Controlling new blood vessel formation is of interest in regenerative medicine and cancer treatment. Heparin, a biopolymer that binds to angiogenic growth factors, was used to nucleate the self-assembly of nanostructures from designed peptide amphiphile molecules. This process yields rigid nanofibers that display heparin chains to orient proteins for cell signaling. In vivo, the nanostructures stimulated extensive new blood vessel formation using nanogram amounts of growth-factor proteins that by themselves did not induce any detectable angiogenesis.

Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in one of 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%), including patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pre-treated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full-dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities. ABSTRACTpression including thrombocytopenia, and dose-limiting peripheral neuropathy (PN) (up to 30% Grade 1/2 and 7-15% Grade 3/4). The PN often leads to discontinuation, and can be debilitating and occasionally irreversible. [19][20][21] Thalidomide is even more strongly implicated in PN, 22 and a recent analysis of patients with newly diagnosed MM revealed that although thalidomide improved efficacy when added to melphalan-prednisone, it negatively impacted safety. 23 Maintenance therapy, as well as consolidation strategies, with many of these drugs are being investigated as important ways to improve and prolong responses in patients with MM, 24 and these extended treatment periods may draw increased attention to tolerability and cumulative toxicities when considering longterm treatment options.Carfilzomib was initially evaluated in 2 phase I studies 25 and PX-171-002 26) investigating two different dosing schedules: 5 consecutive days of a 14-day cycle and 2 consecutive days/week for 3 weeks of a 28-day cycle). Consecutive day dosing demonstrated promising antitumor activity. However, single-agent carfilzomib administered using the 2 consecutive day dosing schedule (PX-171-002) was better tolerated and was chosen for further exploration in ph...

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

Heparin-protein interactions are important in many physiological processes including angiogenesis, the growth of new blood vessels from existing ones. We have previously developed a highly angiogenic self-assembling gel, wherein the self-assembly process is triggered by the interactions between heparin and peptide amphiphiles (PAs) with a consensus heparin binding sequence. In this report, this consensus sequence was scrambled and incorporated into a new peptide amphiphile in order to study its importance in heparin interaction and bioactivity. Heparin was able to trigger gel formation of the scrambled peptide amphiphile (SPA). Furthermore, the affinity of the scrambled molecule for heparin was unchanged as shown by isothermal titration calorimetry and high Förster resonance emission transfer efficiency. However, both the mobile fraction and the dissociation rate constant of heparin, using fluorescence recovery after photobleaching, were markedly higher in its interaction with the scrambled molecule implying a weaker association. Importantly, the scrambled peptide amphiphile-heparin gel had significantly less angiogenic bioactivity as shown by decreased tubule formation of sandwiched endothelial cells. Hence, we believe that the presence of the consensus sequence stabilizes the interaction with heparin and is important for the bioactivity of these new materials.

The mechanism for stem cell mediated improvement following acute myocardial infarction has been actively debated. We support hypotheses that the stem cell effect is primarily paracrine factor-linked. We used a heparin-presenting injectable nanofiber network to bind and deliver paracrine factors derived from hypoxic conditioned stem cell media to mimic this stem cell paracrine effect. Our self-assembling peptide nanofibers presenting heparin were capable of binding paracrine factors from a media phase. When these factor-loaded materials were injected into the heart following coronary artery ligation in a mouse ischemia-reperfusion model of acute myocardial infarction, we found significant preservation of hemodynamic function. Through media manipulation, we were able to determine that crucial factors are primarily less than 30 kDa and primarily heparin-binding. Using recombinant VEGF and bFGF loaded nanofiber networks the effect observed with conditioned media was recapitulated. When evaluated in another disease model, a chronic rat ischemic hind limb, our factor-loaded materials contributed to extensive limb revascularization. These experiments demonstrate the potency of the paracrine effect associated with stem cell therapies and the potential of a biomaterial to bind and deliver these factors, pointing to a potential therapy based on synthetic materials and recombinant factors as an acellular therapy.