Insights on the Dynamic Innovative Tumor Targeted-Nanoparticles-Based Drug Delivery Systems Activation Techniques.

Open AccessCCS ChemistryRESEARCH ARTICLE29 Mar 2022Temperature and Tumor Microenvironment Dual Responsive Mesoporous Magnetic Nanospheres for Magnetothermal Effect-Induced Cancer Theranostics Zhiyi Wang†, Shuren Wang†, Xiaoguang Zhang, Ziyuan Li, Zeeshan Ali, Donghai Yu, Hongtao Zhang, Fugeng Sheng, Song Gao and Yanglong Hou Zhiyi Wang† Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 Institute of Spin-X Science and Technology, South China University of Technology, Guangzhou 510641 , Shuren Wang† Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Xiaoguang Zhang Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Ziyuan Li Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Zeeshan Ali School of Chemical and Materials Engineering, National University of Sciences & Technology, Islamabad 44000 , Donghai Yu Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Hongtao Zhang Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071 , Fugeng Sheng Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071 , Song Gao Institute of Spin-X Science and Technology, South China University of Technology, Guangzhou 510641 and Yanglong Hou *Corresponding author: E-mail Address: [email protected] Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 https://doi.org/10.31635/ccschem.022.202201805 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The development of smart drug delivery systems (SDDSs) based on engineered nanomaterials is important for clinical applications. Nevertheless, controllable administration of chemotherapeutic drugs for deep tumors and the avoidance of side effects caused by off-targeting during delivery remain a great challenge. Herein, a stimulus-responsive system of mesoporous nanospheres (composed of [email protected]2[email protected]2) with good magnetothermal effect is introduced into the tumor microenvironment. This system plays an important role in image-guided controllable targeted drug delivery that is independent of tumor depth. Aggregation-induced emission luminogen-based fluorescence imaging and magnetic resonance imaging were utilized since these techniques visualize the delivery process in real time. In addition, the degraded nanocarriers showed high catalytic activity for Fenton and Fenton-like reactions, upregulating the level of hydroxyl radicals (•OH) in cancer cells to realize chemodynamic therapy. The induced •OH led to the overexpression of pho-STAT3, activating the STAT3 signaling pathway, eventually inducing cancer cell apoptosis. Through metabolic monitoring, this SDDS is removed from the body after its degradation in vivo. The synergistically enhanced therapeutic effect was obtained in the chemo-chemodynamic therapy of 4T1 tumor-bearing mice, offering a platform for efficient cancer therapy with a personalized theranostic strategy. Download figure Download PowerPoint Introduction Pharmacokinetic obstacles have been a major underlying reason for the failure to treat solid tumors, according to cumulative scientific evidence in recent decades.1 It has been generally accepted that pharmacokinetic disorders can be divided into three sublevels: (1) systemic pharmacokinetic disorders, (2) intratumoral pharmacokinetic disorders, and (3) cellular pharmacokinetic disorders. As the intratumoral pharmacokinetics disorders represent a core obstacle for drug delivery,2 to achieve the optimal anticancer effect, anticancer drugs need to be delivered not only to every single micromilieu of solid tumor microregions, but also at cytotoxic concentrations. Tumor cells placed in anticancer drugs with subcytotoxic concentrations of anticancer drug have met with tumor resistance, not just treatment failure.3,4 In other words, the challenge of drug delivery within the solid tumor micromilieu is mainly attributed to the complicated biology of the intratumoral microenvironment.5 Hence, to resolve this issue, a series of stimulus-responsive nanocarrier-mediated drug delivery systems (DDSs), including endogenous stimuli-responsive nanomaterials (NMs) (such as pH, enzyme, and redox),6 exogenous stimuli-responsive NMs,7–10 and multistimuli -esponsive NMs (such as temperature, light, ultrasound, and magnetic field),11,12 have been developed over the past few decades. These nanocarrier-mediated SDDSs have shown several obvious advantages, including greater accumulation of drugs at the diseased or pathological sites, enhanced cellular uptake, prolonged circulation time, high systemic stability, and reduction of toxic effects of the encapsulated compounds on healthy tissues.13–15 All these aspects of DDSs greatly promote the controllability and efficiency of drug delivery for cancer therapy. Nevertheless, the development of DDSs is still restricted by the problems with controllable drug delivery in the deepest tissues and off-targeting in the process of drug delivery. In addition to the drug delivery efficiency mentioned above, the pharmacological effect of drugs will also affect the therapeutic effect in the treatment of major diseases. Hence, some catalytic reactions such as Fenton and Fenton-like reactions