Molecularly imprinted nanoparticles and their releasing properties, bio-distribution as drug carriers

Molecular imprinted nanoparticles(MINPs) can memorize the shape and functional group positions complementary to template, which account for the large drug loading capacity and slow drug release behavior as drug carriers. We synthesized MINPs via precipitation polymerization with vinblastine(VBL) as a model drug, and investigated the drug loading,releasing property in vitro and bio-distribution in vivo. The obtained MINPs, from 300 to 450 nm,had smooth surface and favorable dispersibility. The entrapment efficacy and drug loading capacity of VBL loaded MINPs(MINPs-VBL) were 83.25% and 8.72% respectively. In PBS(pH 7.4),MINPs-VBL showed sustained release behavior. The cumulative release percentage reached about 70% during 216 h and no burst release was observed. The releasing behavior of MINPsVBL in vitro conformed to the first-order kinetics model. MINPs-VBL and commercially available vinblastine sulfate injection(VBL injection) were injected via tail vein of SD rats respectively to investigate the bio-distribution. MINPs-VBL group showed higher concentration of VBL in tissues and serum than VBL injection group after 60 min, and the drug level in liver was the highest. MINPs-VBL exhibited liver targeting trend to some extent, which was based on the evaluation of drug targeting index(DTI) and drug selecting index(DSI).

Preparation of Star-Shaped Polylactic Acid Drug Carrier Nanoparticles

Drug carrier biocompatible and biodegradable nanoparticles of about 15 nm were prepared by solvent evaporation technique from star-shaped poly(D,L-lactide) synthesized using dipentaerythritol as core and Tin (II) ethylhexanoate as catalyst.

Self-assembly Polyrotaxanes Nanoparticles as Carriers for Anticancer Drug Methotrexate Delivery

α-Cyclodextrin/poly(ethylene glycol)(α-CD/PEG) polyrotaxane nanoparticles were prepared via a self-assembly method. Anticancer drug methotrexate(MTX) was loaded in the nanoparticles. The interaction between MTX and polyrotaxane was investigated. The formation, morphology, drug release and in vitro anticancer activity of the MTX loaded polyrotaxane nanoparticles were studied. The results show that the MTX could be efficiently absorbed on the nanoparticles, and hydrogen bonds were formed between MTX andα-CDs. The typical channel-type stacking assembly style of polyrotaxane nanoparticles was changed after MTX was loaded. The mean diameter of drug loaded polyrotaxane nanoparticles were around 200 nm and the drug loading content was as high as about 20%. Drug release profiles show that most of the loaded MTX was released within 8 hours and the cumulated release rate was as high as 98%. The blank polyrotaxane nanoparticles were nontoxicity to cells. The in vitro anticancer activity of the MTX loaded polyrotaxane nanoparticles was higher than that of free MTX.

Nanoparticles for the treatment of spinal cord injury

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

Inorganic nanoparticles for hydrophobic anticancer drug delivery

OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.

Functionalized magnetic nanoparticles for drug delivery in tumor therapy

The side effects of chemotherapy are mainly the poor control of drug release. Magnetic nanoparticles(MNPs) have super-paramagnetic behaviors which are preferred for biomedical applications such as in targeted drug delivery, besides, in magnetic recording, catalysis, and others. MNPs, due to high magnetization response, can be manipulated by the external magnetic fields to penetrate directly into the tumor, thus they can act as ideal drug carriers. MNPs also play a crucial role in drug delivery system because of their high surface-to-volume ratio and porosity. The drug delivery in tumor therapy is related to the sizes, shapes, and surface coatings of MNPs as carriers. Therefore, in this review, we first summarize the effects of the sizes, shapes, and surface coatings of MNPs on drug delivery, then discuss three types of drug release systems, i.e., p H-controlled, temperature-controlled, and magnetic-controlled drug release systems, and finally compare the principle of passive drug release with that of active drug release in tumor therapy.

