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Microneedle arrays provide an efficient tool for transdermal drug delivery in a minimally invasive and painless manner, showing great potential applications in medicine. However, it remains challenging to fabricate the desired microneedle arrays, because of their micron-scale size and fine structure. Novel manufacturing technologies are very wanted for the development of microneedle arrays, which would solidly advance the clinical translation of microneedle arrays. 3D printing technology is a powerful manufacturing technology with superiority in fabricating personalized and complex structures. Currently, 3D printing technology has been employed to fabricate microneedle arrays, which could push more microneedle arrays into clinic and inspire the development of future microneedle arrays. This work reviews the art of 3D printing microneedle arrays, the benefits of fabricating microneedle arrays with 3D printing, and the considerations for clinical translation of 3D-printed microneedle arrays. This work provides an overview of the current 3D-printed microneedle arrays in drug delivery.

Transplantation of encapsulated islets has been shown to hold a promising potential treatment for type 1 diabetes (T1D). However, there are several obstacles to overcome, such as immune rejection by the host of the grafts, sustainability of islet function, and retrievability or replacement of the encapsulated system, hinder their clinical applications. In this study, mini-capsule devices containing islets were fabricated by using digital light processing (DLP) 3D printing. To ensure a high survival rate and low immunogenicity of the fabricated islets, 20s was selected as the most suitable printing condition. Meanwhile, the mini-capsule devices with a groove structure were fabricated to prevent islet cells leakage. Subcutaneous transplantations of encapsulated islets in immunocompetent C57BL/6 mice indicated significant improvement in the symptoms of streptozotocin-induced hyperglycemia without any immunosuppression treatment for at least 15 weeks. In vivo intraperitoneal glucose tolerance tests (IPGTT) performed at different time points demonstrated therapeutically relevant glycemic ameliorate of the device. The implants retrieved after 15 weeks still contained viable and adequate numbers of islet cells. The results of this study indicate that the proposed mini-capsule device can deliver sufficient islet cell mass, prevent islet cells leakage, and maintain long-term cell survival while allowing easy retrieval. Furthermore, the proposed encapsulated islets may help with T1D cellular treatment by overcoming the obstacles of islet transplantation.

Detoxification of glutathione (GSH) and insufficient cellular uptake of cisplatin (CDDP) severely compromised the therapeutic efficacy of CDDP. Here, a nano-delivery system (BT-4@PtPPNPs) for CDDP prodrug (C16-Pt(Ⅳ)-PEG) based on a novel sulfhydryl blocking reagent methyl 2-(methylsulfonyl) benzothiazole-6-carboxylate (BT-4) was developed. On the one hand, BT-4 can deplete GSH in tumor cells by directly interacting with reactive sulfhydryl group on GSH, thereby increasing the cytotoxicity of CDDP. On the other hand, the CDDP prodrug carrier C16-Pt(IV)-PEG can promote the distribution of CDDP in tumors, reduce the probability of unexpected inactivation of CDDP, and reduce the content of GSH in tumor cells during the conversion to CDDP, thereby making CDDP more effective for treatment. The results showed that the optimized BT-4@PtPPNPs with a small particle size (130 nm) exhibited notable cytotoxicity and apoptosis of 4T1 cells. BT-4@PtPPNPs not only significantly improved the uptake of drugs by tumor cells, but also rapidly targeted and accumulated in the tumors for a long time. Moreover, in vivo efficacy studies showed that BT-4@PtPPNPs could effectively inhibit tumor growth, inhibiting 60.85 % of tumors in a 4T1 breast cancer mice model, showing superior antitumor activity, which can be attributed to GSH-triggered CDDP tolerance reversal. Overall, this study provides an attractive and simple strategy to combine novel sulfhydryl blockers and CDDP prodrugs to potentiate the efficacy of CDDP in breast cancer.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell–cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.

