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

doi:10.3390/cancers13040670

Review

. 2021 Feb 7;13(4):670.

doi: 10.3390/cancers13040670.

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

Muhammad Abdur Rahim¹, Nasrullah Jan¹, Safiullah Khan¹, Hassan Shah¹, Asadullah Madni¹, Arshad Khan¹, Abdul Jabar², Shahzeb Khan^{3

4

5}, Abdelbary Elhissi⁶, Zahid Hussain^{7

8}, Heather C Aziz⁹, Muhammad Sohail¹⁰, Mirazam Khan³, Hnin Ei Thu^{11

12}

Affiliations

¹ Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Punjab, Pakistan.
² College of Pharmacy, University of Sargodha, Sargodha 40100, Punjab, Pakistan.
³ Department of Pharmacy, University of Malakand, Chakdara, Dir Lower 18800, Khyber Pakhtunkhwa, Pakistan.
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.
⁷ Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
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.
¹⁰ Department of Pharmacy, COMSATS University Abbottabad Campus, Abbottabad 45550, Khyber Pakhtunkhwa, Pakistan.
¹¹ Research and Innovation Department, Lincolon University College, Petaling Jaya 47301, Selangor, Malaysia.
¹² Innoscience Research Institute, Skypark, Subang Jaya 47650, Selangor, Malaysia.

PMID: 33562376
PMCID: PMC7914759
DOI: 10.3390/cancers13040670

Review

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

Muhammad Abdur Rahim et al. Cancers (Basel). 2021.

. 2021 Feb 7;13(4):670.

doi: 10.3390/cancers13040670.

Authors

Affiliations

¹ Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Punjab, Pakistan.
² College of Pharmacy, University of Sargodha, Sargodha 40100, Punjab, Pakistan.
³ Department of Pharmacy, University of Malakand, Chakdara, Dir Lower 18800, Khyber Pakhtunkhwa, Pakistan.
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.
⁷ Department of Pharmaceutics & Pharmaceutical Technology, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
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.
¹⁰ Department of Pharmacy, COMSATS University Abbottabad Campus, Abbottabad 45550, Khyber Pakhtunkhwa, Pakistan.
¹¹ Research and Innovation Department, Lincolon University College, Petaling Jaya 47301, Selangor, Malaysia.
¹² Innoscience Research Institute, Skypark, Subang Jaya 47650, Selangor, Malaysia.

PMID: 33562376
PMCID: PMC7914759
DOI: 10.3390/cancers13040670

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.

Keywords: chemotherapy; prodrugs; stimuli-responsive drug delivery systems; tumor.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

**Figure 1**
Renowned Stimuli-Responsive Drug Delivery Systems for Cancer Chemotherapy.

**Figure 2**
Cancer Cell-Specific Cytotoxicity by Active and Passive Targeting of Chemotherapeutic Agent(s).

**Figure 3**
Molecular Transitions in Stimuli-Responsive Lipid-based Drug Delivery Systems used for Cancer Chemotherapy (“L.T” represents Lipophilic Tail, “H.H” represents Hydrophilic Head, “DPPC” represents 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, “DSPC” represents 1,2-distearoyl-sn-glycero-3-phosphocholine, “HSPC” represents hydrogenated soy phosphatidylcholine, “MSPC” represents 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, “HOPC” represents 1-hexadecenyl-2-oleoyl-sn-glycero-3-phosphocholine, “DPPG” represents 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol, “DSPG” represents 1,2-distearoyl-sn-glycero-3-phosphatidylglycerol, “DMPG” represents 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol, “DSPE-PEG₂₀₀₀” represents 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000], “DMPE” represents 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, “DOPE” represents 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine).

**Figure 4**
General Concept Regarding Stimuli-Responsive Lipid-Based Drug Delivery Systems Used for Cancer Chemotherapy.

**Figure 5**
Stimuli-Responsive Prodrugs for Cancer Chemotherapy. “mPEG₅₀₀₀-b-(HPMAmLac2-r-AzEMA)-DOX-PropGA3” represents poly(ethylene glycol)₅₀₀₀-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate]2-2-azidoethyl methacrylate-doxorubicin propargyl glucuronide A3 prodrug, “mPEG-b-PLA-g-DOX” represents mPolyethyleneglycol-b-norbornene functionalized polylactic acid-grafted doxorubicin.

**Figure 6**
Stimuli-Responsive Carrier/Polymer-based Nanoparticle for Cancer Chemotherapy.

**Figure 7**
Molecular Dynamic Simulation of (A) siRNA-based dendrimers, (B) interaction between 4 20-mer chitosan (CS) and 9 exendin-4 molecules in the absence/presence of Fe3+ at pH 6.5, (C) docking scheme 2D model representing the affinity and (D) selectivity of nanoparticles towards healthy and cancerous cells (adopted with Copyright permission).

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References

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[1] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590. - DOI - PubMed

[2] Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7–30. doi: 10.3322/caac.21590. - DOI - PubMed

[3] Leao D., Craig P., Godoy L., Leite C., Policeni B. Response Assessment in Neuro-Oncology Criteria for Gliomas: Practical Approach Using Conventional and Advanced Techniques. Am. J. Neuroradiol. 2020;41:10–20. doi: 10.3174/ajnr.A6358. - DOI - PMC - PubMed

[4] Leao D., Craig P., Godoy L., Leite C., Policeni B. Response Assessment in Neuro-Oncology Criteria for Gliomas: Practical Approach Using Conventional and Advanced Techniques. Am. J. Neuroradiol. 2020;41:10–20. doi: 10.3174/ajnr.A6358. - DOI - PMC - PubMed

[5] Medina M.A., Oza G., Sharma A., Arriaga L., Hernández Hernández J.M., Rotello V.M., Ramirez J.T. Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. Int. J. Environ. Res. Public Health. 2020;17:2078. doi: 10.3390/ijerph17062078. - DOI - PMC - PubMed

[6] Medina M.A., Oza G., Sharma A., Arriaga L., Hernández Hernández J.M., Rotello V.M., Ramirez J.T. Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. Int. J. Environ. Res. Public Health. 2020;17:2078. doi: 10.3390/ijerph17062078. - DOI - PMC - PubMed

[7] Thorat N.D., Bauer J. Functional smart hybrid nanostructures based nanotheranostic approach for advanced cancer treatment. Appl. Surf. Sci. 2020:146809. doi: 10.1016/j.apsusc.2020.146809. - DOI

[8] Thorat N.D., Bauer J. Functional smart hybrid nanostructures based nanotheranostic approach for advanced cancer treatment. Appl. Surf. Sci. 2020:146809. doi: 10.1016/j.apsusc.2020.146809. - DOI

[9] Galluzzi L., Buqué A., Kepp O., Zitvogel L., Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28:690–714. doi: 10.1016/j.ccell.2015.10.012. - DOI - PubMed

[10] Galluzzi L., Buqué A., Kepp O., Zitvogel L., Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28:690–714. doi: 10.1016/j.ccell.2015.10.012. - DOI - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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