Drug Loading Ratio Research Articles

Self‐Nanoformulating Poly(2‐oxazoline) and Poly(2‐oxazine) Copolymers Based Amorphous Solid Dispersions as Microneedle Patch: A Formulation Study

AbstractA pioneering approach in the domain of transdermal drug delivery systems (TDDS) is introduced by using microneedles (MNs) fabricated from an amorphous solid dispersion comprising only a model drug and an amphiphilic block copolymer to form a drug nanoformulation upon MN dissolution. To maximize drug loading and ensure consistent release, a minimalist formulation that achieves 40 wt% drug loading, which is a significant improvement over existing methods, is developed. Using scanning electron microscopy, the morphology of MNs is examined across a spectrum of drug loading ratios, demonstrating the consistency in structure and integrity. Mechanical testing confirms the MNs' proficiency in effective skin penetration. A comparative study on the formation of polymeric micelles underscores the innovative concept of a “nano‐in‐micro drug delivery system”. The results demonstrate that MNs manufactured from an amorphous solid dispersion of drug and amphiphilic block copolymer with ultra‐high loading enhance the availability and release dynamics of hydrophobic drugs, positioning them as a tool for enhancing TDDS. This study sets a new benchmark in the utilization of polymer‐drug nanoformulations for transdermal applications and underscores the capacity for high drug loading and the creation of adaptable drug delivery mechanisms for the studied amphiphilic block copolymer.

Quantitative Visualization of Lipid Nanoparticle Fusion as a Function of Formulation and Process Parameters.

Lipid nanoparticles (LNPs) have proven to be promising delivery vehicles for RNA-based vaccines and therapeutics, particularly in LNP formulations containing ionizable cationic lipids that undergo protonation/deprotonation in response to buffer pH changes. These nanoparticles are typically formulated using a rapid mixing technique at low pH, followed by a return to physiological pH that triggers LNP-LNP fusion. A detailed understanding of these dynamic processes is crucial to optimize the overall performance and efficiency of LNPs. However, knowledge gaps persist regarding how particle formation mechanisms impact drug loading and delivery functions. In this work, we employ single-molecule Convex Lens-induced Confinement (CLiC) microscopy in combination with Förster resonance energy transfer (FRET) measurements to study LNP fusion dynamics in relation to various formulation parameters, including lipid concentration, buffer conditions, drug loading ratio, PEG-lipid concentrations, and ionizable lipid selection. Our results reveal a strong correlation between the measured fusion dynamics and the formulation parameters used; these findings are consistent with DLS and Cryo-TEM-based assays. These measurements offer a cost-effective method for characterizing and screening potential drug candidates and can provide additional insights into their design, with opportunities for optimization.

A biomimetic lubricating nanosystem for synergistic therapy of osteoarthritis

Failure of articular cartilage lubrication and inflammation are the main causes of osteoarthritis (OA), and integrated treatment realizing joint lubrication and anti-inflammation is becoming the most effective treat model. Inspired by low friction of human synovial fluid and adhesive chemical effect of mussels, our work reports a biomimetic lubricating system that realizes long-time lubrication, photothermal responsiveness and anti-inflammation property. To build the system, a dopamine-mediated strategy is developed to controllably graft hyaluronic acid on the surface of metal organic framework. The design constructs a biomimetic core–shell structure that has good dispersity and stability in water with a high drug loading ratio of 99%. Temperature of the solution rapidly increases to 55 °C under near-infrared light, and the hard-soft lubricating system well adheres to wear surfaces, and greatly reduces frictional coefficient by 75% for more than 7200 times without failure. Cell experiments show that the nanosystem enters cells by endocytosis, and releases medication in a sustained manner. The anti-inflammatory outcomes validate that the nanosystem prevents the progression of OA by down-regulating catabolic proteases and pain-related genes and up-regulating genes that are anabolic in cartilage. The study provides a bioinspired strategy to employ metal organic framework with controlled surface and structure for friction reduction and anti-inflammation, and develops a new concept of OA synergistic therapy model for practical applications.