Background Nerve transfer is an important clinical surgical procedure for nerve repair by the coaptation of a healthy donor nerve to an injured nerve. Usually, nerve transfer is performed in an end-to-end manner, which will lead to functional loss of the donor nerve. In this study, we aimed to evaluate the efficacy of 3D-printed branch nerve conduits in nerve transfer. Methods Customized branch conduits were constructed using gelatine-methacryloyl by 3D printing. The nerve conduits were characterized both in vitro and in vivo. The efficacy of 3D-printed branch nerve conduits in nerve transfer was evaluated in rats through electrophysiology testing and histological evaluation. Results The results obtained showed that a single nerve stump could form a complex nerve network in the 3D-printed multibranch conduit. A two-branch conduit was 3D printed for transferring the tibial nerve to the peroneal nerve in rats. In this process, the two branches were connected to the distal tibial nerve and peroneal nerve. It was found that the two nerves were successfully repaired with functional recovery. Conclusions It is implied that the two-branch conduit could not only repair the peroneal nerve but also preserve partial function of the donor tibial nerve. This work demonstrated that 3D-printed branch nerve conduits provide a potential method for nerve transfer.

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.

Background: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. However, whether LHPP is effective to melanoma has not been investigated. Gene therapy provides a new strategy for the treatment of melanoma. Currently, it suffers from the lack of safe and effective gene delivery systems. Methods: A CRGDKGPDC peptide (iRGD) modified hybrid monomethoxy poly(ethylene glycol)-poly(D,L-lactide) nanoparticle (iDPP) was prepared and complexed with a LHPP plasmid, forming an iDPP/LHPP nanocomplex. The iDPP/LHPP nanocomplex was characterized by particle size distribution, zeta potential, morphology, cytotoxicity, and transfection efficiency. The antitumor efficacy of the nanocomplex against melanoma was studied both in vitro and in vivo. Further, the potential epigenetic changes in melanoma induced by iDPP/LHPP nanocomplex were evaluated. Results: The iDPP/LHPP nanocomplex showed high transfection efficiency and low toxicity. Moreover, the nanocomplex displayed a neutral charge that can meet the requirement of intravenous injection for targeted gene therapy. In vitro and in vivo experiments indicated that the iDPP/LHPP nanocomplex significantly inhibited the melanoma growth without causing notable adverse effects. We also found that LHPP played an important role in epigenetics. It regulated the expression of genes related to the proliferation and apoptosis chiefly at the level of transcription. Conclusion: This work demonstrates that the iDPP nanoparticle-delivered LHPP gene has a potential application in melanoma therapy through regulation of the genes associated with epigenetics.

Injectable microgels show great promising applications in cell therapy and drug delivery. Currently, there remains a challenge to rapidly and cost-effectively fabricate customized microgels. Here, we present a digital light processing based three-dimensional (3D) printing process to fabricate microgels with tailored shapes and sizes. The microgels are constructed by the digital light controlled polymerization of photopolymerizable monomer solution within 2 s. By mixing nanoparticle-encapsulated drugs into the monomer solution, the microgels with sustained drug release can be readily prepared. Also, cells can be printed into microgels with survival and proliferation. In conclusion, this study provides a 3D printing process for customizing functional microgels containing drugs or cells with potential therapeutic applications.

Nanoassemblies (NAs) of small-molecule lipophilic prodrugs have been widely investigated for efficient drug delivery in cancer therapy, but their kinetic stability has not attracted sufficient attention in the past studies. Herein, we reported that kinetic stability has a great influence on the drug release from the NAs of lipophilic prodrugs in physiologically relevant media. Based on the co-assembled FRET nanosystems of two lipophilic fluorescent prodrugs, we demonstrated that NAs constructed by lipophilic prodrugs containing shorter alkyl chains or those with higher unsaturated degrees displayed poorer kinetic stability, which further resulted in remarkably faster drug release in mouse plasma and various tissue homogenates. More importantly, these kinetically unstable NAs also induced rapid intracellular drug release, resulting in much more potent cytotoxicity. These findings highlight the crucial role of kinetic stability in determining the drug release from the NAs of lipophilic prodrugs, which would effectively guide their rational designs for cancer therapy.

