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Highlights 1. DDS based on cholesterol, ketoester, and NIPAAm, designed for the delivery of DOX. 2. The ketoester and arrangement of blocks are crucial for anticancer activity. 3. PNPs not only act as transporters but also sensitize the cell to DOX. 4. High cytotoxicity of DOX-loaded PNPs was achieved despite low doses of the drug. 5. PNPs have the proper size, shape, and ζ potential for efficient drug delivery.

Bacterial membrane vesicles (BMVs) are known to be critical communication tools in several pathophysiological processes between bacteria and host cells. Given this situation, BMVs for transporting and delivering exogenous therapeutic cargoes have been inspiring as promising platforms for developing smart drug delivery systems (SDDSs). In the first section of this review paper, starting with an introduction to pharmaceutical technology and nanotechnology, we delve into the design and classification of SDDSs. We discuss the characteristics of BMVs including their size, shape, charge, effective production and purification techniques, and the different methods used for cargo loading and drug encapsulation. We also shed light on the drug release mechanism, the design of BMVs as smart carriers, and recent remarkable findings on the potential of BMVs for anticancer and antimicrobial therapy. Furthermore, this review covers the safety of BMVs and the challenges that need to be overcome for clinical use. Finally, we discuss the recent advancements and prospects for BMVs as SDDSs and highlight their potential in revolutionizing the fields of nanomedicine and drug delivery. In conclusion, this review paper aims to provide a comprehensive overview of the state-of-the-art field of BMVs as SDDSs, encompassing their design, composition, fabrication, purification, and characterization, as well as the various strategies used for targeted delivery. Considering this information, the aim of this review is to provide researchers in the field with a comprehensive understanding of the current state of BMVs as SDDSs, enabling them to identify critical gaps and formulate new hypotheses to accelerate the progress of the field. [ABSTRACT FROM AUTHOR]

The presented research concerns the preparation of polymer nanoparticles (PNPs) for the delivery of doxorubicin. Several block and statistical copolymers, composed of ketoester derivative, N-isopropylacrylamide, and cholesterol, were synthesized. In the nanoprecipitation process, doxorubicin (DOX) molecules were kept in spatial polymeric systems. DOX-loaded PNPs show high efficacy against estrogen-dependent MCF-7 breast cancer cell lines despite low doses of DOX applied and good compatibility with normal cells. Research confirms the effect of PNPs on the degradation of the biological membrane, and the accumulation of reactive oxygen species (ROS), and the ability to cell cycle arrest are strictly linked to cell death. Highlights: DDS based on cholesterol, ketoester, and NIPAAm, designed for the delivery of DOX. The ketoester and arrangement of blocks are crucial for anticancer activity. PNPs not only act as transporters but also sensitize the cell to DOX. High cytotoxicity of DOX-loaded PNPs was achieved despite low doses of the drug. PNPs have the proper size, shape, and ζ potential for efficient drug delivery. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems' responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy. [ABSTRACT FROM AUTHOR]

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] Most nanomedicines with suitable sizes (normally 100–200 nm) exhibit favorable accumulation in the periphery of tumors but hardly penetrate into deep tumors. Effective penetration of nanomedicines requires smaller sizes (less than 30 nm) to overcome the elevated tumor interstitial fluid pressure. Moreover, integrating an efficient diagnostic agent in the nanomedicines is in high demand for precision theranostics of tumors. To this end, a near-infrared light (NIR) −triggered size-shrinkable micelle system (Fe 3 O 4 @AuNFs/DOX-M) coloaded antitumor drug doxorubicin (DOX) and biomodal imaging agent magnetic gold nanoflower (Fe 3 O 4 @AuNFs) was developed to achieve efficient theranostic of tumors. Upon the accumulation of Fe 3 O 4 @AuNFs/DOX-M in the tumor periphery, a NIR laser was irradiated near the tumor sites, and the loaded Fe 3 O 4 @Au NFs could convert the light energy to heat, which triggered the cleavage of DOX-M to the ultra-small micelles (∼5 nm), thus realizing the deep penetration of micelles and on-demand drug release. Moreover, Fe 3 O 4 @AuNFs in the micelles could also be used as CT/MRI dual-modal contrast agent to "visualize" the tumor. Up to 92.6 % of tumor inhibition was achieved for the developed Fe 3 O 4 @AuNFs/DOX-M under NIR irradiation. This versatile micelle system provided a promising drug carrier platform realizing efficient tumor dual-modal diagnosis and photothermal-chemotherapy integration. [ABSTRACT FROM AUTHOR]

