Brain Targeting, Antioxidant Polymeric Nanoparticles for Stroke Drug Delivery and Therapy.

Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.

Quantitating Endosomal Escape of a Library of Polymers for mRNA Delivery.

Endosomal escape is a key step for intracellular drug delivery of nucleic acids, but reliable and sensitive methods for its quantitation remain an unmet need. In order to rationally optimize the mRNA transfection efficiency of a library of polymeric materials, we designed a deactivated Renilla luciferase-derived molecular probe whose activity can be restored only in the cytosol. This probe can be coencapsulated with mRNA in the same delivery vehicle, thereby accurately measuring its endosomal escape efficiency. We examined a library of poly(amine-co-ester) (PACE) polymers with different end groups using this probe and observed a strong correlation between endosomal escape and transfection efficiency (R2 = 0.9334). In addition, we found that mRNA encapsulation efficiency and endosomal escape, but not uptake, were determinant factors for transfection efficiency. The polymers with high endosomal escape/transfection efficiency in vitro also showed good transfection efficiency in vivo, and mRNA expression was primarily observed in spleens after intravenous delivery. Together, our study suggests that the luciferase probe can be used as an effective tool to quantitate endosomal escape, which is essential for rational optimization of intracellular drug delivery systems.

Low-temperature selective catalytic reduction of NO with NH3 over an FeO x /ß-MnO2 composite.

A series of Fe-modified ß-MnO2 (FeO x /ß-MnO2) composite catalysts were prepared by an impregnation method with ß-MnO2 and ferro nitrate as raw materials. The structures and properties of the composites were systematically characterized and analyzed by X-ray diffraction, N2 adsorption-desorption, high-resolution electron microscopy, temperature-programmed reduction of H2, temperature-programmed desorption of NH3, and FTIR infrared spectroscopy. The deNO x activity, water resistance, and sulfur resistance of the composite catalysts were evaluated in a thermally fixed catalytic reaction system. The results indicated that the FeO x /ß-MnO2 composite (Fe/Mn molar ratio of 0.3 and calcination temperature of 450 °C) had higher catalytic activity and a wider reaction temperature window compared with ß-MnO2. The water resistance and sulfur resistance of the catalyst were enhanced. It reached 100% NO conversion efficiency with an initial NO concentration of 500 ppm, a gas hourly space velocity of 45 000 h-1, and a reaction temperature of 175-325 °C. The appropriate Fe/Mn molar ratio sample had a synergistic effect, affecting the morphology, redox properties, and acidic sites, and helped to improve the low-temperature NH3-SCR activity of the composite catalyst.

Tungsten modified natural limonite catalyst for efficient low-temperature selective catalytic reduction of NO removal with NH3: preparation and characterization.

With natural limonite as the precursor and an ammonium tungstate hydrate as modification, the W/limonite composite catalysts were synthesized by the impregnation method. Their structures and properties were systematically characterized and analyzed; the denitrification activity and resistance to water and sulfur on catalysts were investigated. The results indicated that the W/limonite composite with W/Fe mass ratio of 9% and calcination temperature of 300 °C had highly catalytic activity, enhanced resistance to sulfur and water. The NO conversion efficiency was maintained over 85% with NO initial concentration of 500 ppm, the gas hourly space velocity (GHSV) of 36,000 h-1, and reaction temperature of 100 °C, while it was greater than 98% with addition of 200 ppm SO2 and 3 vol. % H2O at the reaction temperature of 250 °C. The superior performance was mainly ascribed to the formation of W-OH species and W = O species with wide dispersion on the surface of goethite or in Fe2O3 lattice defects, to generate more acidic hydroxyl groups and more oxygen defects and strong acidity Brønsted for the SCR reaction.

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery.

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

Multiple stimuli-responsive nanosystem for potent, ROS-amplifying, chemo-sonodynamic antitumor therapy.

Although sonodynamic therapy (SDT) is a promising non-invasive tumor treatment strategy due to its safety, tissue penetration depth and low cost, the hypoxic tumor microenvironment limits its therapeutic effects. Herein, we have designed and developed an oxygen-independent, ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles. The formulated artemether (ART)/Fe3O4-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth. Besides, the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe2+ ions formed in situ at acidic pH and external ultrasound irradiation, which is not affected by hypoxia tumor microenvironment. Consequently, the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs, achieving an incredible antitumor potency. Specifically, upon the chemo-sonodynamic therapy by ART/Fe3O4-loaded PEG-PPMDT NPs, all xenotransplants of human hepatocellular carcinoma (HepG2) in nude mice shrank significantly, and 40% of the tumors were completely eliminated. Importantly, the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures. Further, biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs. Thus, our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.