We report that carbonate esters could turn hydrophobic camptothecin (CPT)-unsaturated fatty acid prodrugs into nanoaggregates in aqueous solution. The active CPT could be rapidly released once triggered by a reductive stimulus when a carbonate ester was combined with a disulfide bond, resulting in a potent in vivo antitumor activity.

Nanoparticles delivering therapeutic genes have promising applications in cancer treatments. Here, we used biodegradable heparin–polyethyleneimine (HPEI) nanoparticles to co-deliver two genes (vesicular stomatitis virus matrix protein, VSVMP; interleukin-12, IL12) for cancer therapy. These HPEI nanoparticles can bind the plasmid expressing VSVMP (pVSVMP) and the plasmid expressing IL12 (pIL12) through electrostatic interactions, and mediate the simultaneous expression of VSVMP and IL12 in colon cancer cells in vitro and in vivo. After intraperitoneal administration, the HPEI/pIL12 + pVSVMP complexes efficiently inhibit the growth of intraperitoneal metastasis of C-26 colon cancer, showing synergistic anticancer efficacy, without obvious systemic adverse effects. While VSVMP induces apoptosis, VSVMP and IL12 synergistically generate an anticancer immune response, which renders the potent anticancer effect of HPEI/pIL12 + pVSVMP. Our data suggest that VSVMP and IL12 could synergistically inhibit cancer survival in vivo, and the HPEI nanoparticle co-delivered VSVMP and IL12 might have potential application in treating intraperitoneal metastasis of colon cancer.

Xun Jin,1 Peilan Zhang,1 Li Luo,1 Hao Cheng,1 Yunzu Li,1 Ting Du,1 Bingwen Zou,2 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, People’s Republic of China; 2Department of Thoracic Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republicof China Abstract: Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65nm and a mean zeta potential of +19.6mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer. Keywords: bladder cancer, drug delivery, nanoparticles, intravesical therapy

Xun Jin,1,* Bingwen Zou,2,* Li Luo,1,* Chuanhong Zhong,3 Peilan Zhang,1 Hao Cheng,1 Yanfang Guo,1 Maling Gou1 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 2Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, 3Department of Neurosurgery, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan Province, People’s Republic of China *These authors contributed equally tothis work Abstract: Cancer chemotherapy can benefit from the combination of different anticancer drugs. Here, we prepared doxorubicin (Dox)- and thioridazine (Thio)-coloaded methoxy poly(ethyleneglycol)-poly(L-lactic acid) (MPEG-PLA) nanoparticles (NPs) for breast cancer therapy. These NPs have an average particle size of 27nm. The drug loading efficiencies of Thio and Dox are 4.71% and 1.98%, respectively. Compared to the treatment of Thio or Dox alone, the combination of Thio and Dox exhibited a synergistic effect in inhibiting the growth of 4T1 breast cancer cells in vitro. In addition, the Thio- and Dox-coloaded MPEG-PLA NPs could efficiently suppress the growth of breast cancer cells in vivo. This study suggests that Thio- and Dox-coloaded MPEG-PLA NPs might have potential applications in breast cancer treatment. Keywords: thioridazine, doxorubicin, codelivery, nanoparticles, breast cancer

Doxorubicin (Dox) is a broad-spectrum antitumor drug used for the treatment of many types of malignant tumors. Although it possesses powerful antitumor activity, its clinical application is seriously encumbered by its unselective distribution and systemic toxicities, particularly myocardial toxicity. Thus, it is imperative to modify Dox to decrease its systemic toxicities and improve its therapeutic index. In the present study, we adopted a novel type of monomethoxy poly(ethylene glycol)-poly(e-caprolactone) (MPEG-PCL) micelles to encapsulate Dox to prepare Dox-loaded MPEG-PCL (Dox/MPEG-PCL) nanoparticles by a controllable self-assembly process. The cellular uptake efficiency and cell proliferation inhibition of the Dox/MPEG-PCL nanoparticles were examined. The antitumor activity of the Dox/MPEG-PCL nanoparticles was tested on a multiple pulmonary metastasis model of melanoma on C57BL/6 mice. Systemic toxicities and survival time were compared between the mice treated with the Dox/MPEG-PCL nanoparticles and free Dox. The potential myocardial toxicity of the Dox/MPEG-PCL nanoparticles was investigated using a prolonged observation period. Encapsulation of Dox in MPEG-PCL nanoparticles significantly improved the cellular uptake and cell proliferation inhibition of Dox in vivo. Intravenous injection of Dox/MPEG-PCL nanoparticles obtained significant inhibition of the growth and metastasis of melanoma in the lung and prolonged survival time compared with free Dox (P