Bacterial membrane vesicles (BMVs) are known to be critical communication tools in several pathophysiological processes between bacteria and host cells. Given this situation, BMVs for transporting and delivering exogenous therapeutic cargoes have been inspiring as promising platforms for developing smart drug delivery systems (SDDSs). In the first section of this review paper, starting with an introduction to pharmaceutical technology and nanotechnology, we delve into the design and classification of SDDSs. We discuss the characteristics of BMVs including their size, shape, charge, effective production and purification techniques, and the different methods used for cargo loading and drug encapsulation. We also shed light on the drug release mechanism, the design of BMVs as smart carriers, and recent remarkable findings on the potential of BMVs for anticancer and antimicrobial therapy. Furthermore, this review covers the safety of BMVs and the challenges that need to be overcome for clinical use. Finally, we discuss the recent advancements and prospects for BMVs as SDDSs and highlight their potential in revolutionizing the fields of nanomedicine and drug delivery. In conclusion, this review paper aims to provide a comprehensive overview of the state-of-the-art field of BMVs as SDDSs, encompassing their design, composition, fabrication, purification, and characterization, as well as the various strategies used for targeted delivery. Considering this information, the aim of this review is to provide researchers in the field with a comprehensive understanding of the current state of BMVs as SDDSs, enabling them to identify critical gaps and formulate new hypotheses to accelerate the progress of the field.

Doxorubicin (DOX) is one of the most commonly used drugs in liver cancer. Unfortunately, the traditional chemotherapy with DOX presents many limitations, such as a systematic release of DOX, affecting both tumor tissue and healthy tissue, leading to the apparition of many side effects, multidrug resistance (MDR), and poor water solubility. Furthermore, drug delivery systems’ responsiveness has been intensively studied according to the influence of different internal and external stimuli on the efficiency of therapeutic drugs. In this review, we discuss both internal stimuli-responsive drug-delivery systems, such as redox, pH and temperature variation, and external stimuli-responsive drug-delivery systems, such as the application of magnetic, photo-thermal, and electrical stimuli, for the controlled release of Doxorubicin in liver cancer therapy, along with the future perspectives of these smart delivery systems in liver cancer therapy.

In the present research, a new nanocarrier for targeted drug delivery to tumor cells based on nanocrystalline cellulose (NCC) was synthesized. For this purpose, firstly, the NCC was prepared from microcrystalline cellulose by acidic hydrolysis and then it was modified by aminopropyl trimethoxy silane (APTMS) as a linker. The L‐cysteine was oxidized to form a disulfide bond and conjugated to modify NCC. Afterwards, the disulfide NCC was reacted with carboxymethyl‐β‐cyclodextrin (CM‐β‐CD) and finally, folic acid (FA) as a targeting agent was embedded into the CD cavity via host‐guest interactions for the synthesis of the NCC targeted nanocarrier. Doxorubicin (DOX) was loaded into nanocarrier spheres and the total release of the NCC targeted nanocarrier is about 71% at pH = 5, and about 48% at pH = 7.4 in 45 hours at 37 °C. In the presence of 10 mM DTT, most of the disulfide bonds are broken and the complex nanocarrier is destroyed, thus drug release increases and reaches 83%. The effect of the drugloaded nanocarrier was investigated on breast cancer cells (MCF7 cells). Characterization was performed using Fourier‐transform infrared spectroscopy (FT‐IR), Thermogravimetric analysis (TGA), Proton nuclear magnetic resonance (1H‐NMR), Scanning electron microscope (SEM), Energy dispersive X‐ray (EDX), and Ultraviolet‐visible spectrophotometry (UV‐Vis) analyses. [ABSTRACT FROM AUTHOR]

