Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

Fast parallel algorithms for short-range molecular dynamics

Exosomes are cell-derived nanovesicles that are involved in the intercellular transportation of materials. Therapeutics, such as small molecules or nucleic acid drugs, can be incorporated into exosomes and then delivered to specific types of cells or tissues to realize targeted drug delivery. Targeted delivery increases the local concentration of therapeutics and minimizes side effects. Here, we present a detailed review of exosomes engineering through genetic and chemical methods for targeted drug delivery. Although still in its infancy, exosome-mediated drug delivery boasts low toxicity, low immunogenicity, and high engineerability, and holds promise for cell-free therapies for a wide range of diseases.

Engineering exosomes for targeted drug delivery

Macrophages play an important role in cancer development and metastasis. Proinflammatory M1 macrophages can phagocytose tumor cells, while anti-inflammatory M2 macrophages such as tumor-associated macrophages (TAMs) promote tumor growth and invasion. Modulating the tumor immune microenvironment through engineering macrophages is efficacious in tumor therapy. M1 macrophages target cancerous cells and, therefore, can be used as drug carriers for tumor therapy. Herein, the strategies to engineer macrophages for cancer immunotherapy, such as inhibition of macrophage recruitment, depletion of TAMs, reprograming of TAMs, and blocking of the CD47-SIRPα pathway, are discussed. Further, the recent advances in drug delivery using M1 macrophages, macrophage-derived exosomes, and macrophage-membrane-coated nanoparticles are elaborated. Overall, there is still significant room for development in macrophage-mediated immune modulation and macrophage-mediated drug delivery, which will further enhance current tumor therapies against various malignant solid tumors, including drug-resistant tumors and metastatic tumors.

Engineering Macrophages for Cancer Immunotherapy and Drug Delivery.

Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery.

Cancer is the second leading cause of death worldwide and patients are in urgent need of therapies that can effectively target cancer with minimal off-target side effects. Exosomes are extracellular nano-shuttles that facilitate intercellular communication between cells and organs. It has been established that tumor-derived exosomes contain a similar protein and lipid composition to that of the cells that secrete them, indicating that exosomes might be uniquely employed as carriers for anti-cancer therapeutics. Methods: We isolated exosomes from two cancer cell lines, then co-cultured each type of cancer cells with these two kinds of exosomes and quantified exosome. HT1080 or Hela exosomes were systemically injected to Nude mice bearing a subcutaneous HT1080 tumor to investigate their cancer-homing behavior. Moreover, cancer cell-derived exosomes were engineered to carry Doxil (a common chemotherapy drug), known as D-exo, were used to detect their target and therapeutic efficacy as anti-cancer drugs. Exosome proteome array analysis were used to reveal the mechanism underly this phenomenon. Results: Exosomes derived from cancer cells fuse preferentially with their parent cancer cells, in vitro. Systemically injected tumor-derived exosomes home to their original tumor tissues. Moreover, compared to Doxil alone, the drug-loaded exosomes showed enhanced therapeutic retention in tumor tissues and eradicated them more effectively in nude mice. Exosome proteome array analysis revealed distinct integrin expression patterns, which might shed light on the underlying mechanisms that explain the exosomal cancer-homing behavior. Conclusion: Here we demonstrate that the exosomes' ability to target the parent cancer is a phenomenon that opens up new ways to devise targeted therapies to deliver anti-tumor drugs.

Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs.

We speculate that exosomes derived from human umbilical cord mesenchymal stromal cells (HUC-MSCs) will accumulate within tumors and have the potential for both tumor location or drug delivery. Methods: To determine proof of concept, HUC-MSC exosomes were labeled with an MRI contrast agent, gadolinium, or a near infrared dye. Exosome accumulation within ectopic osteosarcoma tumor-bearing mice was determined by 14.1 T MRI or bioimaging over 24-48 h after injection. In vitro studies examine the accumulation and physiological effect of exosomes on human and mouse osteosarcoma cell lines by MTT assay, confocal microscopy, and flow cytometry. Results: Systemic HUC-MSC exosomes accumulated continuously in tumor over a 24-48 h post-injection period. In contrast, synthetic lipid nanoparticles accumulate in tumor only for the first 3 h post-injection. Conclusion: These results suggest that HUC-MSCs exosomes accumulate within human or mouse osteosarcoma cells in vitro and in vivo over a 24 to 48 h after infusion.

Biodistribution of gadolinium- and near infrared-labeled human umbilical cord mesenchymal stromal cell-derived exosomes in tumor bearing mice.

Biomimetic Natural Killer Membrane Camouflaged Polymeric Nanoparticle for Targeted Bioimaging

pH-responsive cationic liposome for endosomal escape mediated drug delivery.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics, which is further enhanced with the use of contrast agents (CAs). The most commonly used CAs are gadolinium-based contrast agents (GBCAs), in which gadolinium (Gd) is chelated with organic chelating agents (linear or cyclic). However, the use of GBCA is related to toxic side effect due to the release of free Gd3+ ions from the chelating agents. The repeated use of GBCAs has led to Gd deposition in various major organs including bone, brain, and kidneys. As a result, the use of GBCA has been linked to the development of nephrogenic systemic fibrosis (NSF). Due to the GBCA associated toxicities, some clinically approved GBCAs have been limited or revoked recently. Therefore, there is an urgent need for the development of new strategies to chelate and stabilize Gd3+ ions for contrast enhancement, safety profile, and selective imaging of a pathological site. Toward this endeavor, GBCAs have been engineered using different nanoparticulate systems to improve their stability, biocompatibility, and pharmacokinetics. Throughout this review, some of the important strategies for engineering small molecular Gd3+ chelates into a nanoconstruct is discussed. We focus on the development of GBCAs as liposomes, mesoporous silica nanoparticles (MSNs), polymeric nanocarriers, and plasmonic nanoparticles-based design strategies to improve safety and contrast enhancement for contrast enhanced-magnetic resonance imaging (Ce-MRI). We also discuss the in-vitro/in-vivo properties of strategically designed nanoscale MRI CAs, its potentials, and limitations. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Ramesh Marasini

Papers

Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery.

Biodistribution of gadolinium- and near infrared-labeled human umbilical cord mesenchymal stromal cell-derived exosomes in tumor bearing mice.

Biomimetic Natural Killer Membrane Camouflaged Polymeric Nanoparticle for Targeted Bioimaging

pH-responsive cationic liposome for endosomal escape mediated drug delivery.

Integration of gadolinium in nanostructure for contrast enhanced-magnetic resonance imaging.