have been employed to improve that efficacy. This strategy is considered as the classical chemical reaction in the field of environmental science,16 while the core reaction is to employ Fe2+, Cu+, and other variable valence transition metal ions to catalyze hydrogen peroxide (H2O2) to produce hydroxyl radical (•OH) with strong oxidation under the acidic conditions of the tumor microenvironment (TME).17,18 This strategy, defined as chemodynamic therapy (CDT), is a new treatment strategy with great potential for clinical transformation and development.17 At present, CDT has become a leading subject of cutting-edge research for the interdisciplinary scientific community while the distinctive characteristics of Fenton-like chemistry are the core in the field of chemical biology.19 Considering the fact that the catalyst plays a decisive role in kinetics and efficiency of Fenton and Fenton-like reactions, the selective design of CDT nanocatalysts will prove to be of great significance in improving its therapeutic effect on cancer, and will be given priority to combine with other treatments to achieve a synergistic enhancement effect. As a proof of concept, we designed a special kind of SDDS with degradable mesoporous magnetic nanospheres (NSs) for personalized imaging-guided cancer therapy (Figure 1). Primarily, [email protected]2[email protected]2 NSs with rich mesoporous structures were designed and synthesized as nanocarriers. Then the doxorubicin (DOX) and synthesized aggregation-induced emission luminogen (AIEgen) of TPE-based schiff base (TPE-SB) were filled into the mesopores of the [email protected]2[email protected]2 NSs and encapsulated by phase-change materials (PCMs) (i.e., lauric acid/stearic acid (LA/SA)) to avoid off-targeting during delivery. The combination of TPE-SB-based fluorescence imaging and magnetic resonance imaging (MRI) was used to visualizethe delivery process of SDDSs. Afterward, nucleolin-specific aptamer AS1411 was used to improve the targeting of 4T1 cancer through acylation reaction on the surface of SDDSs as depicted in Figure 1a. These SDDSs showed high catalytic activity for Fenton and Fenton-like reactions, which could upregulate the level of •OH in 4T1 cells, and led to the controlled overexpression of pho-STAT3 to activate the STAT3 signaling pathway so as to induce apoptosis of cancer cells. Hence, such nanocarriers are strongly reccomneded for use in CDT (Figure 1b). Controlled release of DOX was achieved for the SDDSs in mild alternating magnetic fields (AMF). In addition, synergistic enhancement of the cancer therapeutic effect was finally achieved by chemo-chemodynamic therapy in 4T1 tumor-bearing mice. In summary, our study provides a platform for personalized therapy of cancer with smartly engineered design, high-efficiency, targeted and controlled drug delivery, and enhanced therapeutic effect. Figure 1 | (a) Fabrication of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. (b) Schematic representation of magnetothermal effect-induced smart drug delivery system for precision tumor theranostics. Download figure Download PowerPoint Experimental Methods Synthesis of TPE-SB TPE-SB was synthesized by the aldimine condensation between 1,2,4,5-Benzenetetramine and 4-(1,2,2-triphenylvinyl)benzaldehyde (TPE-CHO). First, the hydrochloric acid in amine hydrochloride (1,2,4,5-Benzenetetramine tetrahydrochloride) was removed by extraction operation under alkaline condition; then, the above obtained 1,2,4,5-Benzenetetramine and TPE-CHO were mixed in chloroform solvent for 12 h. Finally the reaction product TPE-SB was isolated and purified by recrystallization. Synthesis of [email protected]2C nanoparticles [email protected]2C nanoparticles (NPs) were synthesized by a thermal decomposition method in oil phase. Typically, copper(II) acetylacetonate (1 mmol), 1-octadecene (ODE) (15 mL), OAm (5 mL) and NH4Br (0.1 mmol) were mixed under a gentle N2 flow for 10 min in a four-necked flask. Then the solution was heated to 120 °C for 30 min to remove the organic impurities. Fe(CO)5 (5 mmol) was injected into the reaction system when the temperature reached 180 °C for 10 min, and the system was raised up to 265 °C for another 30 min. After the system cooled down to room temperature, 27 mL of acetone was added to the system. After centrifugation, the product was washed by ethanol and hexane. Finally, the [email protected]2C NPs were dispersed in hexane. Synthesis of [email protected]2[email protected]2 NSs [email protected]2[email protected]2 NSs were synthesized by coating mesoporous silicon on the surface of [email protected]2C NPs. Typically, [email protected]2C NPs (20 mg NPs in 1 mL hexane) and triethylamine (2 mmol) were dissolved in a mixed solution of cetyltrimethylammonium chloride (CTAC) solution (25 wt %, 24 mL) and deionized water (36 mL). Then the resulting solution was heated to 60 °C for 4 h to remove the hexane. After 4 h, tetraethoxysilane (TEOS) (1 mL, dispersed in 20 mL hexane) was added dropwise into the above mixed solution and continued to react for 48 h. After the reaction, when the system reached room temperature, 50 mL of absolute ethanol was added to the mixture and then centrifuged and collected. The collected product was washed with absolute ethanol three times, and the product was finally dispersed in deionized water for storage. Synthesis of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 was synthesized by the amidation between [email protected]2[email protected]2-LA/SA/DOX/TPE-SB and AS1411. Typically, [email protected]2[email protected]2-LA/SA/DOX/TPE-SB (50.