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG–PDH–mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120–190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

Reactive oxygen species (ROS)-sensitive drug delivery systems (DDS) specifically responding to altered levels of ROS in the pathological microenvironment have emerged as an effective means to enhance the pharmaceutical efficacy of conventional nanomedicines, while simultaneously reducing side effects. In particular, the use of the biocompatible, biodegradable, and non-toxic ROS-responsive thioketal (TK) functional group in the design of smart DDS has grown exponentially in recent years. In the design of TK-based DDS, different technological uses of TK have been proposed to overcome the major limitations of conventional DDS counterparts including uncontrolled drug release and off-target effects. This review will focus on the different technological uses of TK-based biomaterials in smart nanomedicines by using it as a linker to connect a drug on the surface of nanoparticles, form prodrugs, as a core component of the DDS to directly control its structure, to control the opening of drug-releasing gates or to change the conformation of the nano-systems. A comprehensive view of the various uses of TK may allow researchers to exploit this reactive linker more consciously while designing nanomedicines to be more effective with improved disease-targeting ability, providing novel therapeutic opportunities in the treatment of many diseases.

• Revolutionizing drug delivery for precision therapy. • Bioresponsive DDSs enhance cancer treatment safety. • Diabetes management transformed by smart MN patches. • Combining therapy and diagnosis for personalized care. In this review, we highlight the potential of stimuli-responsive drug delivery systems (DDSs) to revolutionize healthcare. Through examining pH, temperature, enzyme, and redox responsiveness, the presented case studies highlight the precision and enhanced therapeutic outcomes achievable with these innovative systems. Challenges, such as complex design and bio-based material optimization, underscore the complete journey from bench to bedside. Clinical strides in magnetically and temperature-responsive systems hint at a promising future for healthcare. However, overcoming issues of stability, durability, penetration depth, sensitivity, and active targeting is crucial. The future envisions theranostic systems, amalgamating targeted therapy and diagnosis, for personalized healthcare. Bio-based materials emerge as pivotal, offering a nuanced approach to complex diseases, such as cancer and diabetes, reshaping the healthcare landscape. [ABSTRACT FROM AUTHOR]

The heme protein cytochrome c (Cyt c) plays pivotal roles in cellular life and death processes. In the respiratory chain of mitochondria, it serves as an electron transfer protein, contributing to the proliferation of healthy cells. In the cell cytoplasm, it activates intrinsic apoptosis to terminate damaged cells. Insight into these mechanisms and the associated physicochemical properties and biomolecular interactions of Cyt c informs on the anticancer therapeutic potential of the protein, especially in its ability to subvert the current limitations of small molecule-based chemotherapy. In this review, we explore the development of Cyt c as an anticancer drug by identifying cancer types that would be receptive to the cytotoxicity of the protein and factors that can be finetuned to enhance its apoptotic potency. To this end, some information is obtained by characterizing known drugs that operate, in part, by triggering Cyt c induced apoptosis. The application of different smart drug delivery systems is surveyed to highlight important features for maintaining Cyt c stability and activity and improving its specificity for cancer cells and high drug payload release while recognizing the continuing limitations. This work serves to elucidate on the optimization of the strategies to translate Cyt c to the clinical market.

Chitosan is a natural polysaccharide that is considered to be biocompatible, biodegradable and non-toxic. The polymer has been used in drug delivery applications for its positive charge, which allows for adhesion with and recognition of biological tissues via non-covalent interactions. In recent times, chitosan has been used for the preparation of graft copolymers with thermoresponsive polymers such as poly-N-vinylcaprolactam (PNVCL) and poly-N-isopropylamide (PNIPAM), allowing the combination of the biodegradability of the natural polymer with the ability to respond to changes in temperature. Due to the growing interest in the utilization of thermoresponsive polymers in the biological context, it is necessary to increase the knowledge of the key principles of thermoresponsivity in order to obtain comparable results between different studies or applications. In the present review, we provide an overview of the basic principles of thermoresponsivity, as well as a description of the main polysaccharides and thermoresponsive materials, with a special focus on chitosan and poly-N-Vinyl caprolactam (PNVCL) and their biomedical applications.

