nanoparticles (NPs). Our results show that PEGylation increased the particle sizes from 256.7 nm (pristine nGO) to 324.6 nm (nGO-PEG), the zeta potential from −32.9 to −21.6 mV, and wrinkled the surface of the nanosheets. Furthermore, nGO-PEG exhibited higher absorbance in the NIR region, as compared to unmodified nGO. PEGylated nGO demonstrated enhanced stability in aqueous solution, improved dispensability in the culture medium, containing 10% fetal bovine serum (FBS) and amended biocompatibility. A strong synergic effect of nGO-PEG activated with NIR irradiation for 5 min (1.5 W/cm−2 laser) was observed on cell growth inhibition of low invasive colon cancer cells (HT29) and their wound closure ability while the effect of NIR on cellular morphology was relatively weak. Our results show that PEGylation of nGO combined with NIR irradiation holds the potential for a biocompatible smart nanocarrier in colon cancer cells with enhanced physicochemical properties and higher biological compatibility. For that reason, further optimization of the irradiation process and detailed screening of nGO-PEG in combination with NIR and chemotherapeutics on the fate of the colon cancer cells is a prerequisite for highly efficient combined nanothermal and photothermal therapy for colon cancer.

Nanonutraceuticals: The New Frontier of Supplementary Food.

In the last few decades, the combination between nanotechnology and nutraceutics has gained the attention of several research groups. Nutraceuticals are considered as active compounds, abundant in natural products, showing beneficial effects on human health. Unfortunately, the uses, and consequently the health benefits, of many nutraceutical products are limited by their unsuitable chemico-physical features. For example, many nutraceuticals are characterized by low water solubility, low stability and high susceptibility to light and oxygen, poor absorption and potential chemical modifications after their administration. Based on the potential efficacy of nutraceuticals and on their limiting features, nanotechnology could be considered a revolutionary innovation in empowering the beneficial properties of nutraceuticals on human health, thus enhancing their efficacy in several diseases. For this reason, nanotechnology could represent a new frontier in supplementary food. In this review, the most recent nanotechnological approaches are discussed, focusing on their ability to improve the bioavailability of the most common nutraceuticals, providing an overview regarding both the advantages and the possible limitations of the use of several nanodelivery systems. In fact, although the efficacy of smart nanocarriers in improving health benefits deriving from nutraceuticals has been widely demonstrated, the conflicting opinions on the mechanism of action of some nanosystems still reduce their applicability in the therapeutic field.

A novel ‘smart’ PNIPAM-based copolymer for breast cancer targeted therapy: Synthesis, and characterization of dual pH/temperature-responsive lactoferrin-targeted PNIPAM-co-AA

Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel ‘smart’ carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel “super intelligent” lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment.

Ultrasound-Responsive Nanocarriers in Cancer Treatment: A Review.

The safe and effective delivery of anticancer agents to diseased tissues is one of the significant challenges in cancer therapy. Conventional anticancer agents are generally cytotoxins with poor pharmacokinetics and bioavailability. Nanocarriers are nanosized particles designed for the selectivity of anticancer drugs and gene transport to tumors. They are small enough to extravasate into solid tumors, where they slowly release their therapeutic load by passive leakage or biodegradation. Using smart nanocarriers, the rate of release of the entrapped therapeutic(s) can be increased, and greater exposure of the tumor cells to the therapeutics can be achieved when the nanocarriers are exposed to certain internally (enzymes, pH, and temperature) or externally (light, magnetic field, and ultrasound) applied stimuli that trigger the release of their load in a safe and controlled manner, spatially and temporally. This review gives a comprehensive overview of recent research findings on the different types of stimuli-responsive nanocarriers and their application in cancer treatment with a particular focus on ultrasound.

Graphene-based nanomaterial system: a boon in the era of smart nanocarriers

Owing to its exceptional electronic, mechanical, thermal, as well as optoelectronic characteristics, graphene—a planar sheet with one-atom thickness and made of carbon atoms closely packed in quite a honeycomb crystal lattice—has already earned special consideration. The investigated characteristics or even applications of such a two-dimensional configuration of the structure of carbon have already created novel innovative opportunities in place of all of the future devices as well as nanosystems. These graphene systems have also been recognized as a potential drug-delivery carrier intended for target specific or even controlled drug delivery, which could be designed by utilizing various internal or external stimuli. This review predominantly focuses on graphene's synthesis and derivative, design of stimuli-responsive nanosystems, and applications in various fields. It is highlighted that with remarkable progress in graphene-related research, graphene's overall execution has a long road ahead to go.

DNA-Assisted Smart Nanocarriers: Progress, Challenges, and Opportunities.