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.12 mmol), and N-hydroxysuccinimide (NHS) (0.15 mmol) were dissolved in 10 mL of N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES) buffer (pH 7.2) with stirring at room temperature. After 4 h, AS1411 (5 OD) was added in the above mixture, and it continued to react for 24 h. Finally, the reaction product was isolated and purified by dialysis. In addition, the synthesis of [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 was consistent with the above synthesis process. Degradation experiment in vitro Degradation of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB in vitro was directly observed in the time-dependent structural evolution of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB in different pH conditions by transmission electron microscope (TEM) during the degradation evaluation. Typically, [email protected]2[email protected]2-LA/SA/DOX/TPE-SB was added into phosphate-buffered saline (PBS) buffer. To investigate the pH influence on biodegradation, the PBS buffer solution with different pH conditions was adopted (pH 7.4, 6.5, and 5.4). All the evaluations were based on the concentration of 10 mg mL−1 [email protected]2[email protected]2-LA/SA/DOX/TPE-SB. The testing solution was put into a water bath (at 37 °C) under slow magnetic stirring (i.e., at 300 rpm) for 9 days. Samples were taken at different time points (0, 1, 2, 3, 4, and 9 days), and the morphological changes of the samples were observed by TEM. Magnetothermal effect of [email protected]2[email protected]2-LA/SA/DOX 1.5 mL of [email protected]2[email protected]2-LA/SA/DOX dispersions with different concentrations (of 0, 20, 40, 60, 80, and 100 mg L−1) were tested by AMF (heating current: 9A, oscillation frequency: 45–50 kHz) for 5 min, and their temperature in solution was recorded by an online-type thermocouple thermometer. Cell culture NIH3T3 and 4T1 cell lines were obtained from the Cancer Institute and Hospital of the Chinese Academy of Medical Science. All cell-culture-related reagents were purchased from Invitrogen. RPMI-1640 culture medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin was used to culture cells at 37 °C under 5% CO2 with 100% humidity. Colocalization of lysosomes and NSs assay The as-prepared sample of [email protected]2[email protected]2 NSs was conjugated with. 4T1 cells (5 × 104 cells per well) which was then seeded into a glass-bottom cell culture dish (20 mm). When the cell density reached 80–90%, the cells were then incubated with [email protected]2[email protected]2 NSs for 6 h. Subsequently, 4T1 cells were counterstained with Lyso-Tracker Green (L7526, Life TechnologiesTM, United States) and 4′,6-diamidino-2-phenylindole (DAPI) (C0060, Solaribio, Beijing, China) for 15 min. Finally, the cells were washed with PBS three times for NIR-II fluorescence imaging observation through multidimensional confocal microfluorescence imaging system (FLIM+confocal+AFM, Q2, ISS-USA). Double staining of living/dead cells assay Double staining of the living/dead cells assay was measured by Calcein-AM/PI Double Stain Kit (40747ES76, Yeasen, Shanghai, China). 4T1 cells were seeded into a 24-well culture plate (2 × 104 cells per well). When the cell density reached 70%, the cells were then incubated with [email protected]2[email protected]2 NSs for 24 h. After washing out the free NPs with PBS, fresh culture medium was added. AMF (oscillation frequency: 45–50 kHz, heating current: 9 A) was then used to cover the cells for 5 min. The staining was carried out as per given instructions. The cells were finally visualized using an inverted microscope (Olympus IX71). Fluorescence imaging of reactive oxygen species generation in 4T1 cells The reactive oxygen species (ROS)-generating capabilities of control group (saline) and [email protected]2[email protected]2 NSs were assessed by dihydrorhodamine 123 (DHR123) respectively. DHR123 staining was carried out as follows: cells were incubated with saline or [email protected]2[email protected]2 NSs (60 mg L−1) for 24 h. Then, 1 μg of DHR123 was added to cell media under laser irradiation (808 nm, 0.3 W cm−2) for 1 min. Confocal laser scanning microscopy and flow cytometry were used to observe the fluorescence intensity of DHR123 (λex/em = 488 nm/520 nm, n = 3). Intracellular ROS assay Intracellular ROS assay was measured by ROS Assay Kit (S0033, Beyotime, China). 