Peripheral nerve injury is a common disease that often causes disability and challenges surgeons. Drug‐releasable biomaterials provide a reliable tool to regulate the nerve healing‐associated microenvironment for nerve repair. Here, a self‐adhesive bandage is designed that can form a wrap surrounding the injured nerve to promote nerve regeneration and recovery. Via a 3D printing technique, the bandage is prepared with a special structure and made up of two different hydrogel layers that can adhere to each other by a click reaction. The nanodrug is encapsulated in one layer with a grating structure. Wrapping the injured nerve, the grating layer of the bandage is closed to the injured site. The drug can be mainly released to the inner area of the wrap to promote the nerve repair by improving the proliferation and migration of Schwann cells. In this study, the bandage is used to assist the neurorrhaphy for the treatment of complete sciatic nerve transection without obvious defect in rats. Results indicate that the self‐adhesive capacity can simplify the installation process and the drug‐loaded bandage can promote the repairing of injured nerves. The demonstrated 3D‐printed self‐adhesive bandage has potential application in assisting the neurorrhaphy for nerve repair., A self‐adhesive bandage consists of two layers made of two clickable materials. This bandage can adhere itself via a click reaction. Due to big specific surface area of the grating layer and blocking by the outer layer, drug is mainly distributed at the injured site to promote nerve repair and the side effects would be reduced.

Microtissues on the scale of several hundred microns are a promising cell culture configuration resembling the functional tissue units in vivo. In contrast to conventional cell culture, handling of microtissues poses new challenges such as medium exchange, purification and maintenance of the microtissue integrity. Here, we developed magnetic microcryogels to assist microtissue formation with enhanced controllability and robustness. The magnetic microcryogels were fabricated on-chip by cryogelation and micro-molding which could endure extensive external forces such as fluidic shear stress during pipetting and syringe injection. The magnetically controllable microtissues were applied to constitute a novel separable 3D co-culture system realizing functional enhancement of the hepatic microtissues co-cultured with the stromal microtissues and easy purification of the hepatic microtissues for downstream drug testing. The magnetically controllable microtissues with pre-defined shapes were also applied as building blocks to accelerate the tissue assembly process under magnetic force for bottom-up tissue engineering. Finally, the magnetic microcryogels could be injected in vivo as cell delivery vehicles and tracked by MRI. The injectable magnetic microtissues maintained viability at the injection site indicating good retention and potential applications for cell therapy. The magnetic microcryogels are expected to significantly promote the microtissues as a promising cellular configuration for cell-based applications such as in drug testing, tissue engineering and regenerative therapy.