Layer-by-layer assembled decomposable nanocapsules for light-responsive release of pesticide imidacloprid on Aphis craccivora Koch.

Conventional pesticide formulations are often inefficient because of low biological uptake after spraying. Controlled release nanopesticides can release pesticides precisely in response to specific stimuli, thereby killing pests and pathogens using the least effective concentration. This study aims to develop nanocapsule-based photo-decomposable nanopesticides for efficient pesticide control. The target nanopesticides were successfully fabricated using layer-by-layer assembly of the negative azobenzene-grafted hyaluronic acid (azo-HA) and positivepolydimethyldiallylammonium chloride (polyDADMAC), confirmed by UV-visible, dynamic light scattering, Zeta potential and transmission electron microscopy measurements. The particle size and Zeta potential of the fabricated nanocapsules were 220 nm and +46.1 mV, respectively, and the nanocapsules were found to remain stable for up to 30 days. The optimized drug loading and encapsulation ratio of imidacloprid (IMI) in IMI/azo-HA@polyDADMAC were 21.5% and 91.3%, respectively. Cumulative release of IMI from the nanopesticides increased from ~50% to ~95% upon UV light irradiation (365 nm). The half lethal concentration (LC50) value of the nanopesticides toward Aphis craccivora Koch decreased from 2.22 to 0.55 mg L-1 upon UV light irradiation. The trans to cis transformation of the azo group in HA decomposed IMI/azo-HA@polyDADMAC nanopesticides upon UV irradiation, thus facilitating the release of IMI, resulting in a decrease in the concentration of pesticides required for efficient pesticide control. Our work demonstrated the great potential of light-responsive nanocapsules as a controlled release nanocarrier for efficient and eco-friendly pesticide control in sustainable agriculture. © 2024 Society of Chemical Industry.

Preparation of copolymer 7-hydroxyethyl chrysin loaded PLGA nanoparticles and the in vitro release.

To prepare 7-hydroxyethyl chrysin (7-HEC) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles and to detect the in vitro release. The 7-HEC/PLGA nanoparticles were prepared by emulsification solvent volatilization method. The particle size, polydispersity index (PDI), encapsulation rate, drug loading and zeta potential were measured. The prescription was optimized by single factor investigation combined with Box-Behnken response surface method. Mannitol was used as protectant to prepare lyophilized powder, and the optimal formulation was characterized and studied for the in vitro release. The optimal formulation of 7-HEC/PLGA nanoparticles was as follows: drug loading ratio of 2.12∶20, oil-water volume ratio of 1∶14.7, and 2.72% soybean phospholipid as emulsifier. With the optimal formulation, the average particle size of 7-HEC/PLGA nanoparticles was (240.28±0.96) nm, the PDI was 0.25±0.69, the encapsulation rate was (75.74±0.80)%, the drug loading capacity was (6.98±0.83)%, and the potentiostatic potential was (－18.17±0.17) mV. The cumulative in vitro release reached more than 50% within 48 h. The optimized formulation is stable and easy to operate. The prepared 7-HEC/PLGA nanoparticles have uniform particle size, high encapsulation rate and significantly higher dissolution rate than 7-HEC.

The preparation of pH-sensitive doxorubicin prodrug for enhanced antitumor efficacy

We have produced a micelle nanoparticle with intrinsic pH response, which is formed by self-assembled amphiphilic polyethylene glycol-Schiff-doxorubicin (PEG-Schiff-DOX) prodrug. These nanoparticles can maintain stability well under normal conditions and last for more than a week, but they will rapidly decompose in slightly acidic environments. The concentration of DOX in the nano solution is high with the drug loading ratio of 49.4%. This pH-responsive drug release behavior may lead to higher intracellular drug concentrations and prolonged action times. CCK-8 assays have shown that the nanosuspension exhibits superior anti-tumor activity against HeLa cells compared to free DOX. It is believed that these nanoparticle-based prodrug have great potential for developing DOX formulations for cancer therapy.