Preparation and Stability Evaluation of Size-Controllable PDHCA-β-CD Nanoparticles as Drug Carrier

A novel biocompatible polymer was prepared by grafting the derivate of β-cyclodextrin （6-SH-β-CD） onto poly（3,4-dihydroxycinnamic acid） （PDHCA） via Michael addition. PDHCA-β-CD nanoparticles were prepared by the self-assembly of amphiphilic PDHCA-β-CD polymer with N,N-dimethylformamide （DMF） as good solvent and water as poor solvent. The PDHCA-β-CD nanoparticles were monodispersed with spherical morphology as shown in the scanning electron microscopic （SEM） images in accord with the result of dynamic light scattering （DLS） measurement. The size of the nanoparticles could be controlled from 60 to 180 nm by tuning the grafting degree （GD） of PDHCA-β-CD polymer and also significantly influenced by the amount of water used during the process. These as-prepared nanoparticles were stable without any significant change in the particle size after six-months＇ storage and even after being irradiated by UV at 2〉280 nm for hours. The formation mechanism of PDHCA-β-CD nanoparticles was explored. The content of doxombicin （DOX） loaded onto the nanoparticles was up to 39% with relatively high loading efficiency （approximately 78.8% of initial DOX introduced was loaded）. In vitro release studies suggested that DOX released slowly from PDHCA-β-CD nanoparticles. These features strongly support the potential of developing PDHCA-β-CD nanoparticles as carriers for the controlled delivery of drug.

Dialdehyde starch nanoparticles: Preparation and application in drug carrier

Dialdehyde starch nanoparticles (DASNP) were prepared by the redox reaction of NaIO4 and starch in water-in-oil microemulsion. IR spectrum showed that DASNP had aldehyde groups, and quantitative alkali consumption showed that its dialdehyde content was about (50±5)%. The average diameter of DASNP determined by SEM was about 100 nm. TGA-DTA showed that its thermal stability was better than starch nanoparticle (StNP) and dialdehyde starch (DAS). Its low biological toxicity was detected by cell experiment. Also the best mass ratio of doxorubicin (DOX) to combined DASNP detected by UV-VIS was 15 : 1, and the product was effective for controlled release of DOX. The cell experiment showed that the drug-carrier particle (DOX-DASNP) can release DOX for a long time and strengthened the effect of the anticancer drug. This work demonstrates that the DASNP, which has good thermal stability, small particle size, low biological toxicity, and slowly anticancer drug-releasing to strengthen drug effect, is a potentially useful carrier for anticancer drug.

A new drug carrier:Magnetite nanoparticles coated with amphiphilic block copolymer

This paper reports on the synthesis and characterization of 4 nm magnetite nanoparticles coated with amphiphilic block copolymers of poly(ethyl methacrylate)-b-poly(2-hydroxyethyl methacrylate) (PEMA- b-PHEMA) by surface-initiated atom transfer radical polymerization (ATRP), which can act as new potential carriers for hydrophobic targeted drug delivery. Vibrating sample magnetometer analysis indi-cated that the magnetite nanoparticles were superparamagnetic at room temperature. Thermogravim-etric analysis (TGA) was applied to studying the property of surface of magnetite nanoparticles, and the surface density of macromolecules was calculated. The grafting density of oleic acid, BrMPA and PEMA was 5.8, 3.9, 0.16 chain/nm2 respectively, which indicates that the initiation efficiency decreases due to the influence of large space of oleic acid molecules. In vitro progesterone and (-)-isoproterenol hy-drochloride release in phosphate buffered saline (PBS) at pH 7.0 and 37℃ was conducted in order to demonstrate the function of drug loading and release. The results showed that the amount of drug carried into the core-shell Fe3O4@PEMA-b-PHEMA depends on the length of hydrophobic segment of block copolymer. The release of progesterone (37% after 22 h in our previous work) was compared with the release of (-)-isoproterenol hydrochloride (80% after 50 min), demonstrating that the strong hy-drophobic interaction between hydrophobic segment and drug can effectively control the release of hydrophobic drugs.

Size-transformable nanoparticles with sequentially triggered drug release and enhanced penetration for anticancer therapy

There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.