Jin-Feng Qiu,1 Xiang Gao,1,2 Bi-Lan Wang,1 Xia-Wei Wei,1 Ma-Ling Gou,1 Ke Men,1 Xing-Yu Liu,1 Gang Guo,1 Zhi-Yong Qian,1 Mei-Juan Huang1 1Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Medical School, Sichuan University, Chengdu, People’s Republic of China; 2Medical School and Department of Pathophysiology, College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, People’s Republic of China Abstract: Luteolin (Lu) is one of the flavonoids with anticancer activity, but its poor water solubility limits its use clinically. In this work, we used monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles to encapsulate Lu by a self-assembly method, creating a water-soluble Lu/MPEG-PCL micelle. These micelles had a mean particle size of 38.6 ± 0.6 nm (polydispersity index = 0.16 ± 0.02), encapsulation efficiency of 98.32% ± 1.12%, and drug loading of 3.93% ± 0.25%. Lu/MPEG-PCL micelles could slowly release Lu in vitro. Encapsulation of Lu in MPEG-PCL micelles improved the half-life (t½; 152.25 ± 49.92 versus [vs] 7.16 ± 1.23 minutes, P = 0.007), area under the curve (0–t) (2914.05 ± 445.17 vs 502.65 ± 140.12 mg/L/minute, P = 0.001), area under the curve (0–∞) (2989.03 ± 433.22 vs 503.81 ± 141.41 mg/L/minute, P = 0.001), and peak concentration (92.70 ± 11.61 vs 38.98 ± 7.73 mg/L, P = 0.003) of Lu when the drug was intravenously administered at a dose of 30 mg/kg in rats. Also, Lu/MPEG-PCL micelles maintained the cytotoxicity of Lu on 4T1 breast cancer cells (IC50 = 6.4 ± 2.30 µg/mL) and C-26 colon carcinoma cells (IC50 = 12.62 ± 2.17 µg/mL) in vitro. These data suggested that encapsulation of Lu into MPEG-PCL micelles created an aqueous formulation of Lu with potential anticancer effect. Keywords: luteolin, micelle, MPEG-PCL, cancer therapy

The aim of this study was to prepare PCL-PEG-PCL (PCEC) microspheres to protect camptothecin from hydrolysis, to extend its release time and to enhance its treatment efficacy on colorectal peritoneal carcinomatosis and tumor growth in mice. Camptothecin (CPT)-loaded PCL-PEG-PCL (PCEC) microspheres were prepared by oil-in-water emulsion solvent evaporation method. The particle size, morphological characteristics, encapsulation efficiency, in vitro drug release studies and in vitro cytotoxicity of CPT-loaded PCEC microspheres have been investigated. In vivo studies were carried out on Balb/c male mice bearing colorectal peritoneal carcinomatosis. CPT-loaded PCEC microspheres were applied to abdominal cavity of mice once a week. Free CPT was used as a positive control. On 14th day of treatment, mice were sacrificed and antitumor activities of CPT-loaded PCEC microspheres were evaluated. Compared with control group, a significant decrease in the number of tumor nodes was observed in group treated with CPT-loaded PCEC microspheres. Immunohistochemistry staining of tumor tissues with CD34 revealed that MVD positive cells were significantly reduced in CPT-loaded PCEC microspheres treated group in contrast to other groups (P0.05). The CPT-loaded PCEC microspheres were considered potentially useful to treat the abdominal metastases of colon carcinoma.

Polydiacetylene (PDA) is an excellent color-changing indicator. In this paper, we demonstrate a new and interesting kind of time–temperature chromatic sensor based on PDA vesicle and amphiphilic polymer. In presence of amphiphilic polymers, PDA vesicles could gradually transit from blue to red, which was irreversible and regularly depended on the temperature, time, and properties of amphiphilic polymer (including the concentration, molecular weight, molecular structure, hydrophobicity, and thermo-sensitive property). Higher concentration of amphiphilic polymers resulted in lower color-transition temperature and faster color-transition. Also, higher temperature led to faster color-transition. The color-changing of PDA/amphiphilic polymer matrix may have resulted from the higher temperature and gradual insertion of amphiphilic polymer into PDA, synergistically perturbing the conformation of PDA. The prepared PDA/F127, PDA/F68, PDA/L35 and PDA/Tween-20 aqueous matrix showed potential application in time–temperature chromatic sensors at around 10–50 °C. This work provides a new method to design time–temperature chromatic sensors.

