Abstract. Click chemistry refers to a group of reactions that are fast, simple to use, easy to purify, versatile, regiospecific, and give high product yields. While there are a number of reactions that fulfill the criteria, the Huisgen 1,3-dipolar cycloaddition of azides and terminal alkynes has emerged as the frontrunner. It has found applications in a wide variety of research areas, including materials sciences, polymer chemistry, and pharmaceutical sciences. In this manuscript, important aspects of the Huisgen cycloaddition will be reviewed, along with some of its many pharmaceutical applications. Bioconjugation, nanoparticle surface modification, and pharmaceutical-related polymer chemistry will all be covered. Limitations of the reaction will also be discussed.

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Purpose-To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA).Methods-A new pH-sensitive Dex-containing monomer (MA-Gly-Gly-NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition-fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer-Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats.Results-P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA-Gly-Gly-NHN=Dex. The PDex used for in vitro and in vivo evaluation has a weight average molecular weight (M w ) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects.Conclusions-A HPMA copolymer-dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis.

Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified atazanavir/ritonavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use.

HPMA copolymer-d-aspartic acid octapeptide (D-Asp8) conjugates have been found to target the entire skeleton after systemic administration. In a recent study using the ovariectomized rat model of osteoporosis, we surprisingly discovered that D-Asp8 would favorably recognize resorption sites in skeletal tissues, while another bone-targeting moiety, alendronate (ALN), directs the delivery system to both formation and resorption sites. Atomic force microscopy (AFM) analyses reveal that ALN has a stronger binding force to hydroxyapatite (HA) than D-Asp8. In vitro HA binding studies indicate that D-Asp8 is more sensitive to change of HA crystallinity than ALN. Because the bone apatite in the newly formed bone (formation sites) usually has lower crystallinity than the resorption sites (mainly mature bone), we believe that the favorable recognition of D-Asp8 to the bone resorption sites could be attributed to its relatively weak binding to apatite, when compared to bisphosphonates, and the different levels of crystallinity of bone apatite at different functional domains of the skeleton.

IntroductionThe purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis.MethodsRats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts.ResultsA single systemic administration of P-Dex completely suppressed AA for >20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis.ConclusionsP-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis.

A novel linear multifunctional polyethylene glycol (PEG)-dexamethasone (Dex) conjugate (click PEG-Dex) was synthesized using facile Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a click reaction). Dex was conjugated to the click PEG via an acid-labile hydrazone bond to allow the drug release in pathophysiological environment. To evaluate click PEG’s potential as a versatile drug delivery platform, the click PEG-Dex conjugates were tested in an adjuvant-induced arthritis (AA) rat model. In vivo optical imaging data confirmed the arthrotropism of the conjugates in the arthritic rats. Long-term treatment study revealed that a single click PEG-Dex conjugate administration provided sustained (> 15 days) amelioration of ankle joint inflammation to the AA rats. Treatment with equivalent dose of dexamethasone phosphate sodium (free Dex) only provides temporal resolution of the arthritis, which recurred upon treatment withdrawal. Further histological and bone mineral density comparison between the ankle joints from both click PEG-Dex and free Dex treatment groups confirmed the superior anti-inflammatory and disease modifying effects of the novel polymer-drug conjugates.

Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, restricted infection in HIV reservoirs including gut, lymphoid and central nervous system tissues, is not eliminated. What underlies these events is, in part, poor ART penetrance into each organ across tissue barriers, viral mutation and the longevity of infected cells. We posit that one means to improve these disease outcomes is through nanotechnology. To this end, this review discusses a broad range of cutting-edge nanomedicines and nanomedicine platforms that are or can be used to improve ART delivery. Discussion points include how polymer-drug conjugates, dendrimers, micelles, liposomes, solid lipid nanoparticles and polymeric nanoparticles can be harnessed to best yield cell-based delivery systems. When completely developed, such nanomedicine platforms have the potential to clear reservoirs of viral infection.