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli.

Progress in recent years in the field of stimuli-responsive polymers, whose properties change depending on the intensity of a signal, permitted an increase in smart drug delivery systems (SDDS). SDDS have attracted the attention of the scientific community because they can help meet two current challenges of the pharmaceutical industry: targeted drug delivery and personalized medicine. Controlled release of the active ingredient can be achieved through various stimuli, among which are temperature, pH, redox potential or even enzymes. SDDS, hitherto explored mainly in oncology, are now developed in the fields of dermatology and cosmetics. They are mostly hydrogels or nanosystems, and the most-used stimuli are pH and temperature. This review offers an overview of polymer-based SDDS developed to trigger the release of active ingredients intended to treat skin conditions or pathologies. The methods used to attest to stimuli-responsiveness in vitro, ex vivo and in vivo are discussed.

Introduction: Stimuli-responsive nanocarriers offer unique advantages over the traditional drug delivery systems (DDSs) in terms of targeted drug delivery and on-demand release of cargo drug molecules. Of these, chitosan (CS)-based DDSs offer several advantages such as high compatibility with biological settings. Methods: In this study, we surveyed the literature in terms of the stimuli-responsive nanocarriers and discussed the most recent advancements in terms of CS-based nanosystems and their applications in cancer therapy and diagnosis. Results: These advanced DDSs are able to release the entrapped drugs in response to a specific endogenous stimulus (e.g., pH, glutathione concentration or certain enzymes) or exogenous stimulus (e.g., temperature, light, ultrasound, and magnetic field) at the desired time and target site. Dual-responsive nanocarriers by the combination of different stimuli have also been developed as efficient and improved DDSs. Among the stimuli-responsive nanocarriers, CS-based DDSs offer several advantages, including biocompatibility and biodegradability, antibacterial activity, ease of modification and functionalization, and non-immunogenicity. They are as one of the most ideal smart multifunction DDSs. Conclusion: The CS-based stimuli-responsive multifunctional nanosystems (NSs) offer unique potential for the targeted delivery of anticancer agents and provide great potential for on-demand and controlled-release of anticancer agents in response to diverse external/internal stimuli. [ABSTRACT FROM AUTHOR]

