Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system

Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG–SS–DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer–drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.

Schematic of disulfide/dicarbide-bridged DOX polymer-encapsulated photosensitive drugs Ce6: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.     

Clinical developments of antitumor polymer therapeutics

Polymer therapeutics encompasses polymer–drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds. Nanoparticle-based polymer-conjugated therapeutics are poised to become a leading delivery strategy for cancer treatments as they exhibit prolonged half-life, higher stability and selectivity, water solubility, longer clearance time, lower immunogenicity and antigenicity and often also specific targeting to tissues or cells. Compared to free drugs, polymer-tethered drugs preferentially accumulate in the tumor sites unlike conventional chemotherapy which does not discriminate between the cancer cells and healthy cells, thereby causing severe side-effects. It is also desirable that the drug reaches its site of action at a particular concentration and the therapeutic dose remains constant over a sufficiently long period of time. This can be achieved by opting for new formulations possessing polymeric systems of drug carriers. However, many challenges still remain unanswered in polymeric drug conjugates which need to be readdressed and therefore, can broaden the scope of this field. This review highlights some of the antitumor polymer therapeutics including polymer–drug conjugates, polymeric micelles, polymeric liposomes and other polymeric nanoparticles that are currently under investigation.

Polymer therapeutics encompasses polymer–drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds.     

Development of a pH-sensitive functionalized metal organic framework: in vitro study for simultaneous delivery of doxorubicin and cyclophosphamide in breast cancer

Exploration of an efficient dual-drug based nanocarrier with high drug loading capacity, specific targeting properties, and long-term stability is highly desirable in cancer therapy. Metal–organic frameworks (MOFs) have proven to be a promising class of drug carriers due to their high porosity, crystalline properties with defined structure information, and their potential for further functionalization. To enhance the drug efficacy as well as to overcome the burst effect of drugs, here we synthesized a pH responsive folic acid (FA) and graphene oxide (GO) decorated zeolitical imidazolate frameworks-8 (GO–FA/ZIF-8), for targeted delivery of doxorubicin (DOX) and cyclophosphamide (CP), simultaneously. In this system, DOX molecules were encapsulated in the pores of ZIF-8 during in situ synthesis of ZIF-8 and CP molecules have been captured by the GO surface via hydrogen bonding and π–π interactions as well. Furthermore, the resulting pH-responsive nanocarrier (DOX@ZIF-8/GO–FA/CP) showed in vitro sustained release characteristics (76% of DOX and 80% of CP) by cleavage of chemical bonding and disruption of the MOFs structure under acidic condition (at pH 5.6). Moreover, DOX@ZIF-8/GO–FA/CP has synergistic cytotoxic effects as compared to the combination of both the drugs without ZIF-8/GO–FA when treating MCF-7 and MDA-MB-231 breast cancer cell lines (with a combination index of 0.29 and 0.75 for MCF-7 and MDA-MB-231 cell-lines, respectively). Hence this system can be applied as an effective platform for smart dual drug delivery in breast cancer treatment through its remarkable manageable multidrug release.

Exploration of an efficient dual-drug based nanocarrier with high drug loading capacity, specific targeting properties, and long-term stability is highly desirable in cancer therapy.     

A porous reduced graphene oxide/chitosan-based nanocarrier as a delivery system of doxorubicin

Nowadays, the concept of drug transmission is an important topic in the field of drug delivery research. Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. In this study, we report the development of a novel platform for the loading and release of doxorubicin (DOX). It is based on porous reduced graphene oxide (prGO) nanosheets and chitosan (CS) biocompatible polymer, where prGO can be dispersed in chitosan through amide linkages. The loading and release of DOX on the CS-prGO nanocomposite were investigated by voltammetry, FE-SEM, and FTIR and UV-Vis spectroscopy methods. We showed that chitosan-modified prGO (CS-prGO) was an extremely efficient matrix. An efficient loading of DOX (86% at pH 7.00, time 3 h and initial concentration of 0.5 mg mL⁻¹) was observed on CS-prGO as compared to the case of prGO due to the presence of the –OH and –NH₂ groups of chitosan. At the normal physiological pH of 7.00, approximately 10% of DOX could be released from CS-prGO in a time span of 1 h; however, when exposed to pH 4.00, 25% of DOX was released in 1 h. After 20 h, 18% and 62% of DOX was released at pH 7.00 and 4.00, respectively. This illustrates the major benefits of the developed approach for biomedical applications.