Due to powerful breakthroughs in nanotechnology, smart delivery mechanisms have rapidly emerged for use in diverse applications across biomedical research and therapeutic development. Recent efforts toward understanding stimuli-responsive strategies have led to substantial improvements in their conceptual application and in vitro efficiency. Because disease targets for therapy are often localized in specific cells, organs, or tissues, an enhanced permeability and retention (EPR)-based strategy remains inadequate for accurate drug delivery and release to target regions, resulting in an insufficient drug concentration reaching the target region and undesired side effects. To address these issues, more precise and remote-controlled stimuli-responsive systems, which recognize and react to changes in the pathophysiological microenvironment, were recently elucidated as feasible on-demand drug-delivery systems. In this Perspective, we focus on progress toward stimuli-responsive drug-delivery systems that utilize dynamic DNA molecules by exploiting DNA nanotechnology. DNA structures can be precisely reconfigured by external and internal stimuli to drive the release of a loaded drug in a target region with appropriate microenvironments. We describe the chemical, physical, and biological engineering principles and strategies for constructing DNA-assisted nanocarriers. We also provide a summary of smart nanocarrier systems, organized with respect to the structural changes in the DNA strand in the microenvironment, resulting from changes in pH and temperature and the presence of intracellular oligonucleotides. To do so, we highlight recent advances in related biomedical research and applications as well as discuss major challenges and opportunities for DNA-assisted nanocarriers to guide the development of future in vivo therapies and clinical translation strategies.

Molecular Modelling Guided Modulation of Molecular Shape and Charge for Design of Smart Self-Assembled Polymeric Drug Transporters.

Nanomedicine employs molecular materials for prevention and treatment of disease. Recently, smart nanoparticle (NP)-based drug delivery systems were developed for the advanced transport of drug molecules. Rationally engineered organic and inorganic NP platforms hold the promise of improving drug targeting, solubility, prolonged circulation, and tissue penetration. However, despite great progress in the synthesis of NP building blocks, more interdisciplinary research is needed to understand their self-assembly and optimize their performance as smart nanocarriers. Multi-scale modeling and simulations provide a valuable ally to experiment by mapping the potential energy landscape of self-assembly, translocation, and delivery of smart drug-loaded NPs. Here, we highlight key recent advances to illustrate the concepts, methods, and applications of smart polymer-based NP drug delivery. We summarize the key design principles emerging for advanced multifunctional polymer topologies, illustrating how the unusual architecture and chemistry of dendritic polymers, self-assembling polyelectrolytes and cyclic polymers can provide exceptional drug delivery platforms. We provide a roadmap outlining the opportunities and challenges for the effective use of predictive multiscale molecular modeling techniques to accelerate the development of smart polymer-based drug delivery systems.

A pH-triggered fluorescence-switchable extracellular vesicle for tracing drug release and improving drug delivery.

Extracellular vesicles have shown great potential in drug delivery for clinical applications. However, some obstacles still need to be overcome before their clinical translation, including on demand release of drugs to improve the efficacy and monitoring of the drug release process to ascertain drug dosage. Herein, a pH-triggered fluorescence-switchable extracellular vesicle as a smart nanocarrier is fabricated by loading zwitterionic fluorescent carbon dots (CDs) into macrophage cell-secreted vesicles to achieve improved drug delivery and real-time monitoring of drug release. When circulating in the blood, the zwitterionic CDs loaded in the vesicles can tightly bind the chemotherapeutic drug DOX through electrostatic interactions to avoid premature drug unload. The nanocarriers have a long blood circulation half-life of 15.12 h and a high tumor accumulation of 9.88% ID/g. Meanwhile, the fluorescence of the CDs is in the "off" state due to the fluorescence inner filter effect (IFE) between the DOX and the CDs. When the nanocarriers enter the tumor cells, the low pH of the lysosome leads to charge reversal of the CDs. DOX can be quickly released through electrostatic repulsion and the fluorescence of the CDs turns "on" after the release of the drugs, thus enabling an improved drug delivery and real-time tracking of the drug release process.

Multifunctional nanoplatforms co-delivering combinatorial dual-drug for eliminating cancer multidrug resistance.

Clinically, the primary cause of chemotherapy failure belongs to the occurrence of cancer multidrug resistance (MDR), which directly leads to the recurrence and metastasis of cancer along with high mortality. More and more attention has been paid to multifunctional nanoplatform-based dual-therapeutic combination to eliminate resistant cancers. In addition to helping both cargoes improve hydrophobicity and pharmacokinetic properties, increase bioavailability, release on demand and enhance therapeutic efficacy with low toxic effects, these smart co-delivery nanocarriers can even overcome drug resistance. Here, this review will not only present different types of co-delivery nanocarriers, but also summarize targeted and stimuli-responsive combination nanomedicines. Furthermore, we will focus on the recent progress in the co-delivery of dual-drug using such intelligent nanocarriers for surmounting cancer MDR. Whereas it remains to be seriously considered that there are some knotty issues in the fight against MDR of cancers via using co-delivery nanoplatforms, including limited intratumoral retention, the possible changes of combinatorial ratio under complex biological environments, drug release sequence from the nanocarriers, and subsequent free-drug resistance after detachment from the nanocarriers. It is hoped that, with the advantage of continuously developing nanomaterials, two personalized therapeutic agents in combination can be better exploited to achieve the goal of cooperatively combating cancer MDR, thus advancing the time to clinical transformation.