Spatiotemporally controlled AuNPs@ZIF-8 based nanocarriers for synergistic photothermal/chemodynamic therapy

High efficiency and spatio-temporal control remains a challenge for multi-modal synergistic cancer therapy. Herein, based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), a spatio-temporal controllable photothermal/ chemical dynamic/ chemotherapy three modal synergistic anti-tumor nano-carrier (HAZD) was developed. HAZD has a size of 128.75 ± 11.86 nm, a drug loading ratio of 21.5 ± 2.2 % and an encapsulation efficiency of 71.8 ± 1.7 %. Stability, acid responsive release character, outstanding catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 % and spatio-temporal controllable abilities are also found within this nano-carrier. Furthermore, HAZD performed good antitumor ability in vivo with the comprehensive effects of photothermal/ chemical dynamic/ chemotherapy. The tumor growth inhibition value is 97.1 % within 12 days, indicating its great potential in multi-modal synergistic cancer therapy. Statement of significanceCancer remains one of the major culprits that seriously harm human health currently. With the development of materials and nanotechnology, great improvements have been made in multimodal anti-tumor strategies. However, temporal- and spatial-controllable multi-modal synergistic nanocarriers are urgently awaited for efficient and low-toxicity tumor therapy. This article proposes a spatio-temporally controllable three-modal anti-tumor strategy and designs an anti-tumor drug delivery system based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), which shows acid-responsive release characteristics, catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 %, as well as spatio-temporal controllable abilities. Moreover, it demonstrates outstanding anti-tumor ability, with a tumor growth inhibition value of 97.1 % within 12 days, revealing its significant potential for future personalized and precise anti-tumor treatments.

Development and evaluation of redox-responsive alginate–SS–ibuprofen derivative based anti-tumor target drug delivery system for the controlled release of doxorubicin

Nowadays, self-assembled polymeric micelles from amphiphilic polymer conjugates are urgently needed to enhance drug targeting and release efficiency. On account of the excellent properties of alginate and the redox-responsiveness of disulfide bonds, a redox-sensitive alginate–SS–ibuprofen derivative (LSA–SS–IBU) based anti-tumor target drug delivery system was created by attaching the hydrophobic ibuprofen (IBU) onto the hydrophilic alginate molecular skeleton through disulfide linkages for glutathione (GSH) triggered delivery of doxorubicin hydrochloride (DOX). The structure and self-assembly behavior of the synthesized LSA–SS–IBU was systematically evaluated by FT-IR spectrometer, 1H NMR spectrometer, fluorescence spectrophotometer (FM), transmission electron microscope (TEM) and dynamic light scattering (DLS). Furthermore, the in vitro release of drugs from the LSA–SS–IBU micelles loaded with DOX was examined, along with the assessment of their cytotoxicity to HeLa cells. The resultant LSA–SS–IBU had a critical micelle concentration (CMC) value of 0.19 mg/mL that was able to self-assemble into the spherical micelles with the particle size and zeta potential of 148.2 ± 4.3 nm (PDI = 0.25) and −47.2 ± 0.4 mV, respectively. At a mass ratio of 3:10 for DOX/LSA–SS–IBU, the LSA–SS–IBU micelles achieved drug loading ratio (DLR) and encapsulation efficiency (EE) values of 12.2 % and 46.3 %, respectively. Furthermore, the in vitro drug release study indicated that the total drug release percentage of the drug-encapsulated LSA–SS–IBU micelles in PBS with the presence of 10 mmol/L GSH for 12 h exceeded 67.0 %, demonstrating a substantial increase compared to that in GSH-free PBS. The in vitro cytotoxicity findings indicated that LSA–SS–IBU had good biocompatibility, while the IC50 value and the cell viability of DOX-loaded LSA–SS–IBU micelles cultured with HeLa cells for 48 h was 2.2 μg/mL and less than 20.1 %, respectively, which could significantly inhibit the growth of HeLa cells. Therefore, redox-responsive LSA–SS–IBU micelles had potential applications in cancer therapy for hydrophobic anti-tumor drug delivery.

