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      Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting

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          Abstract

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          Cancer is one of the leading causes of death globally. Several studies, efforts and treatment strategies have been put forth for the treatment of different types of cancers. Several chemotherapeutic agents have been discovered and utilized for the treatment of various types of cancers and tumors, which play an important role in improving the quality of life of patients. The key problems associated with the abovementioned chemotherapeutic agents are the limited target ability and non-selective toxicity. The current review focuses on the achievement of improved targeting of anticancer agents at the tumor microenvironment without affecting normal tissues. The fulfilment of the mentioned objectives by stimuli-responsive drug delivery systems, as physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems through active and passive targeting have extensively been discussed in the current review. The current review will help the wide community of researchers conducting research in targeted drug delivery systems and anticancer treatment strategies.

          Abstract

          The tumor-specific targeting of chemotherapeutic agents for specific necrosis of cancer cells without affecting the normal cells poses a great challenge for researchers and scientists. Though extensive research has been carried out to investigate chemotherapy-based targeted drug delivery, the identification of the most promising strategy capable of bypassing non-specific cytotoxicity is still a major concern. Recent advancements in the arena of onco-targeted therapies have enabled safe and effective tumor-specific localization through stimuli-responsive drug delivery systems. Owing to their promising characteristic features, stimuli-responsive drug delivery platforms have revolutionized the chemotherapy-based treatments with added benefits of enhanced bioavailability and selective cytotoxicity of cancer cells compared to the conventional modalities. The insensitivity of stimuli-responsive drug delivery platforms when exposed to normal cells prevents the release of cytotoxic drugs into the normal cells and therefore alleviates the off-target events associated with chemotherapy. Contrastingly, they showed amplified sensitivity and triggered release of chemotherapeutic payload when internalized into the tumor microenvironment causing maximum cytotoxic responses and the induction of cancer cell necrosis. This review focuses on the physical stimuli-responsive drug delivery systems and chemical stimuli-responsive drug delivery systems for triggered cancer chemotherapy through active and/or passive targeting. Moreover, the review also provided a brief insight into the molecular dynamic simulations associated with stimuli-based tumor targeting.

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          Most cited references300

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          Cancer statistics, 2020

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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            Stimuli-responsive nanocarriers for drug delivery.

            Spurred by recent progress in materials chemistry and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific physical incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)molecular conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temperature, magnetic field, ultrasound intensity, light or electric pulses) or endogenous (changes in pH, enzyme concentration or redox gradients).
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              Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

              In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                07 February 2021
                February 2021
                : 13
                : 4
                : 670
                Affiliations
                [1 ]Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Punjab, Pakistan; muhammadabdurrahim88@ 123456gmail.com (M.A.R.); nasrullahjan14@ 123456gmail.com (N.J.); safiullahkhan856@ 123456gmail.com (S.K.); hasanshah342@ 123456gmail.com (H.S.); arshadpharma77@ 123456gmail.com (A.K.)
                [2 ]College of Pharmacy, University of Sargodha, Sargodha 40100, Punjab, Pakistan; jbkhan522@ 123456gmail.com
                [3 ]Department of Pharmacy, University of Malakand, Chakdara, Dir Lower 18800, Khyber Pakhtunkhwa, Pakistan; dr.mirazam@ 123456uom.edu.pk
                [4 ]Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Westville 3631, Durban 4000, South Africa
                [5 ]Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA
                [6 ]College of Pharmacy, QU Health and Office of VP for Research and Graduate Studies, Qatar University, P.O. Box 2713, Doha, Qatar; aelhissi@ 123456qu.edu.qa
                [7 ]Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates; zhussain@ 123456sharjah.ac.ae
                [8 ]Research Institute for Medical and Health Sciences (SIMHR), University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
                [9 ]Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; heather.radford@ 123456utexas.edu
                [10 ]Department of Pharmacy, COMSATS University Abbottabad Campus, Abbottabad 45550, Khyber Pakhtunkhwa, Pakistan; Msmarwat@ 123456cuiatd.edu.pk
                [11 ]Research and Innovation Department, Lincolon University College, Petaling Jaya 47301, Selangor, Malaysia; eithuu287@ 123456gmail.com
                [12 ]Innoscience Research Institute, Skypark, Subang Jaya 47650, Selangor, Malaysia
                Author notes
                [* ]Correspondence: Asadullah.madni@ 123456iub.edu.pk (A.M.); shahzebkhan@ 123456uom.edu.pk (S.K.); Tel.: +92-62-925-5243 (A.M.); +92-3459492869 (S.K.); Fax: +92-62-925-5565 (A.M.)
                Author information
                https://orcid.org/0000-0002-3464-5435
                https://orcid.org/0000-0002-7700-6887
                https://orcid.org/0000-0003-3596-1760
                Article
                cancers-13-00670
                10.3390/cancers13040670
                7914759
                33562376
                2f78d4e7-de6a-4eb1-8716-d22c19085034
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 December 2020
                : 29 January 2021
                Categories
                Review

                tumor,chemotherapy,stimuli-responsive drug delivery systems,prodrugs

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