Charge-reversal nanoparticles: novel targeted drug delivery carriers

Spurred by significant progress in materials chemistry and drug delivery, charge-reversal nanocarriers are being developed to deliver anticancer formulations in spatial-, temporal- and dosagecontrolled approaches. Charge-reversal nanoparticles can release their drug payload in response to specific stimuli that alter the charge on their surface. They can elude clearance from the circulation and be activated by protonation, enzymatic cleavage, or a molecular conformational change. In this review, we discuss the physiological basis for, and recent advances in the design of charge-reversal nanoparticles that are able to control drug biodistribution in response to specific stimuli, endogenous factors(changes in p H,redox gradients, or enzyme concentration) or exogenous factors(light or thermos-stimulation).

Nanoparticles modified by polydopamine: Working as “drug” carriers

Inspired by the mechanism of mussel adhesion,polydopamine(PDA),a versatile polymer for surface modification has been discovered.Owing to its unique properties like extraordinary adhesiveness,excellent biocompatibility,mild synthesis requirements,as well as distinctive drug loading approach,strong photothermal conversion capacity and reactive oxygen species(ROS)scavenging facility,various PDA-modified nanoparticles have been desired as drug carriers.These nanoparticles with diverse nanostructures are exploited in multifunctions,consisting of targeting,imaging,chemical treatment(CT),photodynamic therapy(PDT),photothermal therapy(PTT),tissue regeneration ability,therefore have attracted great attentions in plenty biomedical applications.Herein,recent progress of PDA-modified nanoparticle drug carriers in cancer therapy,antibiosis,prevention of inflammation,theranostics,vaccine delivery and adjuvant,tissue repair and implant materials are reviewed,including preparation of PDA-modified nanoparticle drug carriers with various nanostructures and their drug loading strategies,basic roles of PDA surface modification,etc.The advantages of PDA modification in overcoming the existing limitations of cancer therapy,antibiosis,tissue repair and the developing trends in the future of PDA-modified nanoparticle drug carriers are also discussed.

Entrapment and Sustained Release of Hydrophobic Drugs with Different Molecular Weights from PHBHHx-PEG Nanoparticles

Biodegradable polymeric nanoparticles are more and more frequently used in drug delivery systems, which represent one of the most rapidly developing areas.Inourpreviousstudy,a novelnaturalhybrid polyester,polyethylene glycol 200 (PEG200) end-capped poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx-PEG) was directly produced by Aeromonas hydrophila fermentation. In this study, the performance of the novel biodegradable PHBHHx-PEG copolyester as a sustained release carrier for hydrophobic drugs with different molecular weights and the in vitro sustained release profile were investigated. 5-Fluorouracil(5-Fu, Mw=130.1), TGX221(Mw=364.4), and Rapamycin(RAP, Mw=914.2) were used as the model drugs. PHBHHx-PEG nanoparticles entrapped with 5-Fu, TGX221 and RAP were fabricated by a modified emulsification/solvent evaporation method, respectively. The average diameter of 5-Fu,TGX221, and RAP loaded PHBHHx-PEG nanoparticles was between 198.2-217.4 nm,and the entrapment efficiency of the three drugs was 62.5%, 93.4% and 91.9%,respectively. The in vitro release profiles of 5-Fu, TGX221 and RAP from PHBHHx-PEG nanoparticles were different. 5-Fu showed faster release rate and an obvious initial burst release phase. TGX221 and RAP were demonstrated to be released more slowly and steadily. The release percentages of 5-Fu, TGX221 and RAP were97.7%, 85.1% and 74.7% after releasing for 72 h. PHBHHx-PEG is a kind of promising material as a carrier for the entrapment and delivery of hydrophobic drugs especially for those drugs with high molecular weight.