Preparation and properties of tumor-targeting lentinan-oleic acid polymer micelles based on folic acid for adriamycin delivery

To develop a natural polysaccharide targeted nanomicelles drug delivery system loaded with the broad-spectrum anti-tumor drug adriamycin (ADM), FA-LNT-OA polymer was synthesized, the ADM/FA-LNT-OA polymer nanomicelles was prepared, and response surface approach was used to optimize the drug loading procedure of the ADM/FA-LNT-OA nanomicelles. Under the optimum conditions, the drug loading ratio was 14.36 ± 0.12% while the entrapment efficiency was 95.17 ± 0.13%. The drug-loaded micelles were spherical, with the size about 170 nm, and the size distribution was uniform. The CMC of ADM/FA-LNT-OA nanomicelles was 48 ± 0.46 μg/mL, their release was more sensitive to pH than that of ADM, and they had good stability. The FA-LNT-OA nanomicelles had good blood compatibility and cell compatibility. In vitro anti-tumor pharmacodynamic studies proved that the IC50 of ADM/FA-LNT-OA nanomicelles on Hela, ES-2 and A549 cells were 48.49 ± 0.25, 63.56 ± 0.68 and 105.93 ± 17.03 μg/mL respectively. Moreover, the plasma elimination half-life of ADM/FA-LNT-OA nanomicelles was 5.341 h, the Tmax was 0.083 h, the CL was 0.017 L/h/kg. Compared with the common ADM formulation, the ADM/FA-LNT-OA nanomicelles prolonged the clearance half-life of ADM, decreased the clearance rate, and extended the retention time of ADM in vivo. In conclusion, the above results laid the foundation for the increase of therapeutic effects and reduction of the clinical toxic and side effects of ADM.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular (IA) injection has proved to be effective in osteoarthritis (OA) therapy, limited by the drug efficiency and short retention time of the drug delivery systems (DDSs). Herein, a series of modified cross-linked dextran (Sephadex, S0) was fabricated by respectively grafting with linear alkyl chains, branched alkyl chains or aromatic chain, and acted as DDSs after ibuprofen (Ibu) loading for OA therapy. This DDSs expressed sustained drug release, excellent anti-inflammatory and chondroprotective effects both in IL-1β induced chondrocytes and OA joints. Specifically, the introduction of a longer hydrophobic chain, particularly an aromatic chain, distinctly improved the hydrophobicity of S0, increased Ibu loading efficiency, and further led to significantly improving OA therapeutic effects. Therefore, hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

T cell redirecting and TLR7/8 agonist encapsulated liposomes targeting HER2+ tumors: Preclinical efficacy, pharmacokinetics and safety evaluations.

e14590 Background: T-cell dependent bispecific antibodies (TDBs) have shown limited success in solid tumor treatments. We hypothesized that it may be due to TDBs limited distribution in solid tumor tissues. We therefore propose to take advantage of the EPR (enhanced permeability and retention) effect of the liposome system to improve the PKPD properties of TDBs. The liposomes are named TRAFsomes (T cell Redirecting Antibody Fragment-anchored Liposomes). HF5050 is a TRAFsome containing on average 6 anti-CD3 and 10 anti-Her2 on each liposome surface and the toll-like TLR-7/8 agonist Resiquimod encapsulated inside at specific lipid to drug ratios. It preclinical efficacy, pharmacokinetics and safety evaluation studies are conducted to support the IND application. Methods: The T cell redirecting and target specific cytotoxic effect of HF5050 were evaluated in five PBMC co-cultured cancer cell models with different Her2 expression. Tumor cells derived from adenoid cystic carcinoma tumor tissues was also included. T cell redirection and activation are examined by T cell surface markers CD25/CD69 and secretion of IFN gamma, Perforin, and granzymes B in the absence and presence of cancer cells. For the incorporation of TLR7/8 agonist Resiquimod, we evaluated the effect of drug dose by varying the drug loading ratios in order to achieve a synergistic effect. For the in vivo efficacy studies, the N87 gastric cancer CDX model and an adenoid cystic carcinoma tumor PDX model were set on PBMC reconstructed humanized NCG-B2M mice. Pharmacokinetic and tissue distribution studies are carried out in tumor bearing mouse models as well. Results: HF5050 has shown to be a highly effective anti-cancer agent in both in vitro and in vivo studies. It mediates T cells-tumor cells redirection and cytotoxicity in a dose-dependent manner, especially in Her-2 highly expressing cell lines. HF5050 also effectively stimulates T cell activation and displays high efficacy in PBMC reconstruct humanized NCG-B2M tumor-bearing mice. Pharmacokinetic research confirms liposome successfully maintains drug levels in the bloodstream, and improves drug accumulation within tumor tissues. Conclusions: Overall, these data demonstrate that HF5050 processing a novel cell bridging function between T cells and tumor cells, and with the capability of activating immune cells. Based on the encouraging preclinical results, HF5050 exhibits promising development potential.