4T1 cells were seeded into a 24-well culture plate (2 × 104 cells per well). When the cell density reached 70%, the cells were then incubated with [email protected]2[email protected]2 NSs for 24 h. After washing out the free NPs with PBS, fresh culture medium was added. AMF (oscillation frequency: 45–50 kHz, heating current: 9 A) was then used to cover the cells for 5 min. The staining was carried out as per given instructions. The cells were finally visualized using an inverted microscope (Olympus IX71) or detected through flow cytometry using BD Fortessa flow cytometer (BD Biosciences). Animals and tumor model Balb/c mice four to five weeks old with an average weight of 20 g were purchased from Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China). An specific pathogen-free (SPF) animal house was provided to mice under a 12 h light and 12 h darkness cycle, and they were fed a standard laboratory diet and tap water ad libitum. For the subcutaneous tumor model, 4T1 cells (2 × 106 cells in 0.1 mL of saline) were injected subcutaneously into these mice. Fluorescence imaging in vivo The 4T1 triple-negative breast cancer (TNBC)-bearing mice were intravenously injected with [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 (20 mg kg−1, 200 μL) for fluorescence imaging in vivo. The fluorescence signal was recorded by the CRi Maestro ex in vivo imaging system (United States) at 0, 3, 6, 12, 24, and 48 h after the injection. To confirm the in vivo distribution of [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411, mice were sacrificed 48 h post-injection. The main organs (liver, heart, lung, spleen, tumor, and kidneys) were collected for imaging and semiquantitative biodistribution analysis (n = 6). MRI in vivo The 4T1 TNBC-bearing mice were intravenously injected with [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 (20 mg kg−1, 200 μL) for MRI in vivo. After the injection, T2 images were obtained at 0, 6, 12, 24, and 48 h by a clinical 3.0 T MRI scanner (Philips, TR = 1200 ms, TE = 30.2 ms, slice thickness = 2.5 mm). The intensity of the MRI signal before injection was used as the control (n = 6). In vivo antitumor efficiency evaluation Mice bearing 200 mm3 4T1 TNBC were randomly divided into six groups: (1) control (only saline); (2) AMF; (3) [email protected]2[email protected]2-LA/SA/TPE-SB; (4) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB; (5) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411; and (6) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411+AMF. Each group contained six mice. After 200 mL of saline or NPs (20 mg kg−1) were intravenously injected into 4T1 tumor-bearing mice for 1, 4, and 7 days, the mice were exposed to AMF (heating current: 9 A, oscillation frequency: 45–50 kHz) for 5 min three times. The changes in body weight and tumor volume during the 20 days of the treatment period were recorded. Histological evaluation Mice from each group were euthanized, and major organs and tumors were recovered, followed by fixing them with 10% neutral buffered formalin after 18 days of treatment. The organs were embedded in paraffin and sectioned at 5 mm. Hematoxylin and eosin (H&E) or Prussian blue staining was performed for histological examination. The slides were observed under an optical microscope (n = 6). Statistical analysis Statistical analysis was carried out by Tukey's post-hoc test with statistical significance assigned at **P < 0.01 (moderately significant), ***P < 0.001 (highly significant), and ****P < 0.0001 (highly significant). Results and Discussion Characterization of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 The procedure for the synthesis of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 is presented in Figure 1a while Figure 1b shows the tumor theranostic precision mechanism of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. Initially, monodispersed core-shell structure [email protected]2C NPs were synthesized by the thermal decomposition method in the oil phase. TEM images clearly show that Cu cores are surrounded by the Fe2C domains with a thickness of nearly 3 nm (Figure 2a). The high-resolution TEM (HRTEM) analysis presented in Figure 2b evidences the lattice of spacing 2.08 Å between two (111) adjacent planes in the Cu region while the lattice spacing is 2.09Å in the Fe2C region, corresponding to the (101) planes of the hexagonal phase. Furthermore, energy dispersive X-ray (EDX) mapping of [email protected]2C NPs (presented in Supporting Information Figure S1), has also confirmed the composition and core-shell structure of [email protected]2C NPs. Subsequently, TEM and scanning electron microscopy (SEM) images [email protected]2[email protected]2 NSs after mSiO2 coating are presented in Figure 2c and Supporting Information Figure S2a. From these images, the estimated total size of [email protected]2[email protected]2 NSs is ∼65 nm. TEM images depicted in Supporting Information Figures S2b and S2c show characteristic lattice spacing of [email protected]2C NPs, which again reassures us that the NPs coated with mSiO2 are [email protected] NPs. EDX mapping and energy dispersive spectroscopy (EDS) line scan of [email protected]2[email protected]2 NSs are shown in Figures 2d and 2e, respectively, which has confirmed the composition and core-shell structure of [email protected]2[email protected]2 It is important to that the X-ray presented in Figure are consistent with TEM The X-ray spectroscopy of Cu and and and Supporting Information Figures and has confirmed the of and in [email protected]2C NPs