Vaccine delivery: Nanopatch‐Targeted Skin Vaccination against West Nile Virus and Chikungunya Virus in Mice (Small 16/2010)

The ‘Nanopatch’ (NP) comprises arrays of densely packed projections with a defined geometry and distribution designed to physically target vaccines directly to thousands of epidermal and dermal antigen presenting cells (APCs). These miniaturized arrays are two orders of magnitude smaller than standard needles—which deliver most vaccines—and are also much smaller than current microneedle arrays. The NP is dry‐coated with antigen, adjuvant, and/or DNA payloads. After the NP was pressed onto mouse skin, a protein payload co‐localized with 91.4 ± 4.1 APC mm⁻² (or 2925 in total) representing 52% of the delivery sites within the NP contact area, agreeing well with a probability‐based model used to guide the device design; it then substantially increases as the antigen diffuses in the skin to many more cells. APC co‐localizing with protein payloads rapidly disappears from the application area, suggesting APC migration. The NP also delivers DNA payloads leading to cutaneous expression of encoded proteins within 24 h. The efficiency of NP immunization is demonstrated using an inactivated whole chikungunya virus vaccine and a DNA‐delivered attenuated West Nile virus vaccine. The NP thus offers a needle‐free, versatile, highly effective vaccine delivery system that is potentially inexpensive and simple to use.     

Dual‐Action Cancer Therapy with Targeted Porous Silicon Nanovectors

There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody‐functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two‐stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity.     

Microneedle‐Assisted,DC‐Targeted Codelivery of pTRP‐2 and Adjuvant of Paclitaxel for Transcutaneous Immunotherapy

This work aims at developing an immunotherapeutic strategy to deliver a cancer DNA vaccine targeting dendritic cells (DCs), to trigger their maturation and antitumor function, and reduce immune escape using a polymeric nanocomplex of paclitaxel (PTX)‐encapsulated sulfobutylether‐β‐cyclodextrin (SBE)/mannosylated N,N,N‐trimethylchitosan (mTMC)/DNA. To enhance DC‐targeting and revoke immunosuppression is the major challenge for eliciting effective antitumor immunity. This codelivery system is characterized by using low‐dose PTX as an adjuvant that is included inside SBE, and the PTX/SBE further serves as an anionic crosslinker to self‐assemble with the cationic mTMC/DNA polyplexes. This system is used in combination with a microneedle for transcutaneous vaccination. Once penetrating into the epidermis, the mannosylated nanocomplexes would preferentially deliver the pTRP‐2 DNA vaccine inside the DCs. Phenotypic maturation is demonstrated by the increased expression of costimulatory molecules of CD80 and CD86, and the elevated secretion of IL‐12p70. The mixed leucocyte reactions reveal that the PTX/SBE‐mTMC/DNA nanocomplexes enhance the proliferation of CD4+ and CD8+ T cells, and inhibit the generation of immune‐suppressive FoxP3+ T cells. The system shows high antitumor efficacy in vivo. The PTX/SBE‐mTMC/DNA nanocomplexes for DC‐targeted codelivery of DNA vaccine and adjuvant PTX yield synergistic effects on the DC maturation and its presenting functions, thus increasing immune stimulation and reducing immune escape.     

Targeted Liposome‐Loaded Microbubbles for Cell‐Specific Ultrasound‐Triggered Drug Delivery

One of the main problems in cancer treatment is disease relapse through metastatic colonization, which is caused by circulating tumor cells (CTCs). This work reports on liposome‐loaded microbubbles targeted to N‐cadherin, a cell–cell adhesion molecule expressed by CTCs. It is shown that such microbubbles can indeed bind to N‐cadherin at the surface of HMB2 cells. Interestingly, in a mixture of cells with and without N‐cadherin expression, binding of the liposome‐loaded microbubbles mainly occurs to the N‐cadherin‐expressing cells. Importantly, applying ultrasound results in the intracellular delivery of a model drug (loaded in the liposomes) in the N‐cadherin‐expressing cells only. As described in this paper, such liposome‐loaded microbubbles may find application as theranostics and in devices aimed for the specific killing of CTCs in blood.     

Photosensitizer‐Incorporated Quadruplex DNA‐Gated Nanovechicles for Light‐Triggered,Targeted Dual Drug Delivery to Cancer Cells

A novel light‐operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer‐incorporated G‐quadruplex DNA‐capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug‐carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell‐specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.     

Bioresponsive Microneedles with a Sheath Structure for H2O2 and pH Cascade‐Triggered Insulin Delivery

Self‐regulating glucose‐responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H₂O₂‐labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano‐sized complex micelles (NCs) with insulin and glucose oxidase of pH‐tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H₂O₂‐scavenging enzyme to mitigate the injury of H₂O₂ toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.     

Mesoporous Silica Nanoparticles Act as a Self‐Adjuvant for Ovalbumin Model Antigen in Mice

Immunization to the model protein antigen ovalbumin (OVA) is investigated using MCM‐41 mesoporous silica nanoparticles as a novel vaccine delivery vehicle and adjuvant system in mice. The effects of amino surface functionalization and adsorption time on OVA adsorption to nanoparticles are assessed. Amino‐functionalized MCM‐41 (AM‐41) shows an effect on the amount of OVA binding, with 2.5‐fold increase in binding capacity (72 mg OVA/g AM‐41) compared to nonfunctionalized MCM‐41 (29 mg OVA/g MCM‐41). Immunization studies in mice with a 10 μg dose of OVA adsorbed to AM‐41 elicits both antibody and cell‐mediated immune responses following three subcutaneous injections. Immunizations at a lower 2 μg dose of OVA adsorbed to AM‐41 particles results in an antibody response but not cell‐mediated immunity. The level of antibody responses following immunization with nanoformulations containing either 2 μg or 10 μg of OVA are only slightly lower than that in mice which receive 50 μg OVA adjuvanted with QuilA, a crude mixture of saponins extracted from the bark of the Quillaja saponaria Molina tree. This is a significant result, since it demonstrates that AM‐41 nanoparticles are self‐adjuvanting and elicit immune responses at reduced antigen doses in vivo compared to a conventional delivery system. Importantly, there are no local or systemic negative effects in animals injected with AM‐41. Histopathological studies of a range of tissue organs show no changes in histopathology of the animals receiving nanoparticles over a six week period. These results establish the biocompatible MCM‐41 silica nanoparticles as a new method for vaccine delivery which incorporates a self‐adjuvant effect.     

Acid Active Receptor‐Specific Peptide Ligand for In Vivo Tumor‐Targeted Delivery

Targeting therapy of tumors in their early stages is crucial to increase the survival rate of cancer patients. Currently most drug‐delivery systems target the neoplasia through the tumor‐associated receptors overexpressed on the cancer cell membrane. However, the expression of these receptors on normal cells and tissues is inevitable, which leads to unwanted accumulation and side effects. Characteristics of the tumor microenvironment, such as acidosis, are pervasive in almost all solid tumors and can be easily accessed. It is shown that the different extracellular pH value can be used to activate/inactivate the receptor‐mediated endocytosis on tumor/normal cells. This idea is implemented by conjugating a shielding molecule at the terminus of a receptor‐specific ligand via a pH‐sensitive hydrazone bond. The acid‐activated detachment of the shielding molecule and enhanced tumor/background accumulation ratio are demonstrated. These results suggest that acid active receptor‐specific peptide ligand‐modified tumor‐targeting delivery systems have potential use in the treatment of tumors.