Bioeliminable Nanohydrogels for Drug Delivery

Abstract

One of the most significant obstacles for systematic delivery of nano-payloads is the foreign particle clearance by the mononuclear phagocyte system (MPS). The majority of biocompatible nanopayloads with charged groups on their surface cannot fully evade the clearance by MPS during systemic circulation. For safe and effective targeted nano-drug delivery in vivo, we describe a novel approach for evading the macrophage clearance. We demonstrate that neutral and hydrophilic materials can effectively evade the macrophage uptake and also quickly degrade into bioeliminable fragments. We show that there is no opsonization effect and no toxic effect on living cells. In addition, the payloads are stable in an aqueous environment and they can release drugs in a cellular environment. These results suggest that the unique properties of this kind of payloads may make them useful for designing new drug delivery systems.The development of payloads for drugs (small molecules, proteins, DNAs and RNAs) has been significantly impacted by the use of nanometer-scale materials. [1][2][3][4][5] It is envisioned that nanosscale payloads can improve the stability and solubility of hydrophobic drugs in physiological environments; can guide payloads to specific sites in organs or cells by tagging with biorecognition markers; alter protein binding affinity and drug bio-distribution in the body by surface modification; change drug pharmacokinetics and pharmaco-dynamics; and decrease immunogenicity.Despite these clear advantages, nanometer sized materials are targets for removal from the circulation by the mononuclear phagocyte system (MPS). The rate and extent of removal is determined by the physico-chemical properties of the materials used. 6 Large, hydrophobic or charged materials are rapidly cleared from systemic circulation by the MPS and are sequestered in the liver, the kidney or the spleen. Thus the design of biocompatible nanoparticle matrices is a critical step in the optimization of nanoplatform (NP)-based drug delivery.The most commonly used synthetic degradable polymers are hydrophobic materials. They find widespread use as biodegradable materials for tissue implant and implant drug release. Nevertheless, their inherent hydrophobicity limits their utility as flexible intravenous drug delivery systems. 7-13 First, the bulk hydrophobic moieties of the polymers slow the enzymatic degradation, prolong the time needed to achieve effective local concentrations of the drug/prodrug and significantly narrows the optimal therapeutic window. 7-10 Persistence of the nanoplatform in the body enhances the probability of coincidental and unintentional adverse effects. Besides, the long-time degradation of these hydrophobic polymers dramatically alters local pH, physiology / pathophysiology and may lead to unwanted degradation of the drug within payloads. 7,12,13 Second, The MPS clearance has to be taken into account during payload Evidence exists for the use of neutral, hydrophilic matrices that reduce protein opsonization in the blood...

Controlled Protein Delivery Based on Enzyme‐Responsive Nanocapsules

“…[10] [11] [12] Note that nano-hydrogels have been synthesized using microemulsion polymerization for general purpose of drug delivery. [13] [14] Generally, enzyme-responsive linkers may also be incorporated within the nano-hydrogels to provide enzyme-responsive delivery capability. However, the synthesis of such nano-hydrogels was generally achieved in reaction media containing significant amount of organic solvent and surfactant, forbidding effective incorporation of active proteins within such nano-hydrogels.…”

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“…Dissolvable and non-biodegradable polymer segments with molecular weight below 40 kDa can be cleared from the body by renal excretion [39,40]. In clinical use, tip-loaded microneedles can be disposed safely because tips are dissolved after insertion into the skin.…”

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“…Magnetic nanoparticles have increasingly been developed for the biomedical applications, particularly in the areas of bioanalysis 56,61,113,217,222,223 , bioseparation 113, 223-229 , biosensing and imaging 62, 230-234 , targeted drug delivery 167,168,170,225,[235][236][237][238][239][240] and cancer therapy 241 . The requirements of surface property for these magnetic nanoparticles are often more rigid than those for nonbiological applications.…”