and [email protected]2[email protected]2 The specific surface of [email protected]2[email protected]2 NSs is Supporting Information Figure while the average size distribution of [email NSs is nm after and analysis Supporting Information Figure also synthesized the before the drug into the mesopores of [email protected]2[email protected]2 As shown in Supporting Information Figure when the of to the of the is which is for the controllable release of drugs in vivo by inducing the magnetothermal effect of through mild In addition, we with TPE-CHO by organic synthesis to TPE-SB Supporting Information Figure This organic product was and by Supporting Information Figure and Supporting Information Figures and and after the of the the of the in the of a high Supporting Information Figure This confirmed that the above were and the TPE-SB were an of TPE-SB and DOX were mixed at a high temperature °C) with and then filled into the mesopores the surface of [email protected]2[email protected]2 NSs by to [email protected]2[email protected]2-LA/SA/DOX/TPE-SB. In addition, we AS1411 on the surface of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB through amidation reaction to realize the targeting of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. It be that the AS1411 has been developed and for cell in as a drug it has been utilized in targeted cancer The of was by the high of the of the of in the Supporting Information Figure Figure | Characterization of [email protected]2[email protected]2 (a) TEM of [email protected]2C NPs. (b) of [email protected]2C NPs. TEM of [email protected]2[email of [email protected]2[email protected]2 line scan of [email protected]2[email protected]2 of [email protected]2C NPs and [email protected]2[email protected]2 of Cu for [email protected]2[email protected]2 of for [email protected]2[email protected]2 Download figure Download PowerPoint of [email protected]2[email in vitro The of [email protected]2[email was by (pH 7.4, 6.5, and TEM imaging after 9 days (Figure and Supporting Information Figure was degradation of [email protected]2[email under these conditions after days, with the prolonged of [email protected]2[email in the PBS buffer (pH obvious degradation was in the other two (pH and also measured the of [email protected]2[email under three of pH conditions for different times by light (Figure which was consistent with the above of TEM. These prove that [email protected]2[email can in a time under acidic The of [email protected]2[email was in 4T1 cells. After 48 h of [email protected]2[email was degraded into NPs in the lysosomes of 4T1 cells. These are shown in the images in Figure It is that the pH of the tumor microenvironment is the and of tumor while pH of and The TEM and of size for [email protected]2[email evidence that the acidic of in mesoporous can finally be degraded into water and through The core [email protected]2C NPs also to a under acidic conditions to achieve In the of the [email protected]2[email has been through these on the above the degradation process of [email protected]2[email is in Figure First, the by the magnetothermal effect of the [email protected]2[email protected]2 NSs is used to the in the mesopores from the solid to the so as to from the Then the mesoporous of the NSs under the of Finally, the degraded NSs are in the of in the resulting in the release of and Figure 3 | evaluation of [email protected]2[email in (a) TEM of [email protected]2[email under three different pH conditions (pH 7.4, 6.5, and over 9 days. (b) of size for [email protected]2[email which measured by imaging of [email protected]2[email in 4T1 Degradation process of [email protected]2[email Download figure Download PowerPoint evaluation at cellular level The above degradation characteristics of the NSs under acid After the degradation of the valence Cu and including and in [email protected]2[email protected]2 NSs The reaction of corresponding Fenton and Fenton-like reaction can be 3 (1) Cu

In recent years, excipient development has become a core area of research in pharmaceutical drug delivery because it influences the formulation development and drug delivery process in various ways. Polymeric drug delivery systems have been of great interest for controlled delivery as they show the great advantage in drug delivery systems because of optimized drug loading and releasing property. Then, the side effects of synthetic polymers far exceed that it leads to some difficulties like they impose dose reduction, treatment delay, or the given therapy is not continuous. With this in mind and together with the need for a protective delivery system for drugs, natural polymeric substances such as biopolymers and their composites are the choice of research as excipient because of their low toxicity, biodegradability, stability, and renewable nature. Furthermore, they have a wide variety of structures, different physiological functions and may provide a variety of biomedical applications, owing to their distinctive properties. The present brief review explores the concept of excipient delivery and the recent advances in both the biopolymers and the methods in the pharmaceutical drug delivery systems.

