Essay Example on Lung cancer is one of the most lethal Cancers

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Lung cancer is one of the most lethal cancers and the second most common cancer in both men and women 1 The long term survival rate of lung cancer patients treated by conventional modalities such as surgery radiation and chemotherapy remains far from satisfactory as anticancer drugs cause undesirable systemic side effects 2 While many systemic nanomedicine based therapies have been developed few have been translated into clinical success such as Abraxane an albumin bound paclitaxel nanoformulation for the treatment of metastatic non small cell lung cancer NSCLC There are a lot of assumptions about nanomedicines without any experimental evidence Until now cancer nanomedicine can be only used for reducing the toxicity of chemotherapeutic agents as well as for local delivery of anticancer agents and as a tool for imaging the tumor microenvironment 3 Direct delivery of drug loaded nanocarriers to the lungs via inhalation combines the advantages of localized delivery with those of using nanocarriers in lung cancer therapy Nanoparticles NPs can escape natural obstacles of the lungs mucociliary clearance alveolar macrophages and enzymatic degradation Moreover they could efficiently accumulate in lung cancer cells thus ensuring higher drug concentration at tumor site However the use of inhalable NPs is hampered by their nano range size 0 5 µm so they could be easily exhaled before reaching site of action 4 In contrast the use of microparticles 



1 5 µm enables deep lung deposition but opsonization by alveolar macrophages still limits their wide application Therefore spray dried inhalable nanocomposites were developed to improve pulmonary drug delivery via combining the merits of both MPs and NPs They are comprised of drug loaded NPs and excipients mainly sugars in the micro range 1 5 µm suitable for deep lung deposition Once nanocomposites reach the alveolar surface the sugar carrier dissolves in alveolar fluids and nanocomposites easily disintegrate into their primary NPs to be internalized by cancer cells 5 Nanocarriers fabricated from natural hydrophilic polymers including proteins and polysaccharides have inherent advantages in terms of biocompatibility non immunogenicity and less opsonization by reticuloendothelial system RES apart from the availability of readily functionalizable groups 6 7 Lactoferrin Lf a single chain iron binding glycoprotein belongs to transferrin Tf family was found to bind to Lf membrane internalization receptors LRP1 LRP2 and Tf receptors TFR1 TFR2 over expressed on the surface of metabolically active highly proliferating cancer cells to fulfill their nutritional demands 8 This privilege could be utilized to develop actively tumor targeted drug delivery system Moreover the cationic nature of Lf enables its binding to negatively charged cell membrane glycosaminoglycans resulting in enhanced cellular internalization via charge based interaction 9 On the other hand chondroitin sulfate ChS is a natural polyanionic glycosaminoglycan characterized by its ability to bind hyaluronic acid CD44 receptors overexpressed on cancer cells which also induces an effective tumor homing property 10 Combining merits of both polymers Lf and ChS in one nanocarrier can enable an effective strategy for lung cancer targeting 



Nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously In our laboratory incorporation of both letrozole and celecoxib in protamine nanocapsules was found to enhance their anti tumor efficacy against breast cancer in vitro and in vivo compared to single free drugs 11 12 Doxorubicin DOX is one of the most potent anti neoplastic agents developed to date against hematological and solid cancers However it causes severe toxicity due to uncontrolled biodistribution disability to deep tumor penetration in addition to rapid plasma clearance 13 On another avenue the herbal drug Ellagic acid EA showed potential radical scavenging and chemopreventive actions Moreover EA was confirmed to be effective in decreasing the lipid peroxidation and increasing the GSH which is essential for its anti carcinogenic potential against lung tumorigenesis However EA suffers from low oral bioavailability attributed to its poor aqueous solubility and extensive first pass effect in addition to low chemical stability due to presence of lactone rings in its structure 14 DOX and EA can act synergistically to induce cell apoptosis via activation of various molecular signals from AMPK AMP activated protein kinase to influence the Bcl 2 Bax apoptosis pathway while EA can further inhibit Nuclear Factor Kappa B activation in addition to direct action on mitochondria 15 Furthermore EA was reported to eliminate drug resistance via inhibition of P glycoprotein efflux pumps thus DOX can work efficiently and avoid cell resistance 



Taken all together a nanocarrier incorporating DOX and EA combination would help improve the anti cancer efficacy of DOX as well as reducing its dose and side effects In this study we propose for the first time up to our knowledge inhalable dry powder Lf ChS nanocomposites for targeted co delivery of DOX and EA for lung cancer therapy First to overcome its high hydrophobicity EA was pre formulated as water soluble nanocrystals NCs prior to incorporation into the hydrophilic Lf ChS NP matrix Second self assembled nanocomplex was developed based on electrostatic interaction between cationic Lf and anionic ChS The water soluble cytotoxic drug DOX was physically co entrapped with EA NCs into the developed nanocomplex The tumor targeting properties of both Lf and ChS would enable internalization of the self targeted protein polysaccharide nanocomplex into lung cancer cells via receptor mediated endocytosis without need for additional targeting ligand Third for deep lung deposition inhalable Lf ChS nanocomposites were developed via spray drying of the dual drug loaded nanocomplex with inert carriers The developed pulmonary delivery system was thoroughly investigated in vitro and in vivo to prove the anti tumor superiority of the combined drug nano delivery compared with the free drug combination


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