A new kind of magnetic targeting induction heating drug carrier and its physical and biological properties

Nano-carbon and iron composite―carbon-coated iron nanoparticles (CCINs) produced by carbon arc method can be used as a new kind of magnetic targeting induction heating drug carrier for cancer therapy. The structure and morphology of CCINs are studied by X-ray diffraction (XRD) and transmission electron microscope (TEM). Mossbauer spectra of these nanoparticles show that they contain only iron and carbon, without ferric carbide and ferric oxide. CCINs can be used as the magnetic drug carrier, with the effect of targeting magnetic induction heating in its inner core and higher drug adsorption in its nano-carbon shell outside because of its high specific surface area. CCINs can absorb Epirubicin (EPI) of 160 μg/mg measured by an optical spectrometer. In acute toxicity experiment with mice, the median lethal dose (LD50) of EPI is 16.9 mg/kg, while that of EPI-CCINs mixture is 20.7 mg/kg and none of the mice died after pure CCINs medication. The results show that pure CCINs belong to non-toxic grade and EPI delivery in mixture with CCINs can reduce its acute toxicity in mice. The magnetic properties of CCINs and their magnetic induction heating are investigated. The iron nanoparticle in its inner core has better magnetism with a good effect on targeting magnetic induction heating. When the CCINs are mixed with physiological salt water and are injected uniformly in pig's liver, the temperature goes up to 48℃. While in the case that CCINs are filled in a certain section of pig's liver, the temperature goes up to 52℃. In both cases the temperature is high enough to kill the cancer cell. CCINs have potential applications in cancer therapy.

Cell-mediated and cell membrane-coated nanoparticles for drug delivery and cancer therapy

Nanotechnology-based drug delivery platforms have been developed over the last two decades because of their favorable features in terms of improved drug bioavailability and stability.Despite recent advancement in nanotechnology platforms,this approach still falls short to meet the complexity of biological systems and diseases,such as avoiding systemic side effects,manipulating biological interactions and overcoming drug resistance,which hinders the therapeutic outcomes of the NP-based drug delivery systems.To address these issues,various strategies have been developed including the use of engineered cells and/or cell membrane-coated nanocarriers.Cell membrane receptor profiles and characteristics are vital in performing therapeutic functions,targeting,and homing of either engineered cells or cell membrane-coated nanocarriers to the sites of interest.In this context,we comprehensively discuss various cell-and cell membrane-based drug delivery approaches towards cancer therapy,the therapeutic potential of these strategies,and the limitations associated with engineered cells as drug carriers and cell membrane-associated drug nanocarriers.Finally,we review various cell types and cell membrane receptors for their potential in targeting,immunomodulation and overcoming drug resistance in cancer.

Cisplatin-loaded Poly(L-glutamic acid)-g-Methoxy Poly(ethylene glycol) Nanoparticles as a Potential Chemotherapeutic Agent against Osteosarcoma

Herein, cisplatin-loaded poly（L-glutamic acid）-g-methoxy poly（ethylene glycol） nanoparticles were evaluated as a potential chemotherapeutic agent against osteosarcoma by using alone or with an i RGD（internalizing RGD, CRGDKDPDC）. The release rate of platinum from the cisplatin-loaded nanoparticles CDDP/PLG160-g-m PEG2K（CDDP-NPs） accelerated with the increase of the acidity of the environment. In vitro test demonstrated that CDDP-NPs could inhibit the proliferation of MNNG/Hos osteosarcoma cells with IC50（72 h） of 12.2 μg·mL^-1. In vivo test for MNNG/Hos osteosarcoma tumor bearing mice exhibited that CDDP-NPs had comparable or slightly higher efficacy but significantly lower side effects in comparison with free CDDP. The coadministration of i RGD could further enhance the anticancer efficacy of CDDP-NPs against MNNG/Hos osteosarcoma without bringing obvious side effects. Therefore, CDDP-NPs using alone or with iRGD have great potential for the treatment of osteosarcoma.

Stimulus-responsive polymeric nanoparticles for biomedical applications

Polymeric nanoparticles with unique properties are regarded as the most promising materials for biomedical applications including drug delivery and in vitro/in vivo imaging.Among them,stimulus-responsive polymeric nanoparticles,usually termed as "intelligent" nanoparticles,could undergo structure,shape,and property changes after being exposed to external signals including pH,temperature,magnetic field,and light,which could be used to modulate the macroscopical behavior of the nanoparticles.This paper reviews the recent progress in stimulus-responsive nanoparticles used for drug delivery and in vitro/in vivo imaging,with an emphasis on double/multiple stimulus-responsive systems and their biomedical applications.

