Surface-Engineered Mucus Penetrating Nucleic Acid Delivery Systems with Cell Penetrating Peptides for the Lungs.

Nucleic acids, both DNA and small RNAs, have emerged as potential therapeutics for the treatment of various lung disorders. However, delivery of nucleic acids to the lungs is challenging due to the barrier property imposed by mucus, which is further reinforced in disease conditions such as chronic obstructive pulmonary disease and asthma. The presence of negatively charged mucins imparts the electrostatic barrier property, and the mesh network structure of mucus provides steric hindrance to the delivery system. To overcome this, the delivery system either needs to be muco-inert with a low positive charge such that the interactions with mucus are minimized or should have the ability to transiently dismantle the mucus structure for effective penetration. We have developed a mucus penetrating system for the delivery of both small RNA and plasmid DNA independently. The nucleic acid core consists of a nucleic acid (pDNA/siRNA) and a cationic/amphipathic cell penetrating peptide. The mucus penetrating coating consists of the hydrophilic biopolymer chondroitin sulfate A (CS-A) conjugated with a mucolytic agent, mannitol. We hypothesize that the hydrophilic coating of CS-A would reduce the surface charge and decrease the interaction with negatively charged mucins, while the conjugated mannitol residues would disrupt the mucin-mucin interaction or decrease the viscosity of mucus by increasing the influx of water into the mucus. Our results indicate that CS-A-mannitol-coated nanocomplexes possess reduced surface charge, reduced viscosity of artificial mucus, and increased diffusion in mucin suspension as well as increased penetration through the artificial mucus layer as compared to the non-coated ones. Further, the coated nanocomplexes showed low cytotoxicity as well as higher transfection in A-549 and BEAS-2B cells as compared to the non-coated ones.

Albumin Nanoparticles Surface Decorated with a Tumor-Homing Peptide Help in Selective Killing of Triple-Negative Breast Cancer Cells.

In this article, we describe a method of delivery of doxorubicin using a novel tumor-homing peptide-based albumin nanoparticle system to triple-negative breast cancer cells (TNBC). The absence and reduced expression of the hormone (estrogen, progesterone) and HER2 (human epidermal growth factor 2) receptors, respectively, render TNBC patients nonsusceptible to different available targeted therapies. These peptide-modified nanoparticles could be taken up by TNBC cells more effectively than their bare counterparts. The drug-loaded peptide-modified nanoparticles achieved an optimal but crucial balance between cell killing in cancerous cells and cell survival in the noncancerous ones. This appears to be because of different routes of entry and subsequent fate of the bare and peptide-modified nanoparticles in cancerous and noncancerous cells. In a TNBC mouse model, the peptide-modified system fared better than the free drug in mounting an antitumor response while not being toxic systemically.

Hydrogel-mediated topical delivery of steroids can effectively alleviate psoriasis via attenuating the autoimmune responses.

Psoriasis is a systemic, relapsing, and chronic autoimmune inflammatory disease of the skin. Topical use of betamethasone, a glucocorticoid, in the form of creams is a common treatment for psoriasis. However, topical use of these creams is challenging due to the ineffective entrapment of steroids, burst release of the entrapped drugs, poor skin permeability, and high toxicity. Herein, we present the engineering of a betamethasone-loaded topical hydrogel (B-Gel) that can efficiently entrap steroids with high spreadability, and can also maintain the sustained release of drugs. We used an imiquimod (IMQ) induced ear psoriasis model, and demonstrated that topical application of B-Gel can mitigate the autoimmune inflammation reactions, and leads to a reduction in erythema, induration, scaling, and ear thickness. As interleukin 17 (IL-17) secreting T helper 17 (Th17) cells and γδ+ T cells are responsible for psoriasis, B-Gel treatment witnessed a reduction in the infiltration of leukocytes, CD4+ T cells, Th17 T cells, and dermal γδ+ T cells. We further demonstrated that B-Gel mediated reduction of IL-1ß, IL-17, and K16 (marker for keratinocyte proliferation) is responsible for alleviation of psoriasis. Therefore, the non-greasy nature of the hydrogel with a cooling effect provides an alternative for topical application of steroids.