Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer–drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving...

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies.

The RNA interference (RNAi) pathway regulates mRNA stability and translation in nearly all human cells. Small double-stranded RNA molecules can efficiently trigger RNAi silencing of specific genes, but their therapeutic use has faced numerous challenges involving safety and potency. However, August 2018 marked a new era for the field, with the US Food and Drug Administration approving patisiran, the first RNAi-based drug. In this Review, we discuss key advances in the design and development of RNAi drugs leading up to this landmark achievement, the state of the current clinical pipeline and prospects for future advances, including novel RNAi pathway agents utilizing mechanisms beyond post-translational RNAi silencing.

The current state and future directions of RNAi-based therapeutics.

Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination

The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

The delivery of therapeutic oligonucleotides.

RNA-Targeted Therapeutics.

Introduction: Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile: prime requisites considered during the selection of any excipient in formulation development.Areas covered: The unique properties and applications of PEG have been discussed at length in the existing literature. However, a proper guidance on selection of PEG grade to cater to one’s purpose is lacking. This article provides preliminary guidelines to formulators on selection of appropriate PEG grade, typically based on its physico-chemical properties and role-based functional application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each application area.Expert opinion: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular...

Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications

Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

Curcumin is a promising therapeutic agent that exhibits manifold therapeutic activities. However, it is challenging to study curcumin as it exhibits poor aqueous solubility and low permeability and it is a substrate for P-glycoprotein (P-gp). It is readily metabolized in the body, but many active metabolites of curcumin have been identified that could also be exploited for therapy. Strategies for the oral bioenhancement of curcumin to leverage the potential of curcumin as a therapeutic molecule are discussed here in light of these challenges. A brief discussion of conventional bioenhancement strategies using cyclodextrin complexes, solid dispersions, and solid self-emulsifying drug delivery systems is given. However, the major focus of this review is the application of nano-based approaches to the bioenhancement of curcumin. A description of the main advantages of nanosystems is followed by a detailed review of various nanosystems of curcumin, including nanosuspensions and various carrier-based nanosystems. Each nanosystem considered here is first briefly introduced, and then studies of the nanosystem containing curcumin are discussed. Lipid-based systems including liposomes and solid lipid nanoparticles, microemulsions, self-microemulsifying drug-delivery systems, nanoemulsions, and polymeric nanoparticles—which are widely explored—are dealt with in detail. Other miscellaneous systems discussed include inorganic nanoparticles, micelles, solid nanodispersions, phytosomes, and dendrimers. The possibility of using intact nanoparticles to achieve the targeted oral delivery of curcumin and thus harness the benefits of this wonder nutraceutical is an exciting prospect.

Enhancing Curcumin Oral Bioavailability Through Nanoformulations

Oral folate fortification has been successful in many developed nations, however, developing countries still face low compliance and high incidence of folate deficiency associated with low birth weight infants and preterm deliveries. We report safe and efficient approach for transdermal systemic folate delivery using fluidising liposomes (120 ± 4 nm) stabilised within 3D matrix of naturally occurring cosmetic bases: Fuller’s earth and henna with room temperature stability. The proof of stratum corneum fluidisation was established ex-vivo by Langmuir-Blodgett film, FTIR and confocal imaging in rat skin. In-vivo topical application in rats showed 11-fold increase in plasma folate within 2 hr, confirming systemic delivery through skin. Efficacy study in folate deficient rats over 4 weeks showed significantly higher plasma levels compared to oral delivery with significant skin depot. Sub-acute toxicity studies in rats at 750-fold higher doses showed safety after 4 weeks daily application. Primary irritation patch test on 25 healthy human volunteers proved non-irritant nature of the nutricosmetics. The technology is first demonstration of transdermal folate fortification with nanosized liposome incorporated in cosmetics, without synthetic surfactants/ethanol or need of external energy. The platform technology opens the possibility of delivering multiple nutrients systemically through skin and can be scaled for affordable community fortification.

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Anisha A. D’Souza

Papers

Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications

Asialoglycoprotein receptor mediated hepatocyte targeting - strategies and applications.

Enhancing Curcumin Oral Bioavailability Through Nanoformulations

Stable Liposome in Cosmetic Platforms for Transdermal Folic acid delivery for fortification and treatment of micronutrient deficiencies

Bioenhanced oral curcumin nanoparticles: Role of carbohydrates.