靶向表皮生长因子受体的百秋李醇纳米颗粒抑制非小细胞肺癌裸鼠皮下移植瘤生长的作用及机制

目的探讨靶向表皮生长因子受体(EGFR)的百秋李醇(PA)纳米颗粒对非小细胞肺癌(NSCLC)肿瘤生长的抑制作用及其机制。方法①利用二硬脂酰基磷脂酰乙醇胺-聚乙二醇-EGFR靶向肽AA1(DSPE-PEG-AA1)脂质体负载PA,构建靶向EGFR的PA脂质体纳米颗粒(EGFR-PA-NP)。②将人NSCLC A549细胞(2×106个/只)接种于裸鼠腋下,建立肺癌异种皮下移植瘤裸鼠模型。10只模型裸鼠随机分为PA脂质体纳米颗粒(PA-NP)组和EGFR-PA-NP组(n=5),分别尾静脉注射给予20 mg·kg^(-1)相应药物,24 h后剥取肿瘤、癌旁、肝、肺、心、脑、肾、脾、胃、小肠等组织,液相色谱-质谱(LC-MS)法检测药物在体内的组织分布情况。③20只模型裸鼠随机分为模型组(100μL)、PA组(15 mg·kg^(-1))、PA-NP组(15 mg·kg^(-1))和EGFR-PA-NP组(15 mg·kg^(-1))(n=5),分别尾静脉注射给予相应干预,隔日1次,共28 d。28 d后观察药物对裸鼠皮下移植瘤生长的影响。通过原位末端转移酶标记(TUNEL)检测法检测皮下移植瘤中肿瘤细胞凋亡情况,免疫荧光染色法检测皮下移植瘤中血小板-内皮细胞黏附分子(CD31)表达情况,免疫组化染色法和Western blot法检测皮下移植瘤中蛋白激酶B(Akt)、磷酸化(p)-Akt、哺乳动物雷帕霉素靶蛋白(mTOR)和p-mTOR表达水平。结果①制备的EGFR-PA-NP粒径为(122±6.90)nm、Zeta电位为(-24.28±3.76)mV、包封率为85.24%、载药量为8.09%,符合纳米颗粒特征。②LC-MS法检测药物组织分布结果显示,EGFR-PA-NP组药物在裸鼠瘤体内的富集量是PA-NP组的3倍,显著高于PA-NP组(P<0.05)。③在裸鼠A549皮下移植瘤模型中,PA组、PA-NP组和EGFR-PA-NP组裸鼠瘤体体积明显小于模型组(P<0.05),而EGFR-PA-NP组瘤体体积明显小于PA-NP组(P<0.05)。与PA-NP组相比,EGFR-PA-NP组肿瘤中凋亡细胞数量显著增加(P<0.05),CD31蛋白表达水平显著降低(P<0.05),并且p-Akt、p-mTOR表达水平显著降低(P<0.05)。结论EGFR-PA-NP能够通过促进肿瘤细胞凋亡、抑制肿瘤血管新生发挥抗肺癌作用,其机制与抑制Akt/mTOR通路激活相关。

Hydrogel-based local drug delivery strategies for spinal cord repair

Spinal cord injury results in significant loss of motor, sensory, and autonomic functions. Although a wide range of therapeutic agents have been shown to attenuate secondary injury or promote regeneration/repair in animal models of spinal cord injury, clinical translation of these strategies has been limited, in part due to difficulty in safely and effectively achieving therapeutic concentrations in the injured spinal cord tissue. Hydrogelbased drug delivery systems offer unique opportunities to locally deliver drugs to the injured spinal cord with sufficient dose and duration, while avoiding deleterious side effects associated with systemic drug administration. Such local drug delivery systems can be readily fabricated from biocompatible and biodegradable materials. In this review, hydrogel-based strategies for local drug delivery to the injured spinal cord are extensively reviewed, and recommendations are made for implementation.