Challenges and opportunities in the delivery of cancer therapeutics: update on recent progress.

Global cancer prevalence has continuously increased in the last decades despite substantial progress achieved for patient care. Cancer is no longer recognized as a singular disease but as a plurality of different ones, leading to the important choice of the drug administration route and promoting the development of novel drug-delivery systems (DDS). Due to their structural diversity, therapeutic cancer drugs present specific challenges in physicochemical properties that can adversely affect their efficacy and toxicity profile. These challenges are addressed by innovative DDS to improve bioavailability, pharmacokinetics and biodistribution profiles. Here, we define the drug delivery challenges related to oral, intravenous, subcutaneous or alternative routes of administration, and review innovative DDS, marketed or in development, that answer those challenges.

Organic Nanoscrolls from Electrostatic Interactions between Peptides and Lipids: Assembly Steps and Structure.

An important aspect of cells is their shape flexibility that gives them motion but also a high adaptation versatility to their environment. This shape versatility is mediated by different types of protein-membrane interactions among which electrostatic plays an important role. In the present work we examined the interaction between a small dicationic peptide, that possesses self-assembly properties, and lipid model membranes. The peptide, lanreotide, spontaneously forms nanotubes in water that have a strictly uniform diameter. In the current work, we show that the interaction between the cationic peptide and negatively charged bilayers of lipids induces the formation of myelin sheath-like structures that we call nanoscrolls. By deciphering the different steps of formation and the molecular structure of the self-assembly, we show how electrostatics modify the spontaneous peptide and lipid way of packing.

Lanreotide Depot: An Antineoplastic Treatment of Carcinoid or Neuroendocrine Tumors.

PURPOSE: Peptide drugs for antineoplastic therapies usually have low oral bioavailability and short in vivo half-lives, requiring less preferred delivery methods. Lanreotide depot is a sustained-release somatostatin analog (SSA) formulation produced via an innovative peptide self-assembly method. Lanreotide is approved in the USA and Europe to improve progression-free survival (PFS) in patients with unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and also approved in Europe for symptom control in carcinoid syndrome associated with GEP-NETs. This review discusses how the distinct molecule and formulation of lanreotide depot provide advantages to patients and health care providers, as well as the most recent clinical evidence demonstrating the safety and efficacy of lanreotide depot in inhibiting tumor growth and controlling hormonal symptoms in GEP-NETs. METHODOLOGY AND RESULTS: The lanreotide depot formulation confers a remarkable pharmacokinetic profile with no excipients, comprised only of lanreotide acetate and water. Of note, lanreotide depot constitutes an example for peptide self-assembly based formulations, providing insights that could help future development of sustained-release formulations of other antineoplastic peptides. Most patients with GEP-NETs will present with inoperable or incurable disease; thus, medical management for symptoms and tumor control plays a crucial role. Recent long-term clinical studies have demonstrated that lanreotide depot is well tolerated, prolongs PFS in GEP-NET patients, and significantly reduces symptoms related to carcinoid syndrome. CONCLUSIONS: The unique depot formulation and delivery method of lanreotide confer advantages in the treatment of metastatic GEP-NETs, contributing to improvements in NET-related symptoms and PFS without reducing quality of life in this patient population.

Development of a micro-turbulent flow chromatography focus mode method for drug quantitation in discovery bioanalysis.

An online turbulent flow chromatography method coupled to tandem mass spectrometry (TFC-MS/MS) has been developed within our bioanalytical group, suited to the analysis of mid to late stage discovery compounds. A dual column configuration utilising isocratic focusing of the analyte upon the analytical column maintained an excellent peak shape for a large proportion of compounds encountered and enabled consistent quantitation to sub-nanogram concentrations (<15 pg on column). Furthermore, the low sample injection volume coupled with rapid column washing using basic and acidic mobile phases, has proved advantageous in removing sample carryover and also the overall exposure to biological material; favourable for good system robustness. All the data discussed were generated with a method cycle time of 5 min providing accurate quantitation (acceptance criteria based upon FDA method validation guidelines) with multiple analytes and biological matrices.

Evaluation of water-compatible molecularly imprinted polymers as solid-phase extraction sorbents for the selective extraction of sildenafil and its desmethyl metabolite from plasma samples.

The evaluation of molecularly imprinted polymers (MIPs) as selective sorbents for the solid-phase extraction of sildenafil and its principal metabolite, desmethylsildenafil, was investigated. Two MIPs were synthesised using structural analogues of sildenafil as templates, and a comparison of the performance of the two MIP sorbents in organic and aqueous media was performed. Additionally, the feasibility of applying molecularly imprinted solid-phase extraction (MISPE) to the clean-up of plasma samples containing sildenafil and desmethylsildenafil was investigated. A preliminary, quantitative MISPE for the determination of both compounds in plasma was also performed. The results showed that the MIPs used for the selective extraction of sildenafil gave better compound recovery when aqueous samples were used in comparison to organic-based samples. A preliminary, quantitative MISPE of sildenafil and desmethylsildenafil indicated that the imprinted materials could be used successfully as SPE sorbents for sample pre-treatment for the determination of sildenafil, and related compounds, in plasma.