Charge reversal yolk-shell liposome co-loaded JQ1 and doxorubicin with high drug loading and optimal ratio for synergistically enhanced tumor chemo-immunotherapy via blockade PD-L1 pathway

Antitumor immunotherapy has become a powerful therapeutic modality to identify and kill various malignant tumors by harnessing the immune system. However, it is hampered by the immunosuppressive microenvironment and poor immunogenicity in malignant tumors. Herein, in order to achieve multi-loading of drugs with different pharmacokinetic properties and targets, a charge reversal yolk-shell liposome co-loaded with JQ1 and doxorubicin (DOX) into the poly (D,L-lactic-co-glycolic acid) (PLGA) yolk and the lumen of the liposome respectively was engineered to increase hydrophobic drug loading capacity and stability under physiological conditions and further enhance tumor chemotherapy via blockade programmed death ligand 1 (PD-L1) pathway. This nanoplatform could release less JQ1 compared to traditional liposomes to avoid drug leakage under physiological conditions due to the protection of liposomes on JQ1 loaded PLGA nanoparticles while the release of JQ1 increased in an acidic environment. In the tumor microenvironment, released DOX promoted immunogenic cell death (ICD), and JQ1 blocked the PD-L1 pathway to strengthen chemo-immunotherapy. The in vivo antitumor results demonstrated the collaborative treatment of DOX and JQ1 in B16-F10 tumor-bearing mice models with minimized systemic toxicity. Furthermore, the orchestrated yolk-shell nanoparticle system could enhance the ICD effect, caspase 3 activation, and cytotoxic T lymphocyte infiltration while inhibiting PD-L1 expression, provoking a strong antitumor effect, whereas yolk-shell liposomes encapsulating only JQ1 or DOX showed modest tumor therapeutic effects. Hence, the cooperative yolk-shell liposome strategy provides a potential candidate for enhancement of hydrophobic drug loading and stability, showing potential for clinic application and synergistic cancer chemo-immunotherapy.

Formulation and Characterisation of Carbamazepine Orodispersible 3D-Printed Mini-Tablets for Paediatric Use.

One of the main challenges to paediatric drug administration is swallowing difficulties, hindering the acceptability of the medicine and hence clinical outcomes. This study aims at developing a child-appropriate dosage form, the orodispersible mini-tablet (ODMT), using the model drug carbamazepine (CBZ). This dosage form was prepared and 3D-printed via a semi-solid extrusion technique. Design of Experiment methods were applied for optimising the formulation. The formulation with 40% (w/w) of SSG (superdisintegrant) and 5% (w/w) of PVP K30 (binder) was selected and loaded with CBZ. The drug-loaded tablets were characterised by a mean hardness of 18.5 N and a disintegrating time of 84 s, along with acceptable friability. The mean drug loading ratio of the tablets was tested as 90.56%, and the drug release rate in 0.1 M HCl reached 68.3% at 45 min. Excipients showed proper compatibility with the drug in physical form analysis. Taste assessment via an E-tongue was also conducted, where the drug did not show bitter taste signals at a low concentration in the taste assessment, and the sweetener also blocked bitterness signals in the testing. To this end, ODMTs were found to be potential candidates for child-appropriate dosage forms delivering CBZ.

Recent developments in natural biopolymer based drug delivery systems.