Plant-based foods contain flavonoids, belonging to the polyphenols class. The phytochemical and phyto-pharmacological sciences advancement has enabled composition elucidation and biological activities of various medicinal plant products. The efficacy of medicinal plants can be measured on the basis of bio-active constituents they comprise. Flavonoid is one of the classes among the bio-active constituents that are hydrophilic in nature. They have low bioavailability and efficacy due to low absorption, as they cannot cross cells lipid membrane due to larger molecular size. A variety of novel drug delivery systems have been developed for polyphenolic compounds to enhance the relative bioavailability. However, if novel drug delivery technology is applied, it may reduce the adverse effects and increase the efficacy of several herbs and their compounds. Herbal medicines were not encouraged for novel formulations development for a long time due to lack of scientific justification and processing difficulties, such as individual drug components identification, extraction and standardization in complex poly-herbal systems. However, advance phytopharmaceutical research can reduce the scientific thirst (e.g, pharmacokinetics determination, mechanism of action, the accurate dose required, site of action etc.) for herbal medicines to be incorporated in novel drug delivery systems, such as nanoparticles (NPs), liposomes, matrix systems, and micro-emulsions (-E) etc. by improving activity by reducing the side effects and required dose. Various drug delivery technologies have been summarized in this chapter which can be used for flavonoids loaded polymeric drug delivery systems.

Chapter 14 - Nanoparticles for the targeted drug delivery in lung cancer

Advances in Drug Delivery

Lipid-based innovations have achieved new heights during the last few years as an essential component of drug development. The current challenge of drug delivery is liberation of drug agents at the right time in a safe and reproducible manner to a specific target site. A number of novel drug delivery systems has emerged encompassing various routes of administration, to achieve controlled and targeted drug delivery. Microparticulate lipoidal vesicular system represents a unique technology platform suitable for the oral and systemic administration of a wide variety of molecules with important therapeutic biological activities, including drugs, genes, and vaccine antigens. The success of liposomes as drug carriers has been reflected in a number of liposome-based formulations, which are commercially available or are currently undergoing clinical trials. Also, novel lipid carrier-mediated vesicular systems are originated. This paper has focused on the lipid-based supramolecular vesicular carriers that are used in various drug delivery and drug targeting systems.

Advances in Immunogenic Cell Death for Cancer Immunotherapy

Objective: The aim of this study was to provide researchers in the medical field with information about leaders, collaborations, and trends in the field of polymer-based drug delivery systems (DDS) using bibliometric analysis. Methods: a three-step process were followed: (1) data identification using PubMed. English papers published during the last five years (2018-2022) were included. (2) Data extraction and cleansing. (3) Data analysis based on publication-related metrics and science mapping using VOSviewer. Results: A total of 1532 papers related to polymers in DDS were included. With 476 papers, China was the greatest contributor to this field as a source country. Kannan RM, by working on DDS in ocular and neurodegenerative diseases,was the most influential author in this field. Surprisingly, collaboration among organizations and countries were limited. Regarding key concepts, cancer and antineoplastic drugs have been extensively studied using various types of polymeric systems. Conclusion: By uncovering key concepts related to polymer-based DDS, our results can provide researchers with ideas for investigation and help them position their contributions to the field.

Antisense LNA-loaded nanoparticles of star-shaped glucose-core PCL-PEG copolymer for enhanced inhibition of oncomiR-214 and nucleolin-mediated therapy of cisplatin-resistant ovarian cancer cells.

Clay materials are widely used in drug delivery systems due to their unique characteristics. Montmorillonite is a major component of bentonite and it has a large surface area, better swelling capacity, and high adsorption capacity. The modification of natural bentonite could improve its sorption ability for new emerging applications. Recent advancements in the polymer-silicate composite have novel biomedical applications in drug delivery, tissue regeneration, wound healing, cancer therapy, enzyme immobilization, diagnostic and therapeutic devices, etc. Perspective view of the montmorillonite- polymer composite as a pharmaceutical carrier in drug delivery systems has been discussed in this review. Different types of modification of montmorillonite for the development of pharmaceutical formulations have also been documented. Many challenges in clay nanocomposite systems of polymer of natural/synthetic origin are yet to be explored in improving antimicrobial properties, mechanical strength, stimuli responsiveness, resistance to hydrolysis, etc. Drug interaction and binding capability, swelling of clay may be carried out for finding possible applications in monitoring delivery systems. Pharmaceutical properties of active drugs in the formulation could also be improved along with dissolution rate, solubility, and adsorption. The clay-incorporated polymeric drug delivery systems may be examined for a possible increase in swelling capacity and residence time after mucosal administration.

