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Advanced Drug Delivery Reviews (v.63, #10-11)

Editorial Board (pp. ii).

Lymphatic drug delivery: therapy, imaging and nanotechnology by Mark S. Cohen Theme Editor; M. Laird Forrest Theme Editor (pp. 865-866).

Role of the lymphatics in cancer metastasis and chemotherapy applications by Jennifer D. McAllaster; Mark S. Cohen (pp. 867-875).

The lymphatic system was first described centuries ago. The recent discovery of various molecular markers has allowed for more in-depth research of the lymphatic system and its role in health and disease. The lymphatic system has recently been elucidated as playing an active role in cancer metastasis. The knowledge of the active processes involved in lymphatic metastasis provides novel treatment targets for various malignancies.Display Omitted

Keywords: Lymphatic metastasis; Lymphangiogenesis; Vascular endothelial growth factors; Lymphatic anatomy; Lymphatic vasculature; Lymphatic endothelial cells

Advances in lymphatic imaging and drug delivery by Satish K. Nune; Padmaja Gunda; Bharat K. Majeti; Praveen K. Thallapally; M. Laird Forrest (pp. 876-885).

Cancer remains the second leading cause of death after heart disease in the US. While metastasized cancers such as breast, prostate, and colon are incurable, before their distant spread, these diseases have invaded the lymphatic system as a first step in their progression. Hence, proper evaluation of the disease state of the lymphatics which drain a tumor site is crucial to staging and the formation of a treatment plan. Current lymphatic imaging modalities with visible dyes and radionucleotide tracers offer limited sensitivity and poor resolution; however, newer tools using nanocarriers, quantum dots, and magnetic resonance imaging promise to vastly improve the staging of lymphatic spread without needless biopsies. Concurrent with the improvement of lymphatic imaging agents, has been the development of drug carriers that can localize chemotherapy to the lymphatic system, thus improving the treatment of localized disease while minimizing the exposure of healthy organs to cytotoxic drugs. This review will focus on the use of various nanoparticulate and polymeric systems that have been developed for imaging and drug delivery to the lymph system, how these new devices improve upon current technologies, and where further improvement is needed.

Keywords: Drug delivery; Polymeric carriers; Lymphatic system; Sentinel lymph nodes; Quantum dots; Dendrimers

Imaging of the interaction of cancer cells and the lymphatic system by Hop S. Tran Cao; Michele McElroy; Sharmeela Kaushal; Robert M. Hoffman; Michael Bouvet (pp. 886-889).

A thorough understanding of the lymphatic system and its interaction with cancer cells is crucial to our ability to fight cancer metastasis. Efforts to study the lymphatic system had previously been limited by the inability to visualize the lymphatic system in vivo in real time. Fluorescence imaging can address these limitations and allow for visualization of lymphatic delivery and trafficking of cancer cells and potentially therapeutic agents as well. Here, we review recent articles in which antibody–fluorophore conjugates are used to label the lymphatic network and fluorescent proteins to label cancer cells in the evaluation of lymphatic delivery and imaging.Display Omitted

Keywords: Antibody–fluorophore conjugate; Cancer cell; Lymphatic delivery

Targeting the lymphatics using dendritic polymers (dendrimers) by Lisa M. Kaminskas; Christopher J.H. Porter (pp. 890-900).

Dendrimers are unique biomaterials that are constructed by the stepwise addition of layers (generations) of polymer around a central core. They can be constructed with a range of molecular weights and have a polyfunctional surface that facilitates the attachment of drugs and pharmacokinetic modifiers such PEG or targeting moieties. These properties have led to considerable interest in the development of dendrimers for a range of biomedical applications. After subcutaneous administration, larger dendrimers in particular (>8nm), preferentially drain from the injection site into the peripheral lymphatic capillaries and therefore have potential as lymphatic imaging agents for magnetic resonance and optical fluorescence lymphangiography and as vectors for drug-targeting to lymphatic sites of disease progression. In general, lymphatic targeting of dendrimers is enhanced by increasing size although ultimately larger constructs may be incompletely absorbed from the injection site. Increasing hydrophilicity and reducing surface charge enhances drainage from subcutaneous injection sites, but the reverse is true of uptake into lymph nodes where charge and hydrophobicity promote retention. Larger hydrophilic dendrimers are also capable of extravasation from the systemic circulation, absorption into the lymphatic system and recirculation into the blood. Lymphatic recirculation may therefore be a characteristic of PEGylated dendrimers with long systemic circulation times.Display Omitted

Keywords: Dendrimer; Lymphatic transport; Magnetic resonance imaging; Drug delivery; Lymphangiography; Pharmacokinetics; Bioavailability; Polymer; Protein

Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles by Shuang Cai; Qiuhong Yang; Taryn R. Bagby; M. Laird Forrest (pp. 901-908).

