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Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

Fluorescent imaging with fluorophores has become a powerful way to explore complex biological systems and visualize nanoparticles for drug delivery. However, it is challenging to develop fluorophores with ideal physical and optical properties. We report a method to synthesize cyanine nanodots with a single-molecule structure, well-defined particle size, customizable fluorescent spectrum, and bright and stable fluorescence. These cyanine nanodots are acquired by the divergent synthesis of cyanine-dye-cored polylysine (PLL) dendrimers. We demonstrated the feasibility of the method by synthesizing cyanine 3 (Cy3), cyanine 5 (Cy5), or cyanine 7 (Cy7) cored single-molecule nanodots up to eight generations with a size of around 11 nm. We show that these cyanine nanodots are capable of multiple biomedical applications, including multicolor cellular tracing and cancer imaging. These cyanine nanodots possess many merits of organic dots and quantum dots that are promising for future application.

Orally administrable anticancer nanomedicines are highly desirable due to their easy and repeatable administration, but are not yet feasible because the current nanomedicine cannot simultaneously overcome the strong mucus and villi barriers and thus have very low bioavailability (BA). Herein, this work presents the first polymeric micelle capable of fast mucus permeation and villi absorption and delivering paclitaxel (PTX) efficiently to tumors with therapeutic efficacy even better than intravenously administered polyethylene glycol based counterpart or free PTX. Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA), a water-soluble polyzwitterion, is highly nonfouling to proteins and other biomacromolecules such as mucin but can weakly bind to phospholipids. Therefore, the micelle of its block copolymer with poly(ε-caprolactone) (OPDEA-PCL) can efficiently permeate through the viscous mucus and bind to villi, which triggers transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation. The orally administered micelles deliver PTX to tumors, efficiently inhibiting the growth of HepG2 and patient-derived hepatocellular carcinoma xenografts and triple-negative breast tumors. These results demonstrate that OPDEA-based micelles may serve as an efficient oral nanomedicine for delivering other small molecules or even large molecules.

PURPOSE Non-invasive early accurate detection of malignant breast cancer is paramount to the clinical management of the life-threatening disease. Here, we aim to test a small peptide targeted MRI contrast agent, ZD2-Gd(HP-DO3A), specific to an oncoprotein, extradomain-B fibronectin (EDB-FN), in the tumor microenvironment for MR molecular imaging of breast cancer. METHOD EDB-FN expression in 4T1 and MDA-MB-231 cancers was analyzed with quantitative real-time PCR and western blot. Primary and metastatic triple negative breast cancer mouse models were developed using 4T1 and MDA-MB-231 cells. Contrast-enhanced MRI was carried out to evaluate the use of ZD2-Gd(HP-DO3A) in detecting 4T1 and MDA-MB-231 primary and metastatic tumors. RESULTS EDB-FN was abundantly expressed in the extracellular matrix (ECM) of both the primary and metastatic TNBC tumors. In T1 -weighted MRI, ZD2-Gd(HP-DO3A) generated superior contrast enhancement in primary TNBC tumors than a nonspecific clinical agent Gd(HP-DO3A), during 30 min after contrast injection. ZD2-Gd(HP-DO3A) also produced a significant increase in contrast-to-noise ratio (CNR) of TNBC metastases, enabling sensitive localization and delineation of metastases that occulted in non-contrast-enhanced or Gd(HP-DO3A)-enhanced MRI. CONCLUSIONS These findings potentiate the use of ZD2-Gd(HP-DO3A) for MR molecular imaging of malignant breast cancers to improve the healthcare of breast cancer patients. Magn Reson Med 79:3135-3143, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The protein corona can significantly modulate the physicochemical properties and gene delivery of polyethylenimine (PEI)/DNA complexes (polyplexes). The effects of the protein corona on the transfection have been well studied in terms of averaged gene expression in a whole cell population. Such evaluation methods give excellent and reliable statistics, but they in general provide the final transfection efficiency without reflecting the dynamic process of gene expression. In this regard the influence of bovine serum albumin (BSA) on the gene expression of PEI polyplexes also on a single cell level via live imaging is analyzed. The results reveal that although the BSA corona causes difference in the overall gene expression and mRNA transcription, the gene expression behavior on the level of individual cell is similar, including the mitosis-dependent expression, distributions of onset time, expression pattern in two daughter cells, and expression kinetics in successfully transfected cells. Comparison of single cell and ensemble data on whole cell cultures indicate that the protein corona does not alter the transfection process after nuclear entry, including cell division, polyplex dissociation, and protein expression. Its influence on other steps of in vitro gene delivery before nuclear entry shall render the difference in the overall transfection.