Chapter 11 - Carbon dots as carriers for the development of controlled drug and gene delivery systems

The provision of appropriate postoperative analgesia should be as important to modern surgery as is intraoperative anesthesia. Potent analgesics, such as morphine, have been available for several hundred years, yet our efficacy in treating acute postoperative pain was until recently abysmal. As late as 1983, 41% of patients rated their pain control inadequate after surgery [1]. The use of self-titration of an analgesic drug to provide postoperative pain management was first achieved in 1968 [2]. The ability to provide self-titration was dependent on developing an appropriate analgesic drug delivery device. It took years for industry to adopt this concept and to develop a commercial device. It also took physicians some time to recognize the utility of this approach to postoperative pain. It did not take patients long to demand patient-controlled analgesia (PCA), which is now widely practiced. There is no doubt that PCA provided a major step forward in the management of acute postoperative pain. Why has PCA provided a more satisfied patient with improved pain relief? Pain is a very subjective sensation, the effective concentration required for pain relief is extremely variable between patients (pharmacodynamic variability) as well as within patients, and lastly, any given dose will result in a different concentration in each individual due to the unique disposition of the drug in the individual (pharmacokinetic variability). In addition, safety is an issue. Potent opiate analgesics have a very narrow therapeutic margin, with doses exceeding the therapeutic concentration producing significant adverse effects (toxicity). Thus, the objective of any analgesic delivery system is to allow safe individual titration of drug dose so patients can maintain themselves within their own therapeutic window. PCA achieves this objective. There are, however, some theoretical disadvantages to PCA. Pain is the most intense soon after awakening. Thus, the required concentration of the analgesic is initially high. To attain an effective concentration requires some form of a large initial dose to fill the volume of distribution. To avoid exceeding the therapeutic concentration, multiple small doses of the opiate are given until adequate analgesia is obtained. For opiates like morphine, which equilibrate slowly from the blood to the brain and receptor, this equilibration period can take several hours. Also, due to redistribution and elimination, once the peak effect of the drug is achieved, drug concentration is continuously decreasing. Thus, PCA does not totally avoid the peaks and valleys of intermittent intramuscular injection, but simply makes them smaller. While PCA has been widely accepted clinical practice, further technologic developments are occurring to further improve drug delivery. Certainly, on a theoretical basis, it is ideal to administer drugs to a target effect (i.e., the clinician sets the targeted effect, e.g., degree of neuromuscular blockade, and the delivery system simply adjusts the dosing rate to achieve this monitored response). Unfortunately, neither anesthesia nor analgesia has readily measurable or quantifiable end-points. Thus, the next best is to be able to administer the drug to an effective concentration. By using pharmacokinetic parameters derived from the disposition of the drug, it is possible to program a computer so that it calculates the dosing regimen necessary to achieve the target plasma concentration (thereby automatically providing the initial loading of the drug) [3]. The efficacy of such devices for the administration of intravenous drugs during anesthesia has been evaluated in many studies over the past 15 yr [3]. Using pharmacokinetic-pharmacodynamic modeling, it is also possible to program the drug delivery device not only to target a plasma concentration but also to target an effect site concentration (i.e., the concentration that is in equilibration with the site of drug effect, e.g., the opiate receptor) [4,5]. This prevents much of the time delay that occurs as the plasma concentration equilibrates with drug receptors in the brain. For example, if a target plasma concentration of fentanyl is selected, it will take approximately 20 min before the full effect of this concentration is observed, whereas if a target effect site concentration is selected the full effect will occur within 3-5 min. Such computer controlled infusion devices [computer assisted continuous infusion (CACI) [6]] can be programmed to almostly instantaneously produce a desired effect concentration and then maintain this concentration. It is a logical step to combine PCA with CACI devices so that patients can rapidly attain and maintain an effective concentration of the analgesic. In this issue of Anesthesia & Analgesia, van den Nieuwenhuyzen et al. [7], although not the first to use such a system, are the first to try to compare the possible advantages of CACI-PCA (referred to as CCIA in their paper) with those of conventional PCA for postoperative pain management. Their results strongly support the superiority of CACI-PCA over conventional patient-controlled administration. This is based on a more rapid achievement of satisfactory analgesia, the time patients spent at the desired level on the visual analog pain scale (VAS; VAS less than 3), and the total number of doses requested by the patient. The CACI-PCA results favoring target-controlled infusion for PCA need to be carefully reviewed. Unfortunately, the authors chose to compare two different drugs using two different delivery modes. It is difficult to determine whether the