Study of the denitration performance of a ceramic filter using a manganese-based catalyst.

A MnO x /γ-Al2O3 catalyst was prepared by impregnation of manganese acetate and alumina. After optimizing the composition, it was loaded into a ceramic filter (CF) by a one-step coating method. The results show that MnO x /γ-Al2O3 had the best denitration activity when the Mn loading was 4 wt% with a calcination temperature of 400 °C. The MnO x /γ-Al2O3 catalyst ceramic filter (MA-CCF) was made by loading the CF twice with MnO x /γ-Al2O3. When face velocity (FV) was 1 m min-1, MA-CCF displayed more than 80% NO conversion at 125-375 °C and possessed a good resistance of H2O and SO2. The abundant surface adsorbed oxygen, dense membrane and high-density fiber structure on the outer layer of CF effectively protected the catalyst and could improve MA-CCF denitration activity. The multiple advantages of MA-CCF made it possible for good application prospects.

Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.

Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2″-thiodiethylene 3,3″-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.

Lipase-catalyzed copolymerization of dialkyl carbonate with 1,4-butanediol and ω-pentadecalactone: synthesis of poly(ω-pentadecalactone-co-butylene-co-carbonate).

Candida antarctica lipase B (CALB) was successfully used to promote synthesis of aliphatic poly(carbonate-co-ester) copolymers from dialkyl carbonate, diol, and lactone monomers. The polymerization reactions were carried out in two stages: first-stage oligomerization under low vacuum, followed by second-stage polymerization under high vacuum. Therefore, copolymerization of ω-pentadecalactone (PDL), diethyl carbonate (DEC), and 1,4-butanediol (BD) yielded PDL-DEC-BD copolymers with a M(w) of whole product (nonfractionated) up to 33 000 and M(w)/M(n) between 1.2 and 2.3. Desirable reaction temperature for the copolymerization was found to be ∼80 °C. The copolymer compositions, in the range from 10 to 80 mol % PDL unit content versus total (PDL + carbonate) units, were effectively controlled by adjusting the monomer feed ratio. Reprecipitation in chloroform/methanol mixture allowed isolation of the purified copolymers in up to 92% yield. (1)H and (13)C NMR analyses, including statistical analysis on repeat unit sequence distribution, were used to determine the polymer microstructures. The synthesized PDL-DEC-BD copolymers possessed near random structures with all possible combinations of PDL, carbonate, and butylene units via either ester or carbonate linkages in the polymer chains and are more appropriately named as poly(PDL-co-butylene-co-carbonate).

Tumor microenvironment triple-responsive nanoparticles enable enhanced tumor penetration and synergetic chemo-photodynamic therapy.

A novel combined chemo/photodynamic therapy has been developed to use pH/ROS/MMP-2 triple-responsive drug nanocarriers for treating solid tumor with an extraordinarily high efficiency. The designed poly(ethylene glycol)-peptide-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-M-PPMT) nanoparticles (NPs) encapsulating anticancer drug sorafenib (SRF) and photosensitizer chlorin e6 (Ce6) are stable in serum-containing aqueous media and can effectively accumulate in tumor as a result of the EPR effect after intravenous administration in vivo. In the presence of MMP-2 overexpressed in extracellular tumor matrix, the PEG-M-PPMT NPs can partially shed PEG corona to form smaller particles and penetrate deep into tumor tissue. After uptake by tumor cells, the acidic endosomal pH and high intracellular ROS level would trigger substantial swelling of the NPs to accelerate the drug release for rapid killing of the cancer cells. In the current combined chemo/photodynamic therapy, the intracellular ROS generation in tumor is amplified by photosensitizer Ce6 activated with external laser irradiation. As the result, the highly elevated intracellular ROS concentration can both directly induce apoptosis of ROS-stressed tumor cells and magnify acceleration of the drug release from the ROS-responsive PEG-M-PPMT NPs to gain extraordinary therapeutic efficacy. In particular, after the chemo-photodynamic therapeutic treatment with SRF/Ce6-loaded PEG-M-PPMT nanoparticles, all human lung tumors (A549) xenografted in nude mice shrank substantially with approximately 29% of the tumors being completely eradicated. Additionally, SRF/Ce6-loaded PEG-M-PPMT NPs show negligible in vivo toxicity toward major organs such as heart, liver, spleen, lung and kidney. These results demonstrate great potential of the combined chemo/photodynamic therapy based on the stimuli-responsive PEG-M-PPMT nanoparticles for efficient tumor treatment.