Cationic polymers dynamically complex DNA into complexes (polyplexes). So, upon dilution, polyplexes easily dissociate and lose transfection ability, limiting their in vivo systemic gene delivery. Herein, it is found that polyplex's stability and endocytosis pathway determine its transfection dose-dependence. The polyplexes of hydrophilic polycations have dose-dependent integrity and lysosome-trafficking endocytosis; at low doses, most of these polyplexes dissociate, and the remaining few are internalized and trapped in lysosomes, abolishing their transfection ability. In contrast, the polyplexes of the polycations with optimal hydrophobicity remain integrated even at low concentrations and enter cells via macropinocytosis directly into the cytosol evading lysosomes, so each polyplex can accomplish its infection process, leading to dose-independent DNA transfection like viral vectors. Furthermore, the tuned hydrophobicity balancing the affinity of anionic poly(γ-glutamic acid) (γ-PGA) to the polyplex surface enables γ-PGA to stick on the polyplex surface as a shielding layer but peel off on the cell membrane to release the naked polyplexes for dose-independent transfection. These findings may provide guidelines for developing polyplexes that mimick a viral vector's dose-independent transfection for effective in vivo gene delivery.

This work aims to develop safe and effective gadolinium (III)-based biodegradable macromolecular MRI contrast agents for blood pool and cancer imaging. A neutral polydisulfide containing macrocyclic Gd-DOTA monoamide (GOLS) was synthesized and characterized. In addition to studying the in vitro degradation of GOLS, its kinetic stability was also investigated in an in vivo model. The efficacy of GOLS for contrast-enhanced MRI was examined with female BALB/c mice bearing 4T1 breast cancer xenografts. The pharmacokinetics, biodistribution, and metabolism of GOLS were also determined in mice. GOLS has an apparent molecular weight of 23.0 kDa with T1 relaxivities of 7.20 mM(-1) s(-1) per Gd at 1.5 T, and 6.62 mM(-1) s(-1) at 7.0 T. GOLS had high kinetic inertness against transmetallation with Zn(2+) ions, and its polymer backbone was readily cleaved by L-cysteine. The agent showed improved efficacy for blood pool and tumor MR imaging. The structural effect on biodistribution and in vivo chelation stability was assessed by comparing GOLS with Gd(HP-DO3A), a negatively charged polydisulfide containing Gd-DOTA monoamide GODC, and a polydisulfide containing Gd-DTPA-bisamide (GDCC). GOLS showed high in vivo chelation stability and minimal tissue deposition of gadolinium. The biodegradable macromolecular contrast agent GOLS is a promising polymeric contrast agent for clinical MR cardiovascular imaging and cancer imaging.

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer-drug conjugates. Current dendrimer-drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer-drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.

Poly(β-aminoester) dendrimers have been prepared. These systems represent the first degradable dual pH- and temperature-responsive dendrimers displaying photoluminescence. The pH/temperature sensitivities are interrelated; the lower critical solution temperature of the dendrimer decreases as the pH of the solution is increased. The sensitivities are mainly due to phase changes of the surface groups with changes in pH or temperature. These dual-responsive dendrimers are very useful in drug delivery. They may be loaded with a hydrophobic drug at low temperature without using organic solvents. The loaded drug is released very slowly and steadily at 37 °C and physiological pH, but can be quickly released at acidic pH, for example the lysosomal pH (pH 4-5), for intracellular drug release. These dendrimers also display strong photoluminescence, which can be exploited for monitoring drug loading and release. Thus, poly(β-aminoester) dendrimers constitute ideal drug carriers since their thermal sensitivity allows the loading of drugs without using organic solvents, their pH sensitivity permits fast intracellular drug release, and their photoluminescence provides a means of monitoring drug loading and release.