Targeted delivery of drug molecules to diseased sites is a great challenge in pharmaceutical and biomedical sciences. Fabrication of drug delivery systems (DDS) to target and/or diagnose sick cells is an effective means to achieve good therapeutic results along with a minimal toxicological impact on healthy cells. Biopolymers are becoming an important class of materials owing to their biodegradability, good compatibility, non-toxicity, non-immunogenicity, and long blood circulation time and high drug loading ratio for both macros as well as micro-sized drug molecules. This review summarizes the recent trends in biopolymer-based DDS, forecasting their broad future clinical applications. Cellulose chitosan, starch, silk fibroins, collagen, albumin, gelatin, alginate, agar, proteins and peptides have shown potential applications in DDS. A range of synthetic techniques have been reported to design the DDS and are discussed in the current study which is being successfully employed in ocular, dental, transdermal and intranasal delivery systems. Different formulations of DDS are also overviewed in this review article along with synthesis techniques employed for designing the DDS. The possibility of these biopolymer applications points to a new route for creating unique DDS with enhanced therapeutic qualities for scaling up creative formulations up to the clinical level.

Rapidly monitorable drug loading system for self-illuminating anticancer via self-enhanced aggregation-induced electrochemiluminescence polymer dots

As a representative of “smart” drug delivery systems (DDSs), multi-functional DDSs is of great significance in the field of drug research and development. Meanwhile, the rapid monitoring of the drug loading ratios is a significant work to study the therapeutic activity of DDSs. Therefore, we develop an efficient drug loading monitorable DDS based on self-enhanced aggregation-induced electrochemiluminescence (AIECL) bi-functional polymer dots (Pdots) for self-illuminating therapy. In detail, a self-enhanced AIECL conjugated polymer is synthesized and modified with tertiary amine as ECL co-reactive group. After anticancer drug doxorubicin (DOX) is loaded in, the ECL signal of Pdots can be gradually quenched by increasing DOX ratios to give a low limit of detection as 0.9% (mDOX/mpolymer), indicating its good performance in the rapid monitoring of drug loading. The drug loaded Pdots can not only indicate their location in cancer cells but also exhibit obvious anticancer property, which demonstrates its application in self-illuminating anticancer therapy. This work reports a novel strategy for accurate and rapid monitoring of the drug loading ratios in DDSs preparation and exhibits its positive role in advanced DDSs developments, which is of great significance in promoting its research development and improving personal and public health.

One-step fabrication of lidocaine/CalliSpheres® composites for painless transcatheter arterial embolization

BackgroundTranscatheter arterial embolization (TAE) is one of the first-line treatments for advanced hepatocellular cancer. The pain caused by TAE is a stark complication, which remains to be prevented by biomedical engineering methods.MethodsHerein, a commercial embolic agent CalliSpheres® bead (CB) was functionally modified with lidocaine (Lid) using an electrostatic self-assembly technique. The products were coded as CB/Lid-n (n = 0, 5, 10, corresponding to the relative content of Lid). The chemical compositions, morphology, drug-loading, and drug-releasing ability of CB/Lid-n were comprehensively investigated. The biocompatibility was determined by hemolysis assay, live/dead cell staining assay, CCK8 assay, immunofluorescence (IHC) staining assay and quantitative real-time PCR. The thermal withdrawal latency (TWL) and edema ratio (ER) were performed to evaluate the analgesia of CB/Lid-n using a plantar inflammation model. A series of histological staining, including immunohistochemistry (IL-6, IL-10, TGF-β and Navi1.7) and TUNEL were conducted to reveal the underlying mechanism of anti-tumor effect of CB/Lid-n on a VX2-tumor bearing model.ResultsLid was successfully loaded onto the surface of CalliSpheres® bead, and the average diameter of CalliSpheres® bead increased along with the dosage of Lid. CB/Lid-n exhibited desirable drug-loading ratio, drug-embedding ratio, and sustained drug-release capability. CB/Lid-n had mild toxicity towards L929 cells, while triggered no obvious hemolysis. Furthermore, CB/Lid-n could improve the carrageenan-induced inflammation response micro-environment in vivo and in vitro. We found that CB/Lid-10 could selectively kill tumor by blocking blood supply, inhibiting cell proliferation, and promoting cell apoptosis. CB/Lid-10 could also release Lid to relieve post-operative pain, mainly by remodeling the harsh inflammation micro-environment (IME).ConclusionsIn summary, CB/Lid-10 has relatively good biocompatibility and bioactivity, and it can serve as a promising candidate for painless transcatheter arterial embolization.

