Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics.

Enhanced Intracellular Delivery and Tissue Retention of Nanoparticles by Mussel-Inspired Surface Chemistry.

Nanomaterials have been broadly studied for intracellular delivery of diverse compounds for diagnosis or therapy. Currently it remains challenging for discovering new biomolecules that can prominently enhance cellular internalization and tissue retention of nanoparticles (NPs). Herein we report for the first time that a mussel-inspired engineering approach may notably promote cellular uptake and tissue retention of NPs. In this strategy, the catechol moiety is covalently anchored onto biodegradable NPs. Thus, fabricated NPs can be more effectively internalized by sensitive and multidrug resistant tumor cells, as well as some normal cells, resulting in remarkably potentiated in vitro activity when an antitumor drug is packaged. Moreover, the newly engineered NPs afford increased tissue retention post local or oral delivery. This biomimetic approach is promising for creating functional nanomaterials for drug delivery, vaccination, and cell therapy.

Self-assembly of affinity-controlled nanoparticles via host-guest interactions for drug delivery.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or ß-cyclodextrin were synthesized. Using poly(ß-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.

Facile Assembly of Cost-Effective and Locally Applicable or Injectable Nanohemostats for Hemorrhage Control.

Currently, there is still unmet demand for effective and safe hemostats to control abnormal bleeding in different conditions. With the aim to develop affordable, safe, effective, easily stored, and low-cost hemostats, we developed a series of positively charged nanoparticles by a facile one-pot assembly approach. In this strategy, nanoparticles were formed by cholic-acid-mediated self-assembly of polyethylenimine (PEI). Regardless of different structures of cholic acids and PEIs, well-defined nanoparticles could be successfully formed. The assembly process was dominated by multiple interactions between cholic acid and PEI, including electrostatic, hydrogen bonding, and hydrophobic forces. In vitro studies showed that assembled nanoparticles effectively induced aggregation and activation of platelets. Local application of aqueous solution containing nanoparticles assembled by different cholic acids and PEIs significantly reduced bleeding times in different rodent models including tail transection in mice as well as liver bleeding and femoral artery bleeding in rats or rabbits. Moreover, intravenous (i.v.) injection of this type of positively charged nanoparticles notably prevented bleeding in the femoral artery in rats by targeting the injured site via opsonization of nanoparticles with fibrinogen. By contrast, a control negatively charged nanoparticle showed no hemostatic activity after i.v. delivery. Also, preliminary evaluations in rats revealed a good safety profile after i.v. administration of assembled nanoparticles at a dose 4-fold higher than that used for hemostasis. These results demonstrated that cholic acid/PEI-assembled positive nanoparticles may function as cost-effective and locally applicable or injectable nanohemostats for hemorrhage control in the civilian setting and on the battlefield.

Engineering of Biocompatible pH-Responsive Nanovehicles from Acetalated Cyclodextrins as Effective Delivery Systems for Tumor Therapy.

There is still an unmet demand for materials with excellent biocompatibility, controlled hydrolytic capability, and elegant responsiveness to chemical or physical stimuli. To engineer biocompatible materials from ß-cyclodextrin (ß-CD), in this study, we synthesized acetalated ß-CDs (Ac-ßCDs) by one-pot acetalation using 2-ethoxypropene as an acetonation reagent, which can be further processed into nanoparticles (NPs) via the emulsion technique. Ac-ßCD NPs showed pH-labile hydrolysis and pH-triggered release of docetaxel (DTX) payload. Both properties were mainly dominated by the molar ratio of linear to cyclic acetal, which can be conveniently modulated by the acetalation time used for materials synthesis. Ac-ßCD NPs were found to be biocompatible in both in vitro cell culture and in vivo acute toxicity evaluations following intravenous injection. In vitro cell culture experiments demonstrated that antitumor activity of DTX against both sensitive and resistant cancer cells was remarkably improved by formulation into Ac-ßCD nanomedicines. In vivo antitumor study also substantiated the dramatically enhanced efficacy of DTX/Ac-ßCD NPs in a melanoma-bearing nude mouse model. These studies demonstrated that NPs derived from Ac-ßCDs may serve as biocompatible and effective carriers for drug delivery.

Biocompatible reactive oxygen species (ROS)-responsive nanoparticles as superior drug delivery vehicles.

A novel reactive oxygen species (ROS)-responsive nanoplatform can be successfully manufactured from a ROS-triggerable ß-cyclodextrin material. Extensive in vitro and in vivo studies validate that this nanoscaled system may serve as a new drug delivery vehicle with well-defined ROS-sensitivity and superior biocompatibility. This nanocarrier can be used for ROS-triggered transport of diverse therapeutics and imaging agents.

The role of surface chemistry in determining in vivo biodistribution and toxicity of CdSe/ZnS core-shell quantum dots.

To examine the effect of surface chemistry and surface charge on in vivo biodistribution and toxicity of CdSe/ZnS core-shell quantum dots (QDs), QDs with positive, negative, or PEG coating are used in this study for in vivo evaluation in a mouse model. The results suggest that QDs coated with cationic polydiallyldimethylammonium chloride (PDDA) preferentially deposit in the lung other than in the liver, while the negative and PEGylated QDs render abundant accumulation in the liver. At higher doses positive QDs with PDDA coating show severe acute toxicity due to pulmonary embolism. Independent of their surface coatings, all QDs cause injuries in specific tissues like liver, spleen, lung, and kidney, after acute and long-term exposure, and the degree of injuries is dominated by their surface properties. For the positively charged QDs, the acute phase toxicity is primarily contributed by the coating material PDDA, while coating on QDs may amplify both in vitro and in vivo toxicity of PDDA. PEGylated QDs display the slightest chronic injuries in the long-term toxicity examination in comparison to positive or negative ones.

Nanostructured poly(L-lactide) matrix as novel platform for drug delivery.

With the aim to establish new strategies for fabricating bioactive nanostructured matrices for controlled drug delivery or potential tissue engineering, a facile and one-pot protocol was developed in this study to produce drug-loaded poly(l-lactide) (PLLA) nanostructures by thermally induced phase separation. Using both steroidal and nonsteroidal anti-inflammatory drugs, we demonstrated that lipophilic drugs can be efficiently incorporated in either nanosheet-like or nanofibrous PLLA matrices. Thus entrapped drug was randomly distributed in the interconnected nanostructures in the form of nanoscaled crystals. In vitro release study revealed that drug release kinetics may be modulated, on the one hand, by the nanostructure of matrices, while on the other hand by the polymer concentration utilized for fabrication. As for hydrophilic compounds, they could be conveniently loaded into nanofibrous structure by post-fabrication absorption. In addition to the conceptual proof of potential applications of nanostructured PLLA matrices for controlled drug delivery, the strategy employed herein offers a new way to construct bioactive scaffolds, such as antibacterial or anti-inflammatory scaffolds, which may find broad applications for tissue regeneration and stem cells-based biotherapy.