Lipase-catalyzed synthesis of poly(amine-co-esters) via copolymerization of diester with amino-substituted diol.

Candida antarctica lipase B (CALB) was found to be an efficient catalyst for copolymerization of diesters with amino-substituted diols to form poly(amine-co-esters) in one step. The copolymerization reactions were carried out at 50-100 degrees C in two stages: first stage oligomerization under 1 atm pressure of nitrogen followed by second stage polymerization under 1-2 mmHg vacuum. The formed copolymers possessed molecular weight (M(w)) up to 59000 and typical polydispersity (M(w)/M(n)) between 1.5 and 2.3. The enzymatic reaction appears to be quite general and accommodates a large number of comonomer substrates with various chain length and substituents. Thus, C(4)-C(12) diesters (i.e., from succinate to dodecanedioate) and diethanolamine comonomers with either an alkyl (methyl, ethyl, n-butyl, t-butyl) or an aryl (phenyl) substituent on nitrogen were successfully incorporated into the poly(amine-co-ester) chains. Biodegradable polyesters bearing tertiary amino groups have been reported to be efficient carriers for gene delivery. The high tolerance of the lipase toward tertiary amino functional groups as described in this paper provides new routes for synthesizing poly(amine-co-esters) with tailored structures for specific biomedical applications.

Enzymatic synthesis of PEGylated lactide-diester-diol copolyesters for highly efficient targeted anticancer drug delivery.

PEGylated lactide-diester-diol copolymers were successfully synthesized via lipase-catalyzed copolymerization, the resultant amphiphilic PEG-poly(L-lactate-co-hexamethylene-co-adipate) (PEG-PLLHA) and PEG-poly(D,L-lactate-co-hexamethylene-co-adipate) (PEG-PDLLHA) block copolymers readily undergo self-assembly processes to form nanosized micelles in aqueous medium, which are stable under physiological conditions in the presence of serum proteins. By conjugating folic acid (FA) to enzymatic synthesized poly(hexamethylene adipate-co-hexamethylene 2,3-epoxy succinate), we could formulate FA-bearing PEG-polyester micelles for docetaxel (DTX) targeting delivery. FA-PEG-PLLHA and FA-PEG-PDLLHA micelles possess efficient cell-targeting capability toward FA receptor-positive cancer cells (e.g., CT-26), which significantly enhances their cellular uptake rates and efficacy of drug-loaded formulations toward such cells. During in vivo anticancer treatments, the FA-bearing micelles are highly capable of targeting and accumulating preferentially in tumor tissues by both active cell-targeting mechanism and passive targeting via the EPR effect. All these desirable properties enable the FA-bearing micelles to deliver DTX with 97% tumor-inhibiting efficiency through systemic delivery, which is favorable in comparison to the values of various DTX nanoparticle formulations reported in literature. Importantly, biosafety assays reveal that all DTX-loaded micelles are biocompatible and safe for in vivo antitumor treatment applications. Thus, FA-PEG-PLLHA and FA-PEG-PDLLHA micelles represent new types of promising anticancer drug nanocarriers for targeted chemotherapy.

Enzymatic multifunctional biodegradable polymers for pH- and ROS-responsive anticancer drug delivery.