The lymphatic system plays a crucial role in the immune system's recognition and response to disease, and most solid cancers initially spread from the primary site via the tumor's surrounding lymphatics before hematological dissemination. Hence, the lymphatic system is an important target for developing new vaccines, cancer treatments, and diagnostic agents. Targeting the lymphatic system by subcutaneous, intestinal, and pulmonary routes has been evaluated and subsequently utilized to improve lymphatic penetration and retention of drug molecules, reduce drug-related systemic toxicities, and enhance bioavailability of poorly soluble and unstable drugs. Lymphatic imaging is an essential tool for the detection and staging of cancer. New nano-based technologies offer improved detection and characterization of the nodal diseases, while new delivery devices can better target and confine treatments to tumors within the nodal space while sparing healthy tissues. This manuscript reviews recent advances in the field of lymphatic drug delivery and imaging and focuses specifically on the development of liposomes and solid lipid nanoparticles for lymphatic introduction via the subcutaneous, intestinal, and pulmonary routes.

Keywords: Lymphatic drug delivery; Lymphatic imaging; Nanotechnology; Engineered liposomes; Solid lipid nanoparticles

The role of the lymphatic system in vaccine trafficking and immune response by Ivy Pal; Joshua D. Ramsey (pp. 909-922).

The development and improvement of vaccines has been a significant endeavor on the part of the medical community for more than the last two centuries, and the success of these efforts is obvious when one considers the millions of lives that have been saved. Recent work in the field of vaccines, however, indicates that vaccines may be developed for even more challenging diseases than those previously addressed. It will be important in achieving this feat to account for the physical and chemical processes related to vaccine trafficking, rather than solely relying on our knowledge of the pathogen and our empirical experience. A thorough understanding of the lymphatic system is essential considering the role it plays in antigen trafficking and all immunological activity. This review describes the results of recent work that provides insight into the physiological processes of the lymphatic system and its various components with an emphasis on vaccine antigen trafficking from the administration site to secondary lymphoid tissues and the ensuing immune response. The review also discusses current challenges in designing vaccines and presents modern strategies for designing vaccines to better interface with the lymphatic system.Display Omitted

Keywords: Abbreviations; APC; Antigen presenting cell; DC; Dendritic cell; pDC; Plasmacytoid dendritic cell; FDC; Follicular dendritic cell; LC; Langerhans cell; TLR; Toll-like receptor; TNF; Tumor necrosis factor; IL; Interleukin; MHC; Major histocompatibility complex; HEV; High endothelial venulesLymphatic system; Vaccine; Antigen; Adjuvant; APC; Lymphocytes

Intestinal lymphatic transport for drug delivery by Yanez Jaime A. Yáñez; Stephen W.J. Wang; Ian W. Knemeyer; Mark A. Wirth; Kevin B. Alton (pp. 923-942).

Intestinal lymphatic transport has been shown to be an absorptive pathway following oral administration of lipids and an increasing number of lipophilic drugs, which once absorbed, diffuse across the intestinal enterocyte and while in transit associate with secretable enterocyte lipoproteins. The chylomicron-associated drug is then secreted from the enterocyte into the lymphatic circulation, rather than the portal circulation, thus avoiding the metabolically-active liver, but still ultimately returning to the systemic circulation. Because of this parallel and potentially alternative absorptive pathway, first-pass metabolism can be reduced while increasing lymphatic drug exposure, which opens the potential for novel therapeutic modalities and allows the implementation of lipid-based drug delivery systems. This review discusses the physiological features of the lymphatics, enterocyte uptake and metabolism, links between drug transport and lipid digestion/re-acylation, experimental model ( in vivo, in vitro, and in silico) of lymphatic transport, and the design of lipid- or prodrug-based drug delivery systems for enhancing lymphatic drug transport.

