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Cardiovascular therapies utilizing targeted delivery of nanomedicines and aptamers

Tan KX, Pan S, Jeevanandam J, Danquah MK

Int J Pharm, 2019 Mar 10;558:413-425.
PMID: 30660748 DOI: 10.1016/j.ijpharm.2019.01.023

Cardiovascular ailments are the foremost trigger of death in the world today, including myocardial infarction and ischemic heart diseases. To date, extraordinary measures have been prescribed, from the perspectives of both conventional medical therapies and surgeries, to enforce cardiac cell regeneration post cardiac traumas, albeit with limited long-term success. The prospects of successful heart transplants are also grim, considering exorbitant costs and unavailability of suitable donors in most cases. From the perspective of cardiac revascularization, use of nanoparticles and nanoparticle mediated targeted drug delivery have garnered substantial attention, attributing to both active and passive heart targeting, with enhanced target specificity and sensitivity. This review focuses on this aspect, while outlining the progress in targeted delivery of nanomedicines in the prognosis and subsequent therapy of cardiovascular disorders, and recapitulating the benefits and intrinsic challenges associated with the incorporation of nanoparticles. This article categorically provides an overview of nanoparticle-mediated targeted delivery systems and their implications in handling cardiovascular diseases, including their intrinsic benefits and encountered procedural trials and challenges. Additionally, the solicitations of aptamers in targeted drug delivery with identical objectives, are presented. This includes a detailed appraisal on various aptamer-navigated nanoparticle targeted delivery platforms in the diagnosis and treatment of cardiovascular maladies. Despite a few impending challenges, subject to additional investigations, both nanoparticles as well as aptamers show a high degree of promise, and pose as the next generation of drug delivery vehicles, in targeted cardiovascular therapy.

Matched MeSH terms: Aptamers, Nucleotide/administration & dosage*
Binding Characterization of Aptamer-Drug Layered Microformulations and In Vitro Release Assessment

Tan KX, Danquah MK, Pan S, Yon LS

J Pharm Sci, 2019 09;108(9):2934-2941.
PMID: 31002808 DOI: 10.1016/j.xphs.2019.03.037

Efficient delivery of adequate active ingredients to targeted malignant cells is critical, attributing to recurrent biophysical and biochemical challenges associated with conventional pharmaceutical delivery systems. These challenges include drug leakage, low targeting capability, high systemic cytotoxicity, and poor pharmacokinetics and pharmacodynamics. Targeted delivery system is a promising development to deliver sufficient amounts of drug molecules to target cells in a controlled release pattern mode. Aptameric ligands possess unique affinity targeting capabilities which can be exploited in the design of high pay-load drug formulations to navigate active molecules to the malignant sites. This study focuses on the development of a copolymeric and multifunctional drug-loaded aptamer-conjugated poly(lactide-co-glycolic acid)-polyethylenimine (PLGA-PEI) (DPAP) delivery system, via a layer-by-layer synthesis method, using a water-in-oil-in-water double emulsion approach. The binding characteristics, targeting capability, biophysical properties, encapsulation efficiency, and drug release profile of the DPAP system were investigated under varying conditions of ionic strength, polymer composition and molecular weight (MW), and degree of PEGylation of the synthetic core. Experimental results showed increased drug release rate with increasing buffer ionic strength. DPAP particulate system obtained the highest drug release of 50% at day 9 at 1 M NaCl ionic strength. DPAP formulation, using PLGA 65:35 and PEI MW of ∼800 Da, demonstrated an encapsulation efficiency of 78.93%, and a loading capacity of 0.1605 mg bovine serum albumin per mg PLGA. DPAP (PLGA 65:35, PEI MW∼25 kDa) formulation showed a high release rate with a biphasic release profile. Experimental data depicted a lower targeting power and reduced drug release rate for the PEGylated DPAP formulations. The outcomes from the present study lay the foundation to optimize the performance of DPAP system as an effective synthetic drug carrier for targeted delivery.

Matched MeSH terms: Aptamers, Nucleotide/administration & dosage
Aptamers as the chaperones (Aptachaperones) of drugs-from siRNAs to DNA nanorobots

Citartan M, Kaur H, Presela R, Tang TH

Int J Pharm, 2019 Aug 15;567:118483.
PMID: 31260780 DOI: 10.1016/j.ijpharm.2019.118483

Aptamers, nucleic acid ligands that are specific against their corresponding targets are increasingly employed in a variety of applications including diagnostics and therapeutics. The specificity of the aptamers against their targets is also used as the basis for the formulation of the aptamer-based drug delivery system. In this review, we aim to provide an overview on the chaperoning roles of aptamers in acting as the cargo or load carriers, delivering contents to the targeted sites via cell surface receptors. Internalization of the aptamer-biomolecule conjugates via receptor-mediated endocytosis and the strategies to augment the rate of endocytosis are underscored. The cargos chaperoned by aptamers, ranging from siRNAs to DNA origami are illuminated. Possible impediments to the aptamer-based drug deliveries such as susceptibility to nuclease resistance, potentiality for immunogenicity activation, tumor heterogeneity are speculated and the corresponding amendment strategies to address these shortcomings are discussed. We prophesy that the future of the aptamer-based drug delivery will take a trajectory towards DNA nanorobot-based assay.