A new family of multifunctional biodegradable block copolymers, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine sebacate-co-2,2'-thiodiethylene sebacate) (PEG-PMT), were synthesized via lipase-catalyzed copolymerization procedures. Amphiphilic PEG-PMT copolymers can be readily transformed into stable micellar nanoparticles through self-assembling processes in aqueous medium. The particle sizes increase dramatically after exposure of the particles to the acidic pH and high reactive oxygen species (ROS) conditions in tumor microenvironments, due to protonation of thioether groups and oxidation of amino groups in the PMT micelle cores, respectively. For example, docetaxel (DTX)-loaded PEG-PM-19 % TS micelles were triggered synergistically by acidic pH and ROS stimuli to release over 85 % of the anti-cancer drug. In particular, DTX/PEG-PMT-19 % TS and DTX/PEG-PMT-48 % TS micelles performed better than commercial Duopafei formulation in prohibiting growth of CT-26 tumors xenografed in vivo (70 % of tumor-inhibiting efficiency). Biosafety analysis revealed that DTX-loaded PEG-PMT nanoparticles possessed minimal toxicity towards normal organs, such as liver and kidney. These experimental data demonstrated that the pH- and ROS-responsive PEG-PMT micelles are promising vectors for both delivery of anti-tumor drugs and their controlled release at tumor intracellular sites.

Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-co-ß-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases.

Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone-co-ß-amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP-2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100-conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin-mediated gene therapy.

Enzymatic synthesis of PEG-poly(amine-co-thioether esters) as highly efficient pH and ROS dual-responsive nanocarriers for anticancer drug delivery.

Novel multifunctional drug nanocarriers have been successfully fabricated from a new type of enzymatically synthesized, biodegradable block copolymer, PEG-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-thiodipropionate) (PEG-PPMT), which was responsive to tumor-relevant acidic pH (5.0-6.5) and intracellular reactive oxygen species (ROS) of tumor cells. The PEG-PPMT copolymers could self-assemble to form nano-scaled particles in aqueous solutions, which are stable in physiological solutions, but swell substantially upon reducing the pH from 7.4 to 5.0 and/or in the presence of ROS on account of the protonation of the tertiary amino groups and oxidation of the thioether groups, causing a hydrophobic to hydrophilic transition in the nanoparticle cores. Consistently, docetaxel (DTX) encapsulated in PEG-PPMT nanoparticles can be triggered in a synergistic manner by acidic pH and a high-ROS environment in tumor cells to release the hydrophobic drug at accelerated rates for efficient tumor growth inhibition. In particular, DTX encapsulated in PEG-PPMT-11% PDL and PEG-PPMT-28% PDL nanoparticles exhibit extraordinarily enhanced potency (95% and 93% tumor-inhibiting efficiency, respectively) in inhibiting the growth of ROS-rich CT-26 tumors xenografted in mice. Importantly, biosafety analyses show minimal toxicity of DTX-loaded PEG-PPMT nanoparticles toward normal organs including liver and kidneys during the in vivo antitumor treatments. These results demonstrate that the PEG-PPMT nanoparticles are promising pH and ROS dual-responsive multifunctional nanocarriers for tumor site specific, controlled release of anticancer drugs to treat ROS-rich tumors.

Lipase-catalyzed synthesis of aliphatic polyesters via copolymerization of lactone, dialkyl diester, and diol.

Candida antarctica lipase (CALB) has been successfully used as catalyst for copolymerization of dialkyl diester with diol and lactone to form aliphatic polyesters. The polymerization reactions were performed using a two stage process: first stage oligomerization under low vacuum followed by second stage polymerization under high vacuum. Use of the two-stage process is required to obtain products with high molecular weights at high yields for the following reasons: (i) the first stage reaction ensures that the monomer loss via evaporation is minimized to maintain 1:1 diester to diol stoichiometric ratio, and the monomers are converted to nonvolatile oligomers; (ii) use of high vacuum during the second stage accelerates equilibrium transesterification reactions to transform the oligomers to high molecular weight polymers. Thus, terpolymers of omega-pentadecalactone (PDL), diethyl succinate (DES), and 1,4-butanediol (BD) with a M w of whole product (nonfractionated) up to 77000 and M w/ M n between 1.7 and 4.0 were synthesized in high yields (e.g., 95% isolated yield). A desirable reaction temperature for the copolymerizations was found to be around 95 degrees C. At 1:1:1 PDL/DES/BD monomer molar ratio, the resultant terpolymers contained equal moles of PDL, succinate, and butylene repeat units in the polymer chains. (1)H and (13)C NMR analyses were used to determine the polyester microstructures. The synthesized PDL-DES-BD terpolymers possessed near random structures with all possible combinations of PDL, succinate, and butylene units via ester linkages in the polymer backbone. Furthermore, thermal stability and crystallinity of a pure PDL-DES-BD terpolymer with 1:1:1 PDL to succinate to butylene unit ratio and M w of 85400 were studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The copolyester was found to be a semicrystalline material with a T g of -34 degrees C and a T m of 64 degrees C, which degrades in a single weight loss step centered at T max = 408 degrees C.