advantageous results were due to the drug or the delivery system. Alfentanil has a very rapid onset of effect as evidenced by its ke0 (the ke0 represents the rate of equilibration between the plasma and the effect site). The ke0 for morphine has not been established, but is considered to be considerably longer than that of alfentanil. The more rapid onset of effective analgesia with target-controlled alfentanil could largely be explained by these differences in ke0 rather than the drug delivery system. Similarly, it is noted that the greatest difference in the time period for which there was a VAS of greater than 3 between the two groups was from 0 to 8 h. This again may simply be explained by the slower onset of effective analgesia with morphine compared to alfentanil, rather than the delivery system. In addition, the incremental doses delivered with each demand may not have been truly equally efficacious; thus, it may have required two demands for morphine to provide the same degree of analgesic relief as one demand for alfentanil. This difference would then readily explain the differences in demand and continued differences in time above a VAS of 3 between the two groups. Of interest and noted by van den Nieuwenhuyzen et al., PCA alfentanil has not provided effective postoperative pain management when given with a conventional PCA device. The authors have demonstrated that when alfentanil is administered using target CACI-PCA for postoperative pain management, it is definitely superior to conventional PCA morphine in providing postoperative pain relief. From this we can infer that through the utilization of CACI-PCA alfentanil becomes a more suitable opiate for postoperative pain management. One of the primary advantages of CACI drug delivery for postoperative analgesia is that it will maintain the drug level within the therapeutic window for longer periods of time. This argument should similarly hold true when using a low-dose continuous infusion in combination with PCA. The combination of a continuous infusion plus PCA has resulted in a greater number of side effects and greater opiate use but no greater pain relief [8]. A possible explanation for this is that pain, after surgery, does not remain constant, but rather is constantly changing. The advantage of a standard PCA regimen is that no drug is being delivered when pain is decreasing or is minimal. It would therefore seem that the ideal delivery system should rapidly achieve an effective concentration and that this concentration should not necessarily be maintained, but should decrease over time to enable patients to keep themselves within their own changing therapeutic window. van den Nieuwenhuyzen et al. [7] in this study creatively addressed this problem by forcing the target-controlled concentration to decrease after 2 h if no patient demand had been made. Is 2 h an appropriate time interval to wait? CACI drug delivery usually uses a single pharmacokinetic set to represent the entire patient population. van den Nieuwenhuyzen et al. demonstrated that the pharmacokinetics of Maitre et al. [9] provided minimal bias and a low-median absolute performance error. This does not exclude the possibility that in any individual patient, over a 2-h period, the target concentration is increasing with the possibility of significant respiratory depression. When evaluating patients on morphine PCA, the authors' philosophy is to adjust the PCA dose to provide one to two patient-demanded doses per hour. Thus, to wait 2 h without a demand prior to allowing the concentration to decrease may be to wait too long. Fortunately, a CACI drug delivery system can be programmed to start decreasing the target concentration at any specified time. Another feature of CACI-PCA that needs to be addressed is the size of the maintenance dose. Most potent opiates have a very steep concentration effect, so it will be necessary to establish appropriate and safe increments in opiate concentration with each demand. Thus, it is important to first confirm the optimal settings for a CACI delivery system when used in the patient-controlled mode, and then compare this to the traditional bolus method of patient-controlled analgesia using the same drug. The use of target-controlled drug delivery in a postoperative setting is relatively new. CACI has established itself as an important tool for the intravenous administration of drugs during anesthesia. As a drug delivery system, CACI is akin to the calibrated vaporizer, which is accepted as the standard delivery system for volatile anesthetics. CACI drug delivery has also proven to be more efficacious than intermittent bolus administration and at least equal to a manual infusion system [10]. As a tool CACI has enabled anesthesiologists to define the concentration effect relationship of drugs used in anesthesia, as well as the effect resulting from the interaction between intravenous drugs providing anesthesia [3]. In addition, CACI has enhanced our understanding of the pharmacokinetic and pharmacodynamic principles related to intravenous administration of anesthetic drugs. Like the concept of PCA, target-controlled drug delivery is dependent on having an accessible device. This is largely dependent on industry embracing this concept and providing a commercial device. The paper by van den Nieuwenhuyzen et al. [7] further demonstrates the use and potential of target-controlled drug delivery within our speciality. We predict with certainty and enthusiasm that, when industry and the regulatory agencies produce a CACI device, it will be widely accepted as another step forward in the never-ending quest to optimize patient care.

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