DNA-toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane-associated but also many intracellular drug-resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug-resistance barriers. The cationic polymer poly(L-lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in-vivo applications. Herein, PLL is used to demonstrate a pH-triggered charge-reversal carrier to solve this problem. PLL's primary amines are amidized as acid-labile β-carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid-labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer-cell targeted nuclear-localization polymer–drug conjugate has, thereby, been developed by introducing folic-acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA-PLL/amide-CPT). The conjugate efficiently enters folate-receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.

A novel polymer (poly[2,2'-(4,4'-bithiazolylene)][N-(2-ethylhexyl)-3,6-carbazylene] (PBTCA) was first synthesized from 2,2′-diamino-4,4′-bithiazole and N-(2-ethylhexyl)-3,6-diformylcarbazole. The structure of the polymer was determined with IR and 1H-NMR spectroscopy. The PBTCA–Nd3+ complex was prepared via the mixing of neodymium trichloride hexahydrate and PBTCA in dimethyl sulfoxide under a nitrogen atmosphere. The magnetic behaviors of the Nd3+ complex of a poly(Schiff base) were measured as a function of the magnetic field strength (0–50 kOe) at 4 K and as a function of the temperature (4–300 K). The results show that PBTCA–Nd3+ is a ferromagnet when the temperature is below 15 K, and above that, it is a diamagnet. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 443–446, 2006

A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of β-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing β-lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects.

Amine-based cationic polymers have been extensively explored as nonviral carriers for gene delivery, but inefficient intracellular unpacking of polymer/DNA complexes (polyplexes) to release plasmids is still a key limiting step to high transfection efficiency. Furthermore, the amine-resulting cationic charges in the polymer chains, and even their degraded fragments, inherently interfere with transgene expression. A cationic polymer capable of converting to uncharged fragments once inside cells would not only quickly release the DNA, but also not interfere with the gene transcription process for efficient gene expression and low toxicity. A new class of polysulfoniums that can degrade into neutral thioether fragments triggered by reactive oxygen species (ROS) is reported. The polysulfoniums condense DNA into nanosized polyplexes, which can be quickly internalized and efficiently escape from endo/lysosomes. In cancer cells, the oxidation of the boronic acid/ester by the elevated ROS levels triggers polysulfonium to break down into neutral thioether fragments, efficiently releasing DNA for gene expression. More importantly, the polyplexes have excellent serum resistance; in vivo, they efficiently deliver the suicide gene pTRAIL to intraperitoneal tumors eliciting effective anticancer activity.

The effect of biaxial orientation by solid- state crossrolling on the morphology of crystalline poly- mers including polypropylene (PP), high density polyeth- ylene (HDPE) and Nylon 6/6 was investigated with polarized optical microscopy, atomic force microscopy, wide-angle X-ray scattering, and small-angle X-ray scatter- ing techniques. It was found that crossrolling gradually changed the initial spherulitic structure into a biaxially ori- ented crystal texture with chain axis of crystals becoming parallel to the rolling direction for all three polymers. The effect of microstructure change on the macromechanical properties was studied in tension at both ambient temper- ature and � 40 � C. In tension at room temperature, the localized necking deformation of HDPE and PP control changed upon orientation into homogeneous deformation for the entire sample length. This was attributed to that the oriented crystal morphology eliminated the stress con- centration, which existed in the original spherulitic struc- ture from lamellae orientation in the polar and equatorial regions. At ambient conditions, the elastic moduli of HDPE and PP were found to decrease slightly with orien- tation whereas the modulus of Nylon 6/6 increased with increasing orientation. This was due to the fact that the amorphous chains of HDPE and PP are in a rubbery state and orientation increased the shear relaxation in the orien- tation direction but the amorphous chains of Nylon 6/6 are in the glassy state inhibited the shear relaxation. Both the yield stress and strain hardening exponent increased with increasing orientation for all three polymers. In ten- sion at � 40 � C, orientation changed the failure mechanism of all three polymers from brittle fracture into ductile fail- ure, as the original spherulitic structure was changed into an oriented structure with chain axis of crystals becoming parallel to the tension direction, which allowed chain slip deformation of crystals and resulted in oriented samples showing ductile failure. V C 2010 Wiley Periodicals, Inc. J Appl Polym Sci 118: 659-670, 2010