Smart drug delivery systems with on-demand drug release capability are rather attractive to realize highly specific cancer treatment. Herein, a novel light-responsive drug delivery platform based on photosensitizer chlorin e6 (Ce6) doped mesoporous silica nanorods (CMSNRs) is developed for on-demand light-triggered drug release. In this design, CMSNRs are coated with bovine serum albumin (BSA) via a singlet oxygen (SO)-sensitive bis-(alkylthio)alkene (BATA) linker, and then modified with polyethylene glycol (PEG). The obtained CMSNR-BATA-BSA-PEG, namely CMSNR-B-PEG, could act as a drug delivery carrier to load with either small drug molecules such as doxorubicin (DOX), or larger macromolecules such as cis-Pt (IV) pre-drug conjugated third generation dendrimer (G3-Pt), both of which are sealed inside the mesoporous structure of nanorods by BSA coating. Upon 660 nm light irradiation with a rather low power density, CMSNRs with intrinsic Ce6 doping would generate SO to cleave BATA linker, inducing detachment of BSA-PEG from the nanorod surface and thus triggering release of loaded DOX or G3-Pt. As evidenced by both in vitro and in vivo experiments, such CMSNR-B-PEG with either DOX or G3-Pt loading offers remarkable synergistic therapeutic effects in cancer treatment, owing to the on-demand release of therapeutics specifically in the tumor under light irradiation. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is the most common form of the chronic inflammatory autoimmune disease characterized by chronic synovitis, synovial proliferation, and cellular infiltration. Further, it leads to bone erosion, destruction of articular cartilage, intense joint pain, swelling, and a high rate of disability, causing an immense load on human health. If the disease is identified early on, and the patient has continuous and timely treatment, many patients can achieve remission. Although research in RA has made considerable progress, conventional therapies are still the most popular treatment options for most people with RA. But, conventional therapies are hampered by various drawbacks, including higher doses, low solubility and permeability, poor bioavailability, a high level of first-pass metabolism, adaptive treatment tolerance (ATT), and long-term drug use. These drawbacks can result in severe side effects and drug toxicity in patients. Advances in polymer science and the application of nanotechnology in drug delivery systems have provided new possibilities in the treatment of RA by developing new-generation smart drug delivery systems (SDDSs). The shortcomings of non-specific drug distribution and uncontrollable drug release by traditional delivery systems have motivated the creation of next-generation SDDSs. These new smart drug delivery treatment methods have significantly changed the course of RA. Such systems can improve drug delivery by virtue of their multi-functionality and targeting capabilities. The ultimate objective of next-generation SDDSs is to deliver medication at the optimal time with precise dosage and efficiency and specificity to the targeted site (such as cells, tissues, and organs), which can aid patients to adhere better to their therapy. This review highlights and discusses the various next-generation SDDSs along with the conventional treatment options available for RA management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The study presents the synthesis of original cholesterol-terminated copolymers comprising acetylacetone-based (AcacI) and N -isopropylacrylamide (NIPAAm) units with a varied arrangement (block and random copolymers). The nanoprecipitation method was used to form empty and doxorubicin-loaded polymeric nanoparticles (PNPs) from these copolymers, which were further studied in terms of their physicochemical and biological properties. Unexpectedly, it was revealed that even empty PNPs are effective against breast cancer cells, specifically towards estrogen-dependent MCF-7 cell line. The anti-cancer efficacy was further improved when a low dose of doxorubicin was introduced to the tested systems. It was shown that the proposed carriers modulate doxorubicin (DOX) compatibility with representatives of normal cells, including immune cells, cardiomyocyte cells, and fibroblasts, and reduce side effects associated with standard chemotherapy. The use of these carriers might be a strategy leading to enhancement of DOX activity in cancer cells which develop resistance through decreased drug penetration or drug efflux. [Display omitted] • Polymeric nanoparticles (PNP) based on cholesterol-terminated copolymers were prepared for the delivery of doxorubicin (DOX). • DOX-loaded PNPs are highly effective against MCF-7 estrogen-dependent breast cancer cells. • High cytotoxicity of DOX-loaded PNPs has been achieved despite low doses of drug encapsulated. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of two original dithiocarbonate RAFT chain-transfer agents based on diacylglycerols. • Well-defined diacylglycerol end-functionalized poly(N-isopropylacrylamide)s and poly(N-vinylcaprolacam)s prepared by RAFT polymerization. • The amphiphilic nature of polymers enables the formation of solid lipid-polymer nanoparticles. • Non-hemolytic and non-toxic properties confirmed by biological tests. Well-defined diacylglycerol end-functionalized poly(N -isopropylacrylamide)s (PNIPAAm) and poly(N -vinylcaprolacam)s (PNVCL) with number-average molar masses (M n) ranging from 1260 to 19 350 g·mol−1 were synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization from xanthate-functionalized diacylglycerols (DAGs) containing palmitic or oleic acid moieties. The formation of polymeric nanoparticles (PNPs) and their thermoresponsive properties was studied. Phase separation temperature dependence on polymer molar mass and hydrophilic/hydrophobic ratio was investigated in phosphate buffer saline (PBS). Biological tests showed that the particles are non-hemolytic and highly compatible with representatives of immune cells - monocyte/macrophage THP-1 cells. The biocompatibility combined with the potential ability to modulate the cell membrane environment make the proposed polymers a promising foundation for drug carriers. [ABSTRACT FROM AUTHOR]