Nowadays, the concept of drug transmission is an important topic in the field of drug delivery research.     

UCN–SiO2–GO: a core shell and conjugate system for controlling delivery of doxorubicin by 980 nm NIR pulse

Herein, graphene oxide (GO) has been attached with core–shell upconversion-silica (UCN–SiO₂) nanoparticles (NPs) to form a GO–UCN–SiO₂ hybrid nanocomposite and used for controlled drug delivery. The formation of the nanocomposite has been confirmed by various characterization techniques. To date, a number of reports are available on GO and its drug delivery applications, however, the synergic properties that arise due to the combination of GO, UCNPs and SiO₂ can be used for controlled drug delivery. New composite UCN@SiO₂–GO has been synthesized through a bio-conjugation approach and used for drug delivery applications to counter the lack of quantum efficiency of the upconversion process and control sustained release. A model anticancer drug (doxorubicin, DOX) has been loaded to UCNPs, UCN@SiO₂ NPs and the UCN@SiO₂–GO nanocomposite. The photosensitive release of DOX from the UCN@SiO₂–GO nanocomposite has been studied with 980 nm NIR laser excitation and the results obtained for UCNPs and UCN@SiO₂ NPs compared. It is revealed that the increase in the NIR laser irradiation time from 1 s to 30 s leads to an increase in the amount of DOX release in a controlled manner. In vitro studies using model cancer cell lines have been performed to check the effectiveness of our materials for controlled drug delivery and therapeutic applications. Obtained results showed that the designed UCN@SiO₂–GO nanocomposite can be used for controlled delivery based therapeutic applications and for cancer treatment.

A GO–UCN–SiO₂ hybrid nanocomposite for loading of doxorubicin and its use in in vitro efficiency for killing carcinoma cells.     

Dual-modal imaging and excellent anticancer efficiency of cisplatin and doxorubicin loaded NaGdF4:Yb3+/Er3+ nanoparticles

NaGdF₄:Yb³⁺/Er³⁺ nanoparticles were synthesized via a modified hydrothermal route. The dependence of structure and morphology on the dosage of sodium polyacrylate was studied by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The as-prepared nanoparticles could be used for T₂ weighted magnetic resonance imaging due to the paramagnetism of Gd³⁺. cis-dichlorodiamineplatinum (CDDP) could be loaded onto NaGdF₄:Yb³⁺/Er³⁺ nanoparticles through binding carboxyl in the form of Pt–O bonds, and doxorubicin (DOX) could be loaded via hydrogen bonding. DOX could also be loaded onto the NaGdF₄–CDDP composite in the same manner, and the loading efficiency of both drugs remained unchanged. Three as-prepared drug delivery systems were used for tumor inhibition both in vitro and in vivo, and the results indicated that NaGdF₄–CDDP–DOX displayed the greatest inhibitory capacity.

The drug delivery system NaGdF₄–CDDP–DOX showed best tumor inhibition capacity both in vitro and in vivo.     

Thermosensitive star polymer pompons with a core–arm structure as thermo-responsive controlled release drug carriers

In contrast with traditional chemotherapy, controlled drug delivery systems provide many advantages. Herein, a thermosensitive star polymer pompon with a core–arm structure was synthesized using a grafting-on method as a thermo-responsive controlled release drug carrier. Single-chain cyclized/knotted poly tetra(ethylene glycol) diacrylate (polyTEGDA) was used as the hydrophobic core, and thermosensitive linear poly(N-isopropylacrylamide-co-N-methylolacrylamide) (poly(NIPAM-co-NMA)) was selected as the hydrophilic arm. Below or above its lower critical solution temperature (LCST), the linear poly(NIPAM-co-NMA) grafted onto the polyTEGDA core adopted a stretched or curled status, respectively, then the drug could be loaded in or extruded out. The LCST of star polyTEGDA-b-poly(NIPAM-co-NMA) was adjusted to slightly above body temperature (37 °C). The antitumor drug doxorubicin (DOX) was successfully loaded into the pompons with a high loading capacity of 19.45%. The cumulative release of DOX from loaded pompons in vitro for 72 hours was 71% and 20.7% at 42 °C and 37 °C, respectively, indicating that the excellent temperature-controlled release characteristics result from the unique thermo-responsive extrusion effect. Moreover, DOX loaded polyTEGDA-b-poly(NIPAM-co-NMA) pompons achieved better antitumor ability against ovarian carcinoma SKOV3 cells at 42 °C compared with that at 37 °C. These results suggest that star polyTEGDA-b-poly(NIPAM-co-NMA) pompons have considerable promise as thermo-responsive controlled drug delivery carriers.

