Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

Chemotherapeutics often failed to elicit optimal antitumor responses against lung cancer due to their limited exposure and accumulation in tumors. To achieve an effective therapeutic outcome of paclitaxel (PTX) against metastatic lung cancer with attenuated systemic and local toxicities, pulmonary delivery of redox-responsive PTX dimeric nanoparticles (NPs) was introduced. PTX dimers conjugated through variable lengths of diacid linkers containing disulfide bonds (−SS−) (i.e., α–PTX–SS–PTX, β–PTX–SS–PTX, and γ–PTX–SS–PTX) were initially synthesized and were subsequently self-assembled into uniform nanosized particles in the presence of vitamin E TPGS with high drug loading capacity (DE > 97%). Among various redox-sensitive scaffolds, β–PTX–SS–PTX NPs exhibited an optimal reactive oxygen species/glutathione-responsive drug release behavior, causing a lower local toxicity profile of PTX in the lungs. The scaffolds also demonstrated excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. Further, they depicted an improved lung retention as compared to the control nanovesicles (β–PTX–CC–PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered β–PTX–SS–PTX NPs exhibited a stronger anticancer potential with reduced systemic toxicity as compared to Taxol intravenous injection containing an equivalent PTX dose. The PTX dimeric NPs could also dramatically reduce the local toxicity relative to Taxol following their pulmonary delivery. Thus, this study presents redox-responsive PTX dimeric NPs as a promising nanomedicine for improved therapeutic efficacy against metastatic lung cancer.

Skin wound especially burn injury is a major threat for public health. One of the pursuits in the current wound healing research is to identify new promising biological materials, which can not only promote tissue repair but also reduce scar formation. In this current study, the potentials of α-lactalbumin (ALA), a tryptophan-rich dietary protein acting as a precursor of neurotransmitter serotonin, to promote the burn wound healing and reduce the scar formation were investigated. The ALA was initially electrospun with polycaprolactone (PCL) to accomplish electrospun nanofibrous mats (ENMs), subsequently assessed for their physicochemical attributes and wound healing efficiency on a burn rat model, and then their healing mechanisms at cellular and molecular levels were explored. The results showed that ALA and PCL were physicochemically compatible in ENMs. The average diameter of various nanofibers was within 183−344 nm. Their wettability and mechanical properties could be readily modulated by adjusting the mass ratios of ALA and PCL from 1/9 to 1/2. The selected ENMs exhibited negligible cytotoxicity and satisfactory adhesion to fibroblasts and promoting the proliferation of the fibroblasts. As compared to pristine PCL based ENMs, the composite scaffolds could accelerate the wound healing process and exhibit effects comparable to a marketed wound dressing over 16 days. Moreover, the ALA/PCL based ENMs could increase the synthesis of type I collagen and decrease the expression of α-smooth muscle actin, conferring that the novel wound dressings could reduce the formation of scars. Collectively, this study demonstrates that the ALA is a promising biological material and could promote the regeneration of burn skins with reduced scar formation, when being loaded on ultrafine fibrous scaffolds, mimicking the structure of the natural extra cellular matrix.

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