Abstract: Polysaccharides are gaining increasing attention as components of stimuli-responsive drug delivery systems, particularly since they can be obtained in a well characterized and reproducible way from the natural sources. Ionic polysaccharides can be readily crosslinked to render hydrogel networks sensitive to a variety of internal and external variables, and thus suitable for switching drug release on–off through diverse mechanisms. Hybrids, composites and grafted polymers can reinforce the responsiveness and widen the range of stimuli to which polysaccharide-based systems can respond. This review analyzes the state of the art of crosslinked ionic polysaccharides as components of delivery systems that can regulate drug release as a function of changes in pH, ion nature and concentration, electric and magnetic field intensity, light wavelength, temperature, redox potential, and certain molecules (enzymes, illness markers, and so on). Examples of specific applications are provided. The information compiled demonstrates that crosslinked networks of ionic polysaccharides are suitable building blocks for developing advanced externally activated and feed-back modulated drug delivery systems. [Copyright &y& Elsevier]

Smart Drug Delivery Systems (SDDS) have emerged as panacea for many clinically useful drugs weighed down with toxicity. The discovery of Amphotericin B as a liposome has raised hopes and directed mammoth efforts in SDDS. The concept of manipulation of toxicity has given rise to additional significant approaches like targeting and use of physico-chemical approaches. Currently the spectrum of SDDS comprises of targeting liposomes, drug loaded biodegradable microspheres, stimuli responsive drug polymer conjugates, smart hydrogels, polymeric micellar particles, intelligent lipoprotein carriers, and nano carriers. There is a wealth of knowledge accumulated worldwide in the area of SDDS, which can be extremely beneficial to industry as well as practitioners of health care. In this article an overview of developments are reviewed. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS)-sensitive drug delivery systems (DDS) specifically responding to altered levels of ROS in the pathological microenvironment have emerged as an effective means to enhance the pharmaceutical efficacy of conventional nanomedicines, while simultaneously reducing side effects. In particular, the use of the biocompatible, biodegradable, and non-toxic ROS-responsive thioketal (TK) functional group in the design of smart DDS has grown exponentially in recent years. In the design of TK-based DDS, different technological uses of TK have been proposed to overcome the major limitations of conventional DDS counterparts including uncontrolled drug release and off-target effects. This review will focus on the different technological uses of TK-based biomaterials in smart nanomedicines by using it as a linker to connect a drug on the surface of nanoparticles, form prodrugs, as a core component of the DDS to directly control its structure, to control the opening of drug-releasing gates or to change the conformation of the nano-systems. A comprehensive view of the various uses of TK may allow researchers to exploit this reactive linker more consciously while designing nanomedicines to be more effective with improved disease-targeting ability, providing novel therapeutic opportunities in the treatment of many diseases. [ABSTRACT FROM AUTHOR]

The heme protein cytochrome c (Cyt c) plays pivotal roles in cellular life and death processes. In the respiratory chain of mitochondria, it serves as an electron transfer protein, contributing to the proliferation of healthy cells. In the cell cytoplasm, it activates intrinsic apoptosis to terminate damaged cells. Insight into these mechanisms and the associated physicochemical properties and biomolecular interactions of Cyt c informs on the anticancer therapeutic potential of the protein, especially in its ability to subvert the current limitations of small molecule-based chemotherapy. In this review, we explore the development of Cyt c as an anticancer drug by identifying cancer types that would be receptive to the cytotoxicity of the protein and factors that can be finetuned to enhance its apoptotic potency. To this end, some information is obtained by characterizing known drugs that operate, in part, by triggering Cyt c induced apoptosis. The application of different smart drug delivery systems is surveyed to highlight important features for maintaining Cyt c stability and activity and improving its specificity for cancer cells and high drug payload release while recognizing the continuing limitations. This work serves to elucidate on the optimization of the strategies to translate Cyt c to the clinical market. [ABSTRACT FROM AUTHOR]

Chitosan is a natural polysaccharide that is considered to be biocompatible, biodegradable and non-toxic. The polymer has been used in drug delivery applications for its positive charge, which allows for adhesion with and recognition of biological tissues via non-covalent interactions. In recent times, chitosan has been used for the preparation of graft copolymers with thermoresponsive polymers such as poly-N-vinylcaprolactam (PNVCL) and poly-N-isopropylamide (PNIPAM), allowing the combination of the biodegradability of the natural polymer with the ability to respond to changes in temperature. Due to the growing interest in the utilization of thermoresponsive polymers in the biological context, it is necessary to increase the knowledge of the key principles of thermoresponsivity in order to obtain comparable results between different studies or applications. In the present review, we provide an overview of the basic principles of thermoresponsivity, as well as a description of the main polysaccharides and thermoresponsive materials, with a special focus on chitosan and poly-N-Vinyl caprolactam (PNVCL) and their biomedical applications. [ABSTRACT FROM AUTHOR]