Herein, a thermosensitive star polymer pompon with a core–arm structure was synthesized using a grafting-on method as a thermo-responsive controlled release drug carrier.     

Designing a high-performance smart drug delivery system for the synergetic co-absorption of DOX and EGCG on ZIF-8

Due to the extreme pore volume and valuable surface area, zeolitic imidazole frameworks (ZIFs) are promising vehicles that enhance the delivery of therapeutic agents to tissues. Furthermore, these nanoporous materials have high stability in the pH and temperature of the surrounding healthy cells (37 °C and pH = 7) and an exotic potential to deform in carcinogenic environment (T > 37 °C and pH ∼ 5.5), which make them perfect smart drug delivery vehicle candidates. In this work, a series of molecular dynamics (MD) and metadynamics simulations have been performed to gain molecular insight into the mechanisms involved in the process of co-loading of doxorubicin (DOX) and EpiGalloCatechin-3 Gallate (EGCG) on ZIF-8, which form a smart drug delivery system (SDDS). The obtained results revealed that DOX was adsorbed on the carrier mostly through electrostatic interactions (E_coul = ∼−1200 kJ mol⁻¹, E_tot = −1700 kJ mol⁻¹), and EGCG was stacked on ZIF-8 mainly via van der Waals interactions (E_L-J = ∼−600 kJ mol⁻¹, E_tot = ∼−1200 kJ mol⁻¹). It is worth mentioning that the drug–drug L-J interactions (E_L-J = ∼500 kJ mol⁻¹) were also important in the co-loading process. The insertion of DOX and EGCG as additive agents to the initial ZIF-8/EGCG and ZIF-8/DOX systems led to the enhancement of the drug–carrier pair interactions to about ∼−2300 kJ mol⁻¹ and ∼−2000 kJ mol⁻¹, respectively. This finding implied that the drug–drug interactions had a complementary role in the development of SDDS via ZIF-8. From the metadynamics simulation, it was found that the geometry of the drugs is a determining factor in an efficient co-loading SDDS.

Adsorption free energy of a molecule depends on where and how the molecule meets ZIF-8 surface.     

pH-responsive polymeric nanoparticles with tunable sizes for targeted drug delivery

Biodegradable nanoparticles (NPs) have shown great promise as intracellular imaging probes, nanocarriers and drug delivery vehicles. In this study, we designed and prepared amphiphilic cellulose derivatives via Schiff base reactions between 2,3-dialdehyde cellulose (DAC) and amino compounds. Polymeric NPs were facilely fabricated via the self-assembly of the as-synthesized amphiphilic macromolecules. The size distribution of the obtained NPs can be tuned by changing the amount and length of the grafted hydrophobic side-chains. Anticancer drugs (DOX) were encapsulated in the NPs and the drug-loaded NPs based on cellulose derivatives were stable in neutral and alkaline environments for at least a month. They rapidly decomposed with the efficient release of the drug in acidic tumor microenvironments. These drug-loaded NPs have the potential for application in cancer treatment.

Novel nanoparticles for efficient drug delivery were designed and constructed using polymeric 2,3-dialdehyde cellulose (DAC). The drug DOX was encapsulated into nanoparticles and underwent thoroughly controlled release in acidic tumor microenvironments.     