This paper developed a new hydrophobic honokiol transdermal delivery system. First, Honokiol was loaded into Pluronic F127 micelles by direct dissolution method assisted by ultrasound. Then the obtained honokiol-loaded F127 micelles were incorporated into thermosensitive F127 hydrogel, which made the composite system bioadhesive. The particle size, drug loading, and encapsulation efficiency were determined. The sol-gel transitions of the copolymer, honokiol release profile in vitro, and the permeation studies in vitro were studied in detail. The lower critical solution temperature (LCST) of the composite system decreases with increase in the mass of honokiol in the system. Honokiol could be sustained released from the system in vitro. In in vitro permeation studies, honokiol could be absorbed per cutem. The described drug delivery system might have great potential application for transdermal delivery of hydrophobic drugs such as honokiol.

Honokiol (HK) shows potential application in cancer treatment, but its poor water solubility restricts clinical application greatly. In this paper, monomethoxy poly(ethylene glycol)–poly(lactic acid) (MPEG–PLA) was synthesized by ring-opening polymerization and processed into nanoparticle for honokiol delivery. Chemical structure of the synthesized polymer was confirmed by 1 H NMR, and its molecular weight was determined by gel permeation chromatography (GPC). Honokiol loaded MPEG–PLA nanoparticles were prepared by solvent extract method. And particle size distribution, morphology, drug loading, drug release profile and anticancer activity in vitro were studied in detail. The described honokiol loaded MPEG–PLA nanoparticles in this paper might be a novel formulation for honokiol delivery.

In the present study, we prepared poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) (PCL-PEG-PCL, PCEC) nanomaterials by solvent-extraction method. The obtained PCEC nanomaterials were studied extensively for acute toxicity and genotoxicity using bacterial reverse mutation test (Ames test), chromosomal aberration test and mouse micronucleus test. All of the Sprague-Dawley rats did not show any mortality and clinical signs of toxicity after intravenous injection at the level of 2.4 g/kg body weight. Thus, the LD50 of PCEC nanomaterials was determined to be greater than 2.4 g/kg. In Ames test, PCEC nanomaterials were negative in Salmonella typhimurium strains TA97, TA98, TA100, TA102, and TA1535 with or without metabolic activation. PCEC nanomaterials did not induce chromosomal aberrations in cultured Chinese hamster lung cells up to 5000 μg/mL with or without metabolic activation. Micronucleus assay demonstrated that PCEC nanomaterials did not significantly increase micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow of ICR mice or suppress bone marrow, indicating they did not cause chromosome aberrations. In conclusion, our results indicated that PCEC nanomaterials did not cause any acute toxicity and genotoxicity in our experimental conditions. Its potential to be a candidate of drug carrier is worth being further investigated.

In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) hydrogel was studied. The prepared PCEC hydrogel undergoes temperature-dependent sol-gel-sol transition, which is a flowing sol at ambient temperature and turns into a non-flowing gel at around physiological body temperature. Furthermore, the sol-gel phase transition mechanism was investigated using (13)C-nuclear magnetic resonance imaging and a laser diffraction particle size analyzer. The in vitro release behaviors of several model drugs, including a hydrophilic small-molecule drug, a hydrophobic small-molecule drug and a macromolecular protein drug, from PCEC hydrogel were also investigated in detail. The results showed that the model drugs could be released from the PCEC hydrogel system over a sustained period. In addition, an anaesthesia assay was conducted using the tail flick latency (TFL) test to evaluate the in vivo controlled drug delivery effect of the PCEC hydrogel system. In the TFL assay, a lidocaine-loaded PCEC hydrogel produced significantly longer-lasting local anaesthetic effects compared with lidocaine aqueous solution at the same dose. Therefore, PCEC hydrogel is promising for use as an injectable local drug delivery system.

Self-assembled polymeric micelles are widely applied in drug delivery system (DDS). In this study, honokiol (HK) loaded micelles were prepared from biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic character without any organic solvent. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of HK and PCEC. The particle size and zeta potential distribution of obtained micelles were determined using Malvern laser particle sizer, and spherical geometry were observed on atomic force microscope (AFM). Otherwise, the thermo-sensitivity of honokiol-loaded micelles was monitored. And the cytotoxicity results of drug loaded micelles showed that the encapsulated honokiol remained potent antitumor effect. Moreover, in vitro release profile demonstrated a significant difference between rapid release of free honokiol and much slower and sustained release of HK-loaded micelles. These results suggested that we have successfully prepared honokiol-loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for honokiol delivery in cancer chemotherapy.