Matched MeSH terms: Aptamers, Nucleotide/administration & dosage*
Towards targeted cancer therapy: Aptamer or oncolytic virus?

Tan KX, Danquah MK, Sidhu A, Ongkudon CM, Lau SY

Eur J Pharm Sci, 2017 Jan 01;96:8-19.
PMID: 27593990 DOI: 10.1016/j.ejps.2016.08.061

Cancer is a leading cause of global mortality. Whilst anticancer awareness programs have increased significantly over the years, scientific research into the development of efficient and specific drugs to target cancerous cells for enhanced therapeutic effects has not received much clinical success. Chemotherapeutic agents are incapable of acting specifically on cancerous cells, thus causing low therapeutic effects accompanied by toxicity to surrounding normal tissues. The search for smart, highly specific and efficient cancer treatments and delivery systems continues to be a significant research endeavor. Targeted cancer therapy is an evolving treatment approach with great promise in enhancing the efficacy of cancer therapies via the delivery of therapeutic agents specifically to and into desired tumor cells using viral or non-viral targeting elements. Viral oncotherapy is an advanced cancer therapy based on the use of oncolytic viruses (OV) as elements to specifically target, replicate and kill malignant cancer cells selectively without affecting surrounding healthy cells. Aptamers, on the other hand, are non-viral targeting elements that are single-stranded nucleic acids with high specificity, selectivity and binding affinity towards their cognate targets. Aptamers have emerged as a new class of bioaffinity targeting elements can be generated and molecularly engineered to selectively bind to diverse targets including proteins, cells and tissues. This article discusses, comparatively, the potentials and impacts of both viral and aptamer-mediated targeted cancer therapies in advancing conventional drug delivery systems through enhanced target specificity, therapeutic payload, bioavailability of the therapeutic agents at the target sites whilst minimizing systemic cytotoxicity. This article emphasizes on effective site-directed targeting mechanisms and efficacy issues that impact on clinical applications.

Matched MeSH terms: Aptamers, Nucleotide/administration & dosage*
Aptamer-Mediated Polymeric Vehicles for Enhanced Cell-Targeted Drug Delivery

Tan KX, Danquah MK, Sidhu A, Yon LS, Ongkudon CM

Curr Drug Targets, 2018 02 08;19(3):248-258.
PMID: 27321771 DOI: 10.2174/1389450117666160617120926

BACKGROUND: The search for smart delivery systems for enhanced pre-clinical and clinical pharmaceutical delivery and cell targeting continues to be a major biomedical research endeavor owing to differences in the physicochemical characteristics and physiological effects of drug molecules, and this affects the delivery mechanisms to elicit maximum therapeutic effects. Targeted drug delivery is a smart evolution essential to address major challenges associated with conventional drug delivery systems. These challenges mostly result in poor pharmacokinetics due to the inability of the active pharmaceutical ingredients to specifically act on malignant cells thus, causing poor therapeutic index and toxicity to surrounding normal cells. Aptamers are oligonucleotides with engineered affinities to bind specifically to their cognate targets. Aptamers have gained significant interests as effective targeting elements for enhanced therapeutic delivery as they can be generated to specifically bind to wide range of targets including proteins, peptides, ions, cells and tissues. Notwithstanding, effective delivery of aptamers as therapeutic vehicles is challenged by cell membrane electrostatic repulsion, endonuclease degradation, low pH cleavage, and binding conformation stability.
OBJECTIVE: The application of molecularly engineered biodegradable and biocompatible polymeric particles with tunable features such as surface area and chemistry, particulate size distribution and toxicity creates opportunities to develop smart aptamer-mediated delivery systems for controlled drug release.
RESULTS: This article discusses opportunities for particulate aptamer-drug formulations to advance current drug delivery modalities by navigating active ingredients through cellular and biomolecular traffic to target sites for sustained and controlled release at effective therapeutic dosages while minimizing systemic cytotoxic effects.
CONCLUSION: A proposal for a novel drug-polymer-aptamer-polymer (DPAP) design of aptamer-drug formulation with stage-wise delivery mechanism is presented to illustrate the potential efficacy of aptamer- polymer cargos for enhanced cell targeting and drug delivery.

Matched MeSH terms: Aptamers, Nucleotide/administration & dosage