Ligand-mediated controlled drug delivery

Disclosed are systems and methods that can be utilized to define and control the delivery rate of a biological agent from a carrier matrix such as a biocompatible hydrogel. The carrier matrices of the present invention can include ligands incorporated within the matrix at a predetermined concentration level (C.sub.LT). In addition, the ligands within the matrix can display a particular, predetermined affinity for the biologically active agents to be delivered by the system. In particular, the affinity between the ligand and the biologically active agent can have a known predetermined dissociation constant (K.sub.D). When utilizing the system, the agent can be incorporated within the matrix due to association of the agent with the ligand. In addition, the agent can be protected from side reactions due to the association of the agent with the ligand. Through particular selection of the parameters C.sub.LT and K.sub.D, the rate of release of the biologically active agent from the matrix can be controlled. The disclosed methods and systems can be advantageously used in both in vivo clinical settings and ex vivo settings, such as tissue engineering applications

Controlled drug delivery from ophthalmic lenses

Poster apresentado no Ciência 2016 – Encontro com a Ciência e Tecnologia em Portugal. Centro de Congressos de Lisboa, 4-6 julho 2016N/

Environmentally-Sensitive Vesicles for Controlled Drug Delivery

The potential uses of phospholipid vesicles in drug delivery have been widely discussed. The present chapter summarizes work from this laboratory on the preparation of lipid vesicles that release their contents in response to specific chemical or physical stimuli. Contributions to this area from other laboratories may be found in references 15-21. The unifying theme of our work has been the use of environmentally sensitive polyelectrolytes to control the structure and permeability of the phospholipid vesicle membrane. In particular, we have found that the large changes in solvation and conformation that accompany the titration of hydrophobic poly(carboxylic acid)s can be exploited to effect phospholipid reorganization from vesicular to micellar form, as illustrated in Scheme I. This idea has been elaborated, as described below, to prepare phospholipid vesicles that respond to changes in pH, temperature or glucose concentration

POROUS NANOMATERIALS AS CONTROLLED DRUG DELIVERY SYSTEMS

MIL-53(Fe) was synthesized by conventional electric (CE) heating, and by ultrasound (UTS) and microwave (MW) irradiation to develop rapid and energy efficient synthesis techniques. MW and UTS conditions rapidly produced small and highly crystalline materials in 10 and 7 minutes, respectively. The energy consumption of UTS and MW irradiation were less than CE heating, confirming that these two technologies are quicker, more efficient and greener alternatives to conventional synthesis methods. The use of MIL-53(Fe), MIL-101, and SBA-15 as matrices for the adsorption and in vitro drug delivery of acetaminophen, progesterone, and stavudine was studied. An initial burst release from both MIL-53(Fe) and MIL-101 was followed by a slow diffusion-controlled release, which occurred for up to 6 and 5 days, respectively. Complete release from SBA-15 occured in as quickly as 30 minutes as a result of rapid drug dissolution and diffusion out of the pores

Nanofabricated biohybrid structures for controlled drug delivery

In medical science and health care, development of new approaches to\ud specifically treat a disease without damaging healthy tissue is of high importance. In this context, the use of drug delivery vehicles that can recognize a disease cell and can specifically and locally deliver a therapeutic agent to that cell offers a good perspective. In this thesis we present the design, fabrication, and characterization of a new hybrid vehicle for controlled drug delivery

Synthesis of polyanhydrides for controlled drug delivery

This thesis is divided into three sections, all related to polyanhydride synthesis: first, attempts at the synthesis of polyanhydride-polyanhydride block copolymers, second, synthesis and characterization of polyethylene glycol containing aromatic polyanhydrides, and third, microwave polymerization of polyanhydrides. A strategy was developed to produce block copolymers of polyanhydrides using a hydroxyamide linker for the controlled release of proteins and higher molecular weight drugs. Block copolymers offer more control over micro structure than random copolymers, which allows for improved controlled release of proteins. The condensation polymerization of anhydrides typically yields random copolymers, therefore making the synthesis of block copolymers difficult. Methods of block copolymer synthesis explored consisted of end-functionalizing a short polyanhydride chain with hydroxylamine and ring opening polymerization through a macro-initiator. A discussion of the various methods explored is presented. Adding ethylene glycol segments to the monomers allows one to tailor the hydrophobicity of the polyanhydride, which in turn dictates the solubility of molecules within the polymer matrix and degradation rate of the polymer. Aromatic diacids were synthesized from chlorinated triethylene and pentaethylene glycols and hydroxy benzoic acid. The diacids were acetylated with acetic anhydride to produce homopolymers of polyanhydrides for the stabilization of proteins and drugs. The glycol containing polyanhydrides were characterized by NMR, GPC, DSC and dissolution testing. The release characteristics of the new polyanhydrides were evaluated with a hydrophilic (Acid Orange) and hydrophobic dye (Rhodamine B Base) and the release mechanisms were investigated. Microwave radiation was used to explore the high throughput synthesis of polyanhydrides for materials library characterization. Aliphatic diacids were acetylated in situ for two minutes in a closed reaction vessel before removal of excess acetic anhydride and subsequent polymerization, all in the microwave. Reaction conditions such as acetic anhydride equivalents, duration of microwave exposure and comparison to conventional polycondensation were explored. Microwave polymerization times of 6 to 8 minutes yielded optimum number average molecular weights in contrast to conventional polycondensation, which took between 1.5 to 2 hours under high vacuum. In conclusion, this thesis explored the synthesis and characterization of various polyanhydride-based homopolymers and copolymers by conventional as well as microwave techniques for controlled drug delivery applications

Oxidation-labile linkers for controlled drug delivery

The continuous symbiosis throughout chemical biology and drug discovery has led to the design of innovative bifunctional molecules for targeted and controlled drug delivery. Among the different tools, protein-drug and peptide-drug conjugates are trend approaches to achieve targeted delivery, selectivity and efficacy. To meet the main goals of these bioconjugates, the selection of the appropriate payloads and linkers is crucial, as they must provide in vivo stability, while they may also help to achieve the therapeutic target and action. In neurodegenerative diseases or some cancer types, where oxidative stress plays an important role, linkers sensitive to oxidative conditions may be able to release the drug once the conjugate achieves the target. Considering specially this specific application, this mini-review covers the most relevant publications on oxidation-labile linkersM.J.M. thanks Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) for the financial support. A.C. thanks FCT for the PhD grant (2021.05149.BD)S