In this article, blank anionic poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) and anionic mannan modified PCEC (MPCEC) nanoparticles with nearly the same particle size and zeta potential were prepared by emulsion solvent evaporation method. Human basic fibroblast growth factor (bFGF) was absorbed onto anionic nanoparticles surface due to electrostatic interaction. The obtained bFGF-nanoparticles complexes were injected subcutaneously into C57BL/6 mice at 20 microg of bFGF/dose on week 0, 1, 2 and 3. The mice serum was collected on week 4, and bFGF-specific autoantibody total IgG, IgG1 and IgG2a titer in serum was determined by ELISA. The results indicated that the autoantibody IgG, IgG1 and IgG2a titer of the mice immunized by bFGF-MPCEC complexes were higher than that immunized by either bFGF-PCEC or bFGF-Alum. This phenomenon might be due to that mannan functionalized MPCEC nanoparticles could be targeted to dendritic cells (DCs) to improve humoral immunity. The prepared anionic mannan modified PCEC nanoparticles (MPCEC) might have great potential application in vaccine delivery systems.

A series of PCL–Pluronic–PCL biodegradable block copolymers were successfully synthesized by ring opening polymerization of ɛ-caprolactone (ɛ-CL) initiated by Pluronic (PEG–PPG–PEG) macromonomer, which were characterized by 1 H NMR and FTIR. Their aqueous solution displayed special gel–sol transition with temperature increased from 4 °C to 70 °C, when the concentration was above corresponding critical gel concentration (CGC). The gel–sol phase diagram was recorded using test tube-inverting method, which depended not only on the hydrophilic/hydrophobic balance in macromolecular structure, but also on heating history of copolymer's aqueous solution. As a result, the gel–sol transition temperature range could be altered according to its practical application, which would be very useful as injectable drug delivery system. To illuminate the mechanism of gel–sol transition, we introduced a typical double layers shell/core structure of PCL–Pluronic–PCL micelles here. The hydrophobic interactions and partly crystallization might be the key gelation machanism for such special gel–sol transition behavior of PCL–Pluronic–PCL aqueous solution.

Hydrolytic degradable PBT/PEG copolymer was synthesized by macromolecular transesterification method from PBT and PEG macromonomers. The resultant copolymers were characterized by (1)H-NMR and GPC. The non-isothermal crystallization behavior of these copolymers was studied by differential scanning calorimetry (DSC). The water absorption and hydrolytic degradation behavior of PBT/PEG copolymers were also studied in detail.

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-α and interferon-γ in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol.

In this article, poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) nanoparticles were successfully prepared for honokiol delivery in vitro. Blank or honokiol loaded PCL-PEG-PCL nanoparticles were prepared in moderate condition by solvent diffusion method without using any surfactants. The prepared blank PCL-PEG-PCL nanoparticles are mono-dispersed and smaller than 200 nm. The particle size increased with increase in polymer concentration and oil-water (O/W) ratio. The prepared PCL-PEG-PCL nanoparticles (40 mg/mL, ca. 106 nm) did not induce hemolysis in vitro. And the 50% inhibiting concentration (IC50) of it (48 h) on HEK293 cells was higher than 5 mg/mL. Honokiol could be efficiently loaded into PCL-PEG-PCL nanoparticles and released from these nanoparticles in an extended period in vitro. After honokiol (HK) was entrapped into PCL-PEG-PCL nanoparticles, the particle size increased with the increase in HK/PCEC mass ratio in feed, and the encapsulated honokiol retained potent anticancer activity in vitro. The PCL-PEG-PCL nanoparticle was suitable for honokiol delivery, and such honokiol loaded PCL-PEG-PCL nanoparticle was a novel honokiol formulation.