A "top-down" approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery.

Gene delivery is known to be a complicated multi-step biological process. It has been observed that subtle differences in the structure and properties of polymeric materials used for gene delivery can lead to dramatic differences in transfection efficiency. Therefore, screening of properties is pivotal to optimizing the polymer. So far, most polymeric materials are built in a "bottom-up" manner, i.e. synthesized from monomers that allow modification of polymer composition or structural factors. With this method, we previously synthesized and screened a library of biodegradable poly(amine-co-ester) (PACE) terpolymers for optimized DNA delivery. However, it can be tedious and time consuming to synthesize a polymer library for screening, particularly when small changes of a factor need to be tested, when multiple factors are involved, and when the effects of different factors are synergistic. In the present work, we evaluate the potential of PACE to deliver mRNA. After observing that mRNA transfection efficiency was highly dependent on both end group composition and molecular weight (MW) of PACE in a synergistic manner, we developed a "top-down" process we called actuation, to simultaneously vary these two factors. Some of the actuated PACE (aPACE) materials presented superior mRNA delivery properties compared to regular PACE, with up to a 106-fold-increase in mRNA transfection efficiency in vitro. Moreover, when aPACE was used to deliver mRNA coding for erythropoietin (EPO) in vivo, it produced high levels of EPO in the blood for up to 48 h without inducing systemic toxicity. This polymer constitutes a new delivery vehicle for mRNA-based treatments that provides safe yet potent protein production.

Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors.

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drug-loaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(ω-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co-DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors.

Enzymatic PEG-Poly(amine-co-disulfide ester) Nanoparticles as pH- and Redox-Responsive Drug Nanocarriers for Efficient Antitumor Treatment.

We have designed and constructed novel multifunctional nanoparticle drug-delivery systems that are stable under physiological conditions and responsive to tumor-relevant pH and intracellular reduction potential. The nanoparticles were fabricated from enzymatically synthesized poly(ethylene glycol) (PEG)-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PPMD) and PEG-poly(ε-caprolactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PCMD) block copolymers via self-assembly processes in aqueous solution. At acidic pH and in the presence of a reductant (e.g., d,l-dithiothreitol or glutathione), the nanosized micelle particles rapidly swell and disintegrate due to the protonation of amino groups and reductive cleavage of disulfide bonds in the micelle cores. Consistently, docetaxel (DTX)-loaded PEG-PPMD and PEG-PCMD micelles can be triggered synergistically by acidic endosomal pH and a high intracellular reduction potential to rapidly release the drug for efficient killing of cancer cells. The drug formulations based on PEG-PPMD and PEG-PCMD copolymers exhibited a substantially higher potency than free DTX in inhibiting tumor growth in mice, whereas their therapeutic effects on important organ tissues were minimal. These results demonstrate that PEG-PPMD and PEG-PCMD nanoparticles have a great potential to serve as site-specific, controlled drug-delivery vehicles for safe and efficient antitumor treatment.

Multifunctional Poly(amine-co-ester-co-ortho ester) for Efficient and Safe Gene Delivery.

Cationic polymers are used for non-viral gene delivery, but current materials lack the functionality to address the multiple barriers involved in gene delivery. Here we describe the rational design and synthesis of a new family of quaterpolymers with unprecedented multifunctionality: acid sensitivity, low cationic charge, high hydrophobicity, and biodegradability, all of which are essential for efficient and safe gene delivery. The polymers were synthesized via lipase-catalyzed polymerization of ortho ester diester, lactone, dialkyl diester, and amino diol monomers. Polymers containing ortho ester groups exhibited acid-sensitive degradation at endosomal pH (4~5), facilitated efficient endosomal escape and unpackaging of the genes, and were efficient in delivering genetic materials to HEK293 cells, human glioma cells, primary mouse melanoma cells, and human umbilical vein endothelial cells (HUVECs). We also developed a highly efficient lyophilized formulation of the nanoparticles, which could be stored for a month without loss of efficiency.