Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Marta Slavkova
 -- 1731 2023-05-05 10:24:57 |
2 format correct
Catherine Yang
 -5 word(s) 1726 2023-05-05 10:59:57 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Slavkova, M.; Tzankov, B.; Popova, T.; Voycheva, C. Drug Delivery Hurdles in Skin Cancer Treatment. Encyclopedia. Available online: https://encyclopedia.pub/entry/43841 (accessed on 18 November 2024).
Slavkova M, Tzankov B, Popova T, Voycheva C. Drug Delivery Hurdles in Skin Cancer Treatment. Encyclopedia. Available at: https://encyclopedia.pub/entry/43841. Accessed November 18, 2024.
Slavkova, Marta, Borislav Tzankov, Teodora Popova, Christina Voycheva. "Drug Delivery Hurdles in Skin Cancer Treatment" Encyclopedia, https://encyclopedia.pub/entry/43841 (accessed November 18, 2024).
Slavkova, M., Tzankov, B., Popova, T., & Voycheva, C. (2023, May 05). Drug Delivery Hurdles in Skin Cancer Treatment. In Encyclopedia. https://encyclopedia.pub/entry/43841
Slavkova, Marta, et al. "Drug Delivery Hurdles in Skin Cancer Treatment." Encyclopedia. Web. 05 May, 2023.
Drug Delivery Hurdles in Skin Cancer Treatment
Edit
This entry is adapted from the peer-reviewed paper 10.3390/gels9050352

Chemotherapy of skin cancer can be either oral, parenteral, or topical. In the first case, only a limited amount of the drug reaches the target site, while the rest reaches other organs, tissues, and cells, and can cause harmful side effects. The case is quite similar in parenteral application together with its invasiveness. Therefore, the local application on different skin cancer forms can gain in therapeutic efficacy and safety. The various types of gel formulations applied topically in the treatment of skin cancer was discussed. The most common gelling agents, their concentration and mechanism of action is also provided. The possibility to combine nanotechnology for improvement of drug loading and delivery by incorporation of nanoparticles into hydrogels is also evaluated. The main methods for gel characterization in the light of topical delivery of chemotherapeutics were summarized.

skin cancer physical hydrogel chemical hydrogel composite gel characterization methods

1. Introduction

Skin is the largest organ in the human body, performing various functions ranging from protection to metabolism. The abnormal growth of the skin cells is referred to as skin cancer and this is the most common cancer type worldwide [1]. There are various types of skin cancer, including benign and malignant variants such as melanoma, squamous cell carcinoma and basal cell carcinoma [2]. Even though skin cancer is lethal in only 2% of cases in general, the malignant forms result in death in more than 80% of cases if not caught early [1]. The management of skin cancer includes surgical excision, radiotherapy, topical drug delivery, and oral therapy [2]. Although surgical treatment is considered the first line approach, topical therapy also has its role [3]. The most commonly prescribed medications are 5-fluorouracil [4][5][6] and imiquimod [5][7][8]. Other active pharmaceutical ingredients (APIs) are either repurposed or subjected to investigation and evaluation because of their topical chemotherapeutic potential in various forms of skin cancer. Some examples are doxorubicin [9], vismodegib [10], sonidegib [11], and metformin [12]. Substances of natural origin (curcumin [13][14], brucine [15], silymarin [16], chrysin [17], daidzein [18], and others) are also considered suitable in the topical treatment of skin cancer.

2. Skin Structure

Skin is a complex organ with the main function to “maintain the insides in and outside out”, acting as a barrier [19]. It consists of three layers—the epidermis, dermis, and hypo-dermis—each having a different composition and properties [20] (Figure 1). The inner hypodermis consists of adipose tissue and rarely plays an important role for drug delivery [19]. The dermis (around 2–4 mm) [21] is built up by a collagen and elastin network in a mucopolysaccharide gel which resembles a hydrogel structure. The vascularity of the dermis enables the transport of the most transdermally delivered drug molecules into the blood, maintaining a high concentration gradient. This layer also includes appendages—hair follicles, sebaceous and sweat glands—which have an impact only on the initial diffusion through the skin [19]. The outermost skin layer—the epidermis—consists mainly of cells, called keratinocytes, which play a lead role in topical drug delivery [22]. The epidermis has two avascular and hydrophobic sections, the viable epidermis and the stratum corneum (SC). The viable epidermis consists of four layers of keratinocytes at different stages of differentiation, melanocytes, Merkel cells, and Langerhans cells. The differentiation of the epidermis starts from inside to outside, and results in the formation of corneocytes—dead, anuclear, flattened, and keratin-rich cells [21]. The corneocytes are surround by lipid matrix composed of triglycerides, cholesterol, free fatty acids and ceramides, and these structures act as the prime barrier to the entry of macro and micro anticancer molecules across the skin, limiting drug delivery [23][24][25]. Normal melanin cells are characterized with physiological pH while tumor cells have a pH in the range 5–6.5 [26]. In the case of melanoma, the acidic pH is responsible for the invasion of surrounding tissues and the malignant cells have higher metastatic capacity [27]
Figure 1. Skin structure and routes of drug transport through cancerous skin after topical anticancer treatment.
Moreover, skin cancer studies revealed there are higher levels of keratin and lipids in cancer cells compared to healthy cells, resulting in a thicker SC layer and consequently a stronger barrier to drug entry, which makes it even more difficult for anticancer molecules to reach the tumor site [22][28]. This is why transdermal drug dosage forms, employed against actinic keratosis (AK) and basal cell carcinoma (BCC), require proper design to reach the deeper epidermal layers [20][29][30]. The optimal particle size needed to achieve transdermal delivery lies in the range 200–400 nm [31]. Nanoparticles with sizes of about 300 nm can reach deeper skin layers through the transappendgeal route [32].

3. Skin Penetration Routes and Factors Influencing Skin Penetration

The penetration of drugs through the skin can happen by three possible routes depending on the physicochemical properties of the active substance: intracellular (through the stratum corneum), intercellular (through the lipid matrix), and through the skin appendages (sweat glands or hair follicles) [19] (Figure 1). The transport via skin appendages (shunt route) is more suitable for hydrophilic molecules, but since the fractional area of appendages is relatively small, this shunt route is not as important for drug delivery [33]. On the other hand, highly lipophilic drug molecules can easily pass through the skin intercellularly via the lipid matrix. The intercellular (transcellular) route is the most complicated one because the drug molecule should repeatedly pass through different media of the “brick wall” [34]. First, the permeant should partition into keratin-filled corneocytes (hydrophilic environment), and after that it should diffuse through the corneocytes, followed by partitioning into the intercellular lipid matrix (lipophilic environment) [35]. Since crossing the lipid bilayers is involved in both transcellular and intercellular routes, diffusion through these lipid media is highly important. Therefore, lipophilic drugs