Two-dimensional diffusiophoretic colloidal banding: Optimizing the spatial and temporal design of solute sinks and sources

In this work, we numerically investigate the impact of two-dimensional solute gradients on the distribution of colloidal particles, i.e., colloidal banding, induced via diffusiophoresis. The solute gradients are generated by spatially arranged sources and sinks that emit/absorb a time-dependent solute flux. First we study a dipole system, i.e., one source and one sink, and discover that interdipole diffusion and flux decay timescales dictate colloidal banding. At timescales shorter than the interdipole diffusion timescale, we observe a rapid enhancement in particle enrichment around the source due to repulsion from the sink. However, at timescales longer than the interdipole diffusion timescale, the source and sink screen each other, leading to a slower enhancement. If the solute flux decays at the timescale of interdipole diffusion, an optimal separation distance is obtained such that particle enrichment is maximized. We find that the partition coefficient between solute inside the source and the bulk strongly impacts the optimal separation distance. Surprisingly, the diffusivity ratio between solute in the source and bulk has a much weaker impact on the optimal dipole separation distance. We also examine an octupole configuration, i.e., four sinks and four sources, arranged in a circle, and demonstrate that the geometric arrangement that maximizes enrichment depends on the radius of the circle. If the radius of the circle is small, it is preferred to have sources and sinks arranged in an alternating fashion. However, if the radius of the circle is large, a consecutive arrangement of sources and sinks is optimal. Our numerical framework introduces a novel method for spatially and temporally designing the banded structure of colloidal particles in two dimensions using diffusiophoresis and opens up new avenues in a field that has primarily focused on one-dimensional solute gradients

Role of synergy and immunostimulation in design of chemotherapy combinations: An analysis of doxorubicin and camptothecin

Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near-their maximum tolerated doses (MTDs), elevating the risk of dose-related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low-dose treatment option for breast cancer. DOX-CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA-MB-231). This combination led to excellent long-term survival of mice bearing MDA-MB-231 tumors at doses roughly five-fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX-CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment. </div

Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses

Propulsion and assembly of remotely powered p-type silicon microparticles

In this letter, we discuss how to prepare millions of uniform p-type silicon (Si) microparticles using top-down fabrication processes and how to remotely control their dynamics when they are suspended in water and powered by external alternating current (AC) electric fields. These microparticles present positively charged carrier types (majority carriers from boron atom doping in the intrinsic Si) and negatively charged carrier types (minority carriers from the free electrons in the Si lattice), which electrostatically affects their negatively charged surfaces and enables a variety of programmable behaviors, such as directional assembly and propulsion. At high AC electric field frequencies ( f > 10 kHz), the microparticles assemble by attractive dielectrophoretic polarization forces. At low electric field frequencies ( f ≤ 10 kHz), the microparticles propel by induced-charge electrophoretic flows. The ability to manipulate the electrostatic potential distribution within and around the microparticles (i.e., by controlling electronic carrier types through doping) is useful for designing a number of new dynamic systems and devices with precise control over their behaviors

Tissue-adhesive hydrogel for multimodal drug release to immune cells in skin

Both innate and adaptive immune systems play a crucial role in the pathology of skin diseases. To control these cells, there is a need for transdermal drug delivery systems that can target multiple cell populations at independently tunable rates. Herein, we describe a tissue-adhesive hydrogel system that contains particles capable of regulating the release of small molecule drugs at defined rates. Resiquimod (a macrophage-targeting drug) and palbociclib (a T cell-targeting drug) are encapsulated within two types of silicone particles embedded within the hydrogel. We demonstrate that drug release is mediated by the crosslink density of the particles, which is decoupled from the bulk properties of the hydrogel. We show that this system can be used to sustainably polarize macrophages toward an anti-tumor phenotype in vitro and ex vivo, and that the hydrogels can remain attached to skin explants for several days without generating toxicity. The hydrogel system is compatible with standard dermatological procedures and allows transdermal passage of drugs. The multimodal, tunable nature of this system has implications in treating a variety of skin disorders, managing infections, and delivering vaccines. Statement of significance: We describe a tissue-adhesive hydrogel that can regulate the release of drugs in a manner that is decoupled from its bulk properties. The mechanism of drug release is mediated by embedded microparticles with well-defined crosslink densities. The significance of this system is that, by encapsulating different drugs into the particles, it is possible to achieve multimodal drug release. We demonstrate this capability by releasing two immunomodulatory drugs at disparate rates. A drug that targets innate immune cells is released quickly, and a drug that targets adaptive immune cells is released slowly. This programmable system offers a direct means by which cellular responses can be enhanced through independent targeting for a variety of transdermal applications, including cancer treatment and vaccine delivery

Systemic Tumor Suppression via Macrophage‐Driven Automated Homing of Metal‐Phenolic‐Gated Nanosponges for Metastatic Melanoma

Abstract Cell‐based therapies comprising the administration of living cells to patients for direct therapeutic activities have experienced remarkable success in the clinic, of which macrophages hold great potential for targeted drug delivery due to their inherent chemotactic mobility and homing ability to tumors with high efficiency. However, such targeted delivery of drugs through cellular systems remains a significant challenge due to the complexity of balancing high drug‐loading with high accumulations in solid tumors. Herein, a tumor‐targeting cellular drug delivery system (MAGN) by surface engineering of tumor‐homing macrophages (Mφs) with biologically responsive nanosponges is reported. The pores of the nanosponges are blocked with iron‐tannic acid complexes that serve as gatekeepers by holding encapsulated drugs until reaching the acidic tumor microenvironment. Molecular dynamics simulations and interfacial force studies are performed to provide mechanistic insights into the “ON‐OFF” gating effect of the polyphenol‐based supramolecular gatekeepers on the nanosponge channels. The cellular chemotaxis of the Mφ carriers enabled efficient tumor‐targeted delivery of drugs and systemic suppression of tumor burden and lung metastases in vivo. The findings suggest that the MAGN platform offers a versatile strategy to efficiently load therapeutic drugs to treat advanced metastatic cancers with a high loading capacity of various therapeutic drugs