Phase-Field Model for Drug Release of Water-Swellable Filaments for Fused Filament Fabrication.

This paper treats the drug release process as a phase-field problem and a phase-field model capable of simulating the dynamics of multiple moving fronts, transient drug fluxes, and fractional drug release from swellable polymeric systems is proposed and validated experimentally. The model can not only capture accurately the positions and movements of the distinct fronts without tracking the locations of fronts explicitly but also predict well the release profile to the completion of the release process. The parametric study has shown that parameters including water diffusion coefficient, drug saturation solubility, drug diffusion coefficient, initial drug loading ratio, and initial porosity are critical in regulating the drug release kinetics. It has been also demonstrated that the model can be applied to the study of swellable filaments and has wide applicability for different materials. Due to explicit boundary position tracking being eliminated, the model paves the way for practical use and can be extended for dealing with geometrically complex drug delivery systems. It is a useful tool to guide the design of new controlled delivery systems fabricated by fused filament fabrication.

DNA Base Pairing-Inspired Supramolecular Nanodrug Camouflaged by Cancer-Cell Membrane for Osteosarcoma Treatment.

Osteosarcoma (OS) is one of the most common bone malignant tumors which mainly develops in adolescents. Although neoadjuvant chemotherapy has improved the prognosis of patients, numerous chemotherapeutic challenges still limit their use. Here, inspired by the Watson-Crick base pairing in nucleic acids, hydrophobic (methotrexate) and hydrophilic (floxuridine) chemo-drugs are mixed and self-assembled into M:F nanoparticles (M:F NPs) through molecular recognition. Then, the obtained NPs are co-extruded with membranes derived from OS cells to form cancer-cell membrane-coated NPs (CCNPs). With protected membranes at the outer layer, CCNPs are highly stable in both physiological and weak acid tumor conditions and possess homologous tumor targeted capability. Furthermore, the proteomic analysis first identifies over 400 proteins reserved in CCNPs, most of them participatingin tumor cell targeting and adhesion processes. In vitro studies reveal that CCNPs significantly inhibit the PI3K/AKT/mTOR pathway, which promotes cell apoptosis and cell cycle arrest. More importantly, cell membrane camouflage significantly prolongs the circulation half-life of CCNPs, elevates the drug accumulation at tumor sites, and promotes anti-tumor efficacy in vivo. As a convenient and effective strategy to construct a biomimetic NP with high drug loading ratio, the CCNPs provide new potentials for precise and synergistic antitumor treatment.

Efficient synthesis of artificial pharmaceutical solid-phase modules for constructing aptamer-drug conjugates

As a promising targeted drug delivery system, aptamer-drug conjugates (ApDCs) can specifically bind with cognate molecular targets for improving therapeutic efficacy and reducing drug toxicity. However, current ApDC strategies suffer from problems caused by the complicated synthesis, relatively high cost, low controllability of drug binding sites and loading ratio. To solve these difficulties, we have designed and synthesized an artificial pharmaceutical solid-phase module of Combretastatin A-4 (CA-4), in which an inactive ingredient was selected as bonding moiety to incorporate with solid phase functionalities. Through solid-phase synthesis technology, this module was automatically and efficiently conjugated with an aptamer at predesigned positions. Biological studies revealed that these ApDCs can not only maintain excellent specific recognition ability, but also possess definite cytotoxicity against tumor cells.

Amino acids and doxorubicin as building blocks for metal ion‐driven self‐assembly of biodegradable polyprodrugs for tumor theranostics

On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms pDTD@M (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. Statement of significanceCompared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.