Evolution of an open-access quantitative bioanalytical mass spectrometry service in a drug discovery environment.

Increased demand for assays for compounds at the early stages of drug discovery within the pharmaceutical industry has led to the need for open-access mass spectrometry systems for performing quantitative analysis in a variety of biological matrices. The open-access mass spectrometers described here are LC/MS/MS systems operated in 'multiple reaction monitoring' (MRM) mode to obtain the sensitivity and specificity required to quantitate low levels of pharmaceutical compounds in an excess of biological matrix. Instigation of these open-access systems has resulted in mass spectrometers becoming the detectors of choice for non-expert users, drastically reducing analytical method development time and allowing drug discovery scientists to concentrate on their core expertise of pharmacokinetics and drug metabolism. Setting up an open-access facility that effectively allows a user with minimal mass spectral knowledge to exploit the MS/MS capability of triple quadrupole mass spectrometers presents a significantly different challenge from setting up qualitative single stage mass spectrometry systems. Evolution of quantitative open access mass spectrometry within a pharmaceutical drug metabolism and pharmacokinetics group, from its beginnings as a single generic system to a series of specialist fully integrated walk-up facilities, is described.

A direct comparison of the performance of ground, beaded and silica-grafted MIPs in HPLC and turbulent flow chromatography applications.

Spherical molecularly imprinted polymers (MIPs) specific to the beta-blocker propranolol have been synthesised using two different approaches and compared to traditional ground monolithic MIPs in HPLC and TFC applications. TFC is a LC technique used for rapid extraction of compounds directly from complex matrices. It can be easily coupled to HPLC and MS for automation of an extraction/analysis procedure. Spherical MIP beads were produced using a suspension polymerisation technique and silica/MIP composite beads by grafting MIP to spherical silica particles using a surface-bound initiator species. Synthesis of both beaded and silica-grafted MIPs was more practical than using the traditional grinding method and yields of spherical particles of the required size between 80 and 100% were routinely achieved. Under HPLC conditions, beaded and ground MIP materials showed a degree of chiral separation for all of the nine beta-blockers tested. The beaded MIP, however, showed much better flow properties and peak shape than the ground material. Silica-grafted MIP showed some separation in five of the drugs and a large improvement in peak shape and analysis times compared with both ground and beaded MIPs. The materials prepared were also used in extraction columns for Turbulent Flow Chromatography (TFC). Although no imprinting effect was observed under typical TFC conditions, beaded polymer materials showed promise for use as TFC extraction columns due to the good flow properties and clean extracts obtained.

Controlled trials of very high dose folic acid, vitamins B12 and B6, intravenous folinic acid and serine for treatment of hyperhomocysteinemia in ESRD.

BACKGROUND: Hyperhomocysteinemia is seen in most hemodialysis (HD) patients and is an independent risk factor for cardiovascular disease. Homocysteine metabolism via remethylation requires activated folate and vitamin B12 and metabolism via transsulfuration requires serine and vitamin B6. Prior studies have shown highly variable effects of supplemental B vitamin and folate therapy for hyperhomocysteinemia. We undertook a fully controlled trial with abnormally high doses of folic acid alone or with supplemental vitamin B6 and B12 compared with active folate alone or with serine. METHODS: Two prospective studies were undertaken in hemodialysis patients. In the first study (protocol A), hyperhomocysteinemia was treated in 77 patients with 30 or 60 mg folic acid with or without vitamins B6 and B12 for eight weeks and compared with matching placebos. In the second study (protocol B), hyperhomocysteinemia was treated in 37 patients with intravenous folinic acid given alone or with serine and compared with matching placebos. All patients received the standard of care treatment with a multivitamin tablet before and throughout the protocol to test the hypothesis that additional therapy is required over and above the routine therapy for maximum reduction in total homocysteine (tHcy). RESULTS: Normal volunteers; The mean (SD) tHcy of 128 normal subjects was 6.5 (4) micromol/L. Protocol A; Plasma folate increased significantly in the groups given folic acid at both four and eight weeks (P = 0.0001 at both time points). Plasma vitamin B12 was significantly increased at four weeks (P = 0.0018) but not at eight weeks (P = 0.064) in those given Vitamin B12. However, tHcy did not differ between treatment groups at baseline (P = 0.63), four weeks (P = 0.79) or eight weeks (P = 0.74). Protocol B: Plasma folate increased significantly at four weeks in those receiving folinic acid (P = 0.0001) but tHcy was not significantly different between groups (P = 0.92). In neither study was there any significant change in tHcy comparing before and during any treatment intervention. CONCLUSIONS: In our studies high dose oral folic acid, intravenous folinic acid, vitamins B6 and B12 and oral serine were ineffective at lowering tHcy in patients on hemodialysis when given folic acid, folinic acid serine or B vitamins in addition to routine folic acid and B vitamin supplements.

Microwave-assisted solid-phase synthesis of phthalimides.

[reaction: see text] A traceless solid-phase synthesis of substituted phthalimides is proposed. The target compounds are obtained within minutes by a microwave-assisted cyclative cleavage in good yields and excellent purities.