Keywords: Drugs; Lymph; Absorption; Transport; Intestine; Formulation; Lipid; Oral; Delivery; Chylomicron

Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations by Samar Hamdy; Azita Haddadi; Ryan W. Hung; Afsaneh Lavasanifar (pp. 943-955).

Development of safe and effective cancer vaccine formulation is a primary focus in the field of cancer immunotherapy. The recognition of the crucial role of dendritic cells (DCs) in initiating anti-tumor immunity has led to the development of several strategies that target vaccine antigens to DCs as an attempt for developing potent, specific and lasting anti-tumor T cell responses. The main objective of this review is to provide an overview on the application of poly (d,l-lactic-co-glycolic acid) nanoparticles (PLGA-NPs) as cancer vaccine delivery system and highlight their potential in the development of future therapeutic cancer vaccines. PLGA-NPs containing antigens along with immunostimulatory molecules (adjuvants) can not only target antigen actively to DCs, but also provide immune activation and rescue impaired DCs from tumor-induced immuosupression.Display Omitted

Keywords: Abbreviations; APCs; antigen presenting cells; BMDC; bone marrow derived dendritic cells; CCR; chemokine receptor; CD40L; CD40 ligand; cDNA; complementary DNA; CFA; complete Freund's adjuvant; CLIP; class II associated in variant chain peptide; CpG; cytosine-phosphate-guanine; CTL; cytotoxic T lymphocyte; DCs; dendritic cells; EBV; Epstein–Barr Virus; ELISPOT; Enzyme-linked immunosorbent spot; ELC; EBV-induced molecule 1 ligand chemokine; ER; endoplasmic reticulum; FDA; Food and Drug administration; Flt3-L; fetal liver tyrosine kinase 3-ligand; GalCer; galactosyl-ceramide; GM-CSF; granulocyte-macrophage colony stimulating factor; HB; hepatitis B; HEV; high endothelial venules; HPV; human papillomavirus; HSP; heat shock protein; ICAM; intercellular adhesion molecule; i.d.; intradermal; IFA; incomplete Freund's adjuvant; i.l.; intralymphatic; IP-10; inducible protein-10; i.t.; intratumoral; IFN-γ; interferon gamma; Ii; invariant chain; IL; interleukin; i.p.; intraperitoneal; ISOCOMs; immune-stimulating complexes; LFA; intercellular adhesion molecule lymphocyte function-associated antigen; LPS; lipopolysaccharide; mAbs; monoclonal antibodies; MHC; major histocompatibility complex; MIP; macrophage inflammatory protein; MPLA; monophosphoryl lipid A; MUC1; mucin-1; NK; natural killer cells; NKT; natural killer T cells; NPs; nanoparticles; NSCLC; non-small cell lung cancer; OVA; ovalbumin; PEG; poly(ethylene glycol); PGE2; prostaglandin E2; PLGA; poly(; d; ,; l; -lactic-co-glycolic acid); RANTES; regulated on activation normal T cell expressed and secreted; RGD; Arg-Gly-Asp; s.c.; subcutaneous; SLC; secondary lymphoid tissue chemokine; TAP; transporter of antigen presentation; Th; T helper; TLR; Toll-like receptor; TNF-α; tumor necrosis factor alpha; Treg; regulatory T cells; TRP2; Tyrosinase related protein-2; VLPs; virus like particlesAdjuvant; Cancer; Vaccine; PLGA

Translational imaging of lymphatics in cancer by Stephanie M. Cohen; Bobbi G. Fishinghawk; Mark S. Cohen (pp. 956-962).

Imaging in the lymphatic system has gone through much advancement over the past 70years since its beginnings. In this review, we will examine the modalities available for lymphatic imaging. We will explore the modern uses of early modalities, such as ultrasound as well as more modern modalities, such as Positron-Emission Tomography (PET). We will also describe some of the new modalities currently in development and their potential uses for the future as well as some of the current imaging modalities being studied in animal models.Novel translational imaging modalities for lymphatic imaging are discussed including clockwise from top left: photoacoustic imaging, nanoconjugated drug delivery and imaging using hyaluoranan, and quantum dot imaging.Display Omitted

Keywords: Ultrasound; MRI; PET; Nanoparticle; Photoacoustic imaging

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Advanced Drug Delivery Reviews (v.63, #10-11)