Progress in recent years in the field of stimuli-responsive polymers, whose properties change depending on the intensity of a signal, permitted an increase in smart drug delivery systems (SDDS). SDDS have attracted the attention of the scientific community because they can help meet two current challenges of the pharmaceutical industry: targeted drug delivery and personalized medicine. Controlled release of the active ingredient can be achieved through various stimuli, among which are temperature, pH, redox potential or even enzymes. SDDS, hitherto explored mainly in oncology, are now developed in the fields of dermatology and cosmetics. They are mostly hydrogels or nanosystems, and the most-used stimuli are pH and temperature. This review offers an overview of polymer-based SDDS developed to trigger the release of active ingredients intended to treat skin conditions or pathologies. The methods used to attest to stimuli-responsiveness in vitro, ex vivo and in vivo are discussed. [ABSTRACT FROM AUTHOR]

The development of smart size-tunable drug delivery nanoplatform enables the solving of the paradox of inconsistent size-dependence of high tumor accumulation and deep penetration during its delivery process, thus achieving superior cancer treatment efficacy. Herein, we report a size-shrinkable nanomicelle complex system with an initial size of 101 nm enabling effective retention around the tumor periphery and could destruct to ultrasmall nanomicelles triggered by a near-infrared (NIR) laser to realize the deep tumor penetration. The nanomicelle system is consisted of an upper critical solution temperature (UCST)-type block copolymer poly(acrylamide-acrylonitrile)-polyethylene glycol-lipoic acid (p(AAm- co -AN)- g -PEG-LA) encapsulating gold nanorods. Upon the irradiation of the NIR laser at the tumor site, gold nanorods could convert the light energy to heat energy, realizing the photothermal ablation of superficial tumor tissue. Concurrently, the large micelles split into a cascade of ultrasmall micelles (∼7 nm), which could easily penetrate into the deep site of the tumor and achieve the in situ "on-demand" release of the loaded drug to exert superior combined photothermal-chemotherapy of cancer. By the precise manipulation of laser, the micelle complex system realized the hierarchical killing from the superficial-to-deep tumor and achieved almost complete tumor growth inhibition on the established xenograft liver tumor mice model.

Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications., Competing Interests: Notes The authors declare no competing financial interest.

Owing to their dendritic architectural features, branched copolymers have been investigated as drug delivery systems. In this paper, an enzyme- and pH-sensitive branched poly[N-(2-hydroxypropyl)methacrylamide] (polyHPMA) copolymer-doxorubicin (DOX) conjugate possessing a molecular weight (MW) of 165 kDa was designed and prepared via a one-pot reaction and drug conjugation. This conjugate's potential as a smart, nanoscale drug delivery system (NDDS) is also investigated. The branched conjugate was capable of forming nanoparticles with a negative surface charge. The self-assembled nanoparticles were 102 nm in diameter as measured by dynamic light scattering (DLS) and 95 nm in diameter via scanning electron microscopy, respectively. The nanoparticles were degraded to low-MW products (23∼25 kDa) in the presence of papain or cathepsin B, and the degradation was monitored via DLS and size-exclusion chromatography. The nanoparticles demonstrated pH-sensitive drug release, as the DOX was attached to the branched copolymer via a hydrazone bond. In comparison to free DOX, the conjugate-based nanoparticles exhibited greater accumulation in breast tumors, resulting in enhanced antitumor therapeutic indexes. Furthermore, widespread dissemination of the conjugate among breast tumor cells was confirmed by immunohistochemical assay. Finally, no obvious systemic toxicities were observed in vivo in normal mice. Thus, the branched HPMA copolymer-DOX conjugate may be employed as a safe and efficient pH- and enzyme-responsive NDDS for cancer therapy.