Development and evaluation of a pH-responsive and water-soluble drug delivery system based on smart polymer coating of graphene nanosheets: an in silico study

The objective of this study is to develop a controlled and water-soluble delivery system for doxorubicin (DOX) based on the coating of graphene (G) with a smart polymer. A combination of polyethyleneimine (PEI) and G–DOX is investigated by performing density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Several parameters have been employed to evaluate the effect of PEI on the adsorption and release mechanisms of DOX. The obtained results indicated that the binding energy of the drug molecule on G in the presence of PEI is enhanced by about 20% under neutral conditions, whereas the drug absorption becomes weaker in an acidic environment so that DOX could be separated from the carrier surface using near-infrared radiation (NIR). Based on the atom in molecule (AIM) theory, two hydrogen bonds with strengths of about −12.59 and −39.99 kJ mol⁻¹ have been established. Furthermore, evaluating the dynamic behavior of the designed systems in water solution shows that the polymer in physiological pH rapidly adsorbed on the drug–carrier complex. However, at acidic pH, it is quickly desorbed from the carrier surface and the G–DOX complex can be exposed to cancer cells. The obtained results of the present research may be used in future experimental work to design smart DDSs.

The objective of this study is to develop a controlled and water-soluble delivery system for doxorubicin (DOX) based on the coating of graphene (G) with a smart polymer.     

Nanoformulation-by-design: an experimental and molecular dynamics study for polymer coated drug nanoparticles

The formulation of drug compounds into nanoparticles has many potential advantages in enhancing bioavailability and improving therapeutic efficacy. However, few drug molecules will assemble into stable, well-defined nanoparticulate structures. Amphiphilic polymer coatings are able to stabilise nanoparticles, imparting defined surface properties for many possible drug delivery applications. In the present article we explore, both experimentally and in silico, a potential methodology to coat drug nanoparticles with an amphiphilic co-polymer. Monomethoxy polyethylene glycol–polycaprolactone (mPEG-b-PCL) diblock copolymers with different mPEG lengths (M_w 350, 550, 750 and 2000), designed to give different levels of colloidal stability, were used to coat the surface of indomethacin nanoparticles. Polymer coating was achieved by a flow nanoprecipitation method that demonstrated excellent batch-to-batch reproducibility and resulted in nanoparticles with high drug loadings (up to 78%). At the same time, in order to understand this modified nanoprecipitation method at an atomistic level, large-scale all-atom molecular dynamics simulations were performed in parallel using the GROMOS53a6 forcefield parameters. It was observed that the mPEG-b-PCL chains act synergistically with the acetone molecules to dissolve the indomethacin nanoparticle while after the removal of the acetone molecules (mimicking the evaporation of the organic solvent) a polymer–drug nanoparticle was formed (yield 99%). This work could facilitate the development of more efficient methodologies for producing nanoparticles of hydrophobic drugs coated with amphiphilic polymers. The atomistic insight from the MD simulations in tandem with the data from the drug encapsulation experiments thus leads the way to a nanoformulation-by-design approach for therapeutic nanoparticles.

Experimental studies of drug–polymer nanoparticle formation combined with molecular dynamics simulations provide atomistic explanations for the high drug loadings obtained.     

Investigation of the adsorption properties of gemcitabine anticancer drug with metal-doped boron nitride fullerenes as a drug-delivery carrier: a DFT study

Anticancer-drug delivery is now becoming a challenging approach for researchers as it allows controlled drug delivery near cancerous cells with minimized generic collection and the avoidance of secondary side effects. Hence in this work, the applications of nanostructures as anticancer drug-delivery carriers were widely investigated to target cancerous tissues. Based on DFT calculations, we investigated the transition metal-doped boron nitride nanostructure as a drug-delivery agent for the gemcitabine drug utilizing the B3LYP/6-31G (d, p) level of theory. In this research, the adsorption energy and electronic parameters of gemcitabine on the interaction with the metal-doped BN nanostructures were studied. It has been observed that metal doping significantly enhances the drug-delivery properties of BN nanostructures. Among the investigated nanostructures, Ni–BN has been found to be the most prominent nanostructure to transport gemcitabine with an elevated value of adsorption energy in both the gas phase (−45.79) and water media (−32.46). The interaction between gemcitabine and BN nanostructures was confirmed through frontier molecular orbitals and stabilization energy analysis. The fractional charge transfer, MEP, NCI, and NBO analyses exposed the charge transfer from drug molecule to the BN nanostructures. Transition density maps and UV-VIS spectra were also plotted to investigate the excited-state properties of the designed complexes. Thus, the present study provides an in-depth interaction mechanism of the gemcitabine drug with BN, which reveals that metal-doped BN nanostructures can be a favorable drug-delivery vehicle for the gemcitabine anticancer drug.

Anticancer-drug delivery is now becoming a challenging approach for researchers as it allows controlled drug delivery near cancerous cells with minimized generic collection and the avoidance of secondary side effects.     

Molecular engineering of the last-generation CNTs in smart cancer therapy by grafting PEG–PLGA–riboflavin

In this work, the effect of environment and additives on the self-assembly and delivery of doxorubicin (DOX) have been studied. A microfluidic system with better control over molecular interactions and high surface to volume ratio has superior performance in comparison to the bulk system. Moreover, carbon nanotube (CNT) and CNT-doped structures have a high surface area to incorporate the DOX molecules into a polymer and the presence of functional groups can influence the polymer–drug interactions. In this work, the interactions of DOX with both the polymeric complex and the nanotube structure have been investigated. For quantification of the interactions, H-bonding, gyration radius, root-mean-square deviation (RMSD), Gibbs free energy, radial distribution function (RDF), energy, and Solvent Accessible Surface Area (SASA) analyses have been performed. The most stable micelle–DOX interaction is attributed to the presence of BCN in the microfluidic system according to the gyration radius and RMSD. Meanwhile, for DOX-doped CNT interaction the phosphorus-doped CNT in the microfluidic system is more stable. The highest electrostatic interaction can be seen between polymeric micelles and DOX in the presence of BCN. For nanotube–drug interaction, phosphorus-doped carbon nanotubes in the microfluidic system have the largest electrostatic interaction with the DOX. RDF results show that in the microfluidic system, nanotube–DOX affinity is larger than that of nanotube–micelle.

In this work, the effect of environment and additives on the self-assembly and delivery of doxorubicin (DOX) have been studied.     

One-step dry synthesis of an iron based nano-biocomposite for controlled release of drugs

Bio-based drug carriers have gained significant importance in Control Drug Delivery Systems (CDDS). In the present work, a new iron-based magnetic nano bio-composite (nano-Fe-CNB) is developed in a one-step dry calcination process (solventless) using a seaweed-based biopolymer. The detailed analysis of the developed nano Fe-CNB is carried out using FE-SEM, HR-TEM, P-XRD, XPS, Raman spectroscopy, FTIR etc. and shows that nano-Fe-CNB consists of nanoparticles of 5–10 nm decorated on 7–8 nm thick 2-D graphitic carbon material. The impregnation of nano-Fe-CNB into the calcium alginate (CA) hydrogel beads is found to have good drug loading capacity as well as pH responsive control release behavior which is demonstrated using doxorubicin (DOX) as a model cancer drug. The drug loading experiments exhibit ∼94% loading of DOX and release shows ∼38% and ∼8% release of DOX at pH 5.4 and 7.4 respectively. The developed nano Fe-CNB facilitates strong electrostatic interactions with cationic DOX molecules at pH 7.4 and thereby restricts the release of the drug at physiological pH. However, at cancer cell pH (5.4), the interaction between the drug and nano-Fe-CNB reduces which facilitates more drug release at pH 5.4. Thus, the developed nano-biocomposite has the potential to reduce the undesired side effects associated with faster release of drugs.

Schematics for synthesis and application of magnetic nano-biocomposite for control release of DOX.     

Construction of a graphene/polypyrrole composite electrode as an electrochemically controlled release system

A new class of stimuli responsive drug delivery systems is emerging to establish new paradigms for enhancing therapeutic efficacy. To date, most electro-responsive systems rely on noble metal electrodes that likely cause the limitations for implantation applications. Herein, a graphene/polypyrrole composite electrode (GN–PPy–FL) was fabricated based on two-dimensional (2D) graphene (GN) film and conductive and biocompatible polypyrrole (PPy) nanoparticles loaded with a negative drug model of fluorescein sodium (FL) via chemical oxidation polymerization. The conductive composite electrode was utilized as a drug carrier to realize the electrically controlled release of the FL. The release rate from conductive nanoparticles can be controlled by the applied voltages. The study provides a multi-stimuli responsive drug release system, demonstrating the potential applications of the controlled release of various drugs, peptides or proteins.

A biocompatible conductive composite electrode GN–PPy–FL can realize controlled release of a drug model triggered by low voltages.     

Doxorobicin as cargo in a redox-responsive drug delivery system capped with water dispersible ZnS nanoparticles

In this work, we have prepared and investigated a redox-responsive drug delivery system (DDS) based on a porous carrier. Doxorubicin (DOX), a chemotherapy medication for treatment of different kinds of cancer, was used as a model drug in the study. DOX was loaded in ordered hexagonal mesoporous silica SBA-15, a nanoporous material with good biocompatibility, stability, large pore size and specific surface area (S_BET = 908 m² g⁻¹, V_P = 0.79 cm³ g⁻¹, d = 5.9 nm) and easy surface modification. To prepare the redox-responsive system, cystamine derivative ligands, with redox active disulphide linkers were grafted onto the surface of SBA-15. To ensure no significant premature release of DOX from the porous system, thioglycolic acid modified ZnS nanoparticles (ZnS–COOH NPs) were used as pore capping agents. The grafted redox-responsive cystamine derivative ligand containing disulphide linkers was bonded by a peptide bond to the thioglycolic acid groups of ZnS–COOH NPs, capping the pores. Once the disulphide bond was cleaved, the ZnS–COOH NPs caps were released and pores were opened to deliver the DOX cargo. The dithiol bond was cleavable by redox active molecules such as dithiothreitol (DTT) or glutathione, the concentration of which in cancer cells is 4 times higher than in healthy cells. The redox release of DOX was studied in two different media, physiological saline solution with DTT and saline without DTT. The prepared DDS proved the concept of redox responsive release. All samples were characterised by powder X-ray diffraction (XRD), transition electron microscopy (TEM), nitrogen adsorption/desorption at 77 K, Fourier-transform infrared spectroscopy (FTIR), thermal analysis and zeta potential measurements. The presence of semiconducting ZnS nanoparticle caps on the pore openings was detected by magnetic measurements using SQUID magnetometry showing that such cargo systems could be monitored using magnetic measurements which opens up the possibilities of using such drug delivery systems as theranostic agents.

Redox-responsive drug delivery system was studied. ZnS nanoparticles served as pore capping agent to prevent premature release of anticancer drug. Such cargo can be monitored by magnetic field which opens possibilities its use in theranostics.     

Dual-generation dendritic mesoporous silica nanoparticles for co-delivery and kinetically sequential drug release

Although multi-drug synergetic therapy is increasingly important in clinical application, sophisticated delivery systems with the ability to deliver multiple drugs and realize sequential release with independently tunable kinetics at different stages are highly desirable. In this study, a dual-generation mesoporous silica nanoparticle (DAMSN) with three-dimensional dendrimer-like structure as an adaptable dual drug delivery system is developed. The DAMSN was synthesized via a heterogeneous interfacial reaction and was of uniformly spherical morphology (150–170 nm) with dendritic structures and hierarchical pores (inner pore, 3.5 nm; outer pore, 8.3 nm). And the inner generation of DAMSN was modified with 3-aminopropyltriethoxysilane (APTMS). The IBU and BSA as model drugs were loaded into the inner generation via covalent conjugation and the outer generation by electrostatic adsorption, respectively. Intriguingly, DAMSN underwent a rapid bio-degradation for about 4 days, partly due to its center-radial dendritic channel structure. The release results showed that IBU was of a typical two-phase release profile with almost zero release in the first 12 h and more sustained release for the following 88 h, while BSA was sustained over a long period of 100 h. Notably, the release behaviors of both drugs can be independently tailored by changing the intrinsic properties of the DAMSN. In addition, DAMSN exhibited good bio-compatibility. These results indicated that the dual-generation, dendrimer-like MSN structure could spatiotemporally present different drugs to realize sequential drug release, and has potential use in the field of tissue engineering and regenerative medicine.

The designed DAMSN could simultaneously load IBU and BSA, and realize sequential drug release efficiently.     

Functionalization of MOF-5 with mono-substituents: effects on drug delivery behavior

Metal organic frameworks (MOFs) are widely used in drug carrier research due to their tunability. The properties of MOFs can be adjusted through incorporation of mono-substituents to obtain pharmaceutical carriers with excellent properties. In this study, different functional groups of –NH₂, –CH₃, –Br, –OH and –CH₂ CH are connected to MOF-5 to analyse the effect of mono-substituent incorporation on drug delivery properties. The resulting MOFs have similar structures, except for Br–MOF. The pore size of this series of MOFs ranges from 1.04 nm to 1.10 nm. Using oridonin (ORI) as a model drug, introduction of the functional groups appears to have a significant effect on the drug delivery performance of the MOFs. The IRMOFs can be ranked according to drug-loading capacity: MOF-5 > HO–MOF-5 > H₃C–MOF-5 = Br–MOF-5 > H₂N–MOF-5 > CH₂ CH–MOF-5. The ORI release from ORI @IRMOFs is explored at two different pH values: 7.4 and 5.5, and the ORI@IRMOFs are ranked according to the cumulative release percentage of ORI: ORI@MOF-5 > ORI@Br–MOF-5 > ORI@H₃C–MOF-5 > ORI@H₂N–MOF-5 > CH₂ CH–MOF-5 > ORI@ HO–MOF-5. In particular, the release behaviour of ORI@MOFs is described through a new model. The different drug delivery performance of MOFs may be due to the complex interactions between MOFs and ORI. In addition, the introduction of single substituents does not change the biocompatibility of MOFs. MTT in vitro experiments prove that this series of MOFs has low cytotoxicity. This study shows that the incorporation of single substituents can effectively adjust the drug delivery behaviour of MOFs, which is conducive to realization of personalized drug delivery modes. The introduction of active groups can also facilitate post-synthesis modification to achieve coupling of targeting groups. MOFs incorporated with single substituents perform favorably in terms of use as biomedical drug delivery alternative carriers in effective drug payload and flexible drug release.

Metal organic frameworks (MOFs) are widely used in drug carrier research due to their tunability.     

Self-assemblies of pluronic micelles in partitioning of anticancer drugs and effectiveness of this system towards target protein

Micelles formed by pluronic triblock copolymers are known to be a promising class of drug delivery vehicles. Quantitative mechanistic insights into the ability of pluronic micelles to improve the solubility of poorly water soluble drugs, encapsulation and delivery of hydrophilic drugs are not available. The current study evaluated the energetics of encapsulation of chemotherapeutic drugs gemcitabine, cytarabine, and hydroxyurea in pluronic F127 and F68 micelles. In addition, the interactions of the drugs released from pluronic micellar media with serum albumin, which is a major circulatory transport protein, and subsequent conformational changes have also been analyzed with the help of calorimetry and spectroscopy. All the drugs showed improved partitioning in F127 micelles, the extent of which slightly increased with temperature rise. Interestingly, drug–protein binding is enhanced upon delivery from pluronic micelles without affecting the conformational integrity of the protein. This study highlights the role of drug functionalities, hydrophobicity, and steric factors towards their partitioning in pluronic micelles. Such studies are important in understanding physicochemical aspects of drug encapsulation and release, and lead to establishing structure–property–energetics correlations for developing suitable nano-drug delivery vehicles.

Micelles formed by pluronic triblock copolymers are known to be a promising class of drug delivery vehicles.     

Effects of pore size on in vitro and in vivo anticancer efficacies of mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSN) have been widely applied for drug delivery systems. To investigate the effects of pore size on anticancer efficacies, MSN with different pore sizes but similar particle sizes and surface charges were synthesized via a microemulsion method. The pore structures of MSN were characterized by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and N₂ adsorption–desorption isotherms. Doxorubicin loaded MSN (DOX/MSN) were prepared and the minimum drug loading capacity was detected in DOX/MSN with a pore size of 2.3 nm (DOX/MSN2). DOX/MSN with a pore size of 8.2 nm (DOX/MSN8) showed a comparable drug loading amount in comparison with ones with a pore size of 5.4 nm (DOX/MSN5). In vitro drug release profiles showed that DOX/MSN5 could release DOX quickly and completely. Compared with DOX/MSN2 and DOX/MSN8, DOX/MSN5 showed the higher cellular uptake and nucleic concentration of DOX in QGY-7703 cells, which led to efficient cell-apoptosis induction and anti-proliferation effect, and thus the optimal in vivo anticancer activities. Taken together, these results highlighted the importance of pore size in anticancer efficacies, which would serve as a guideline in the rational design of MSN for cancer therapy.

MSN with suitable pore sizes achieved an outstanding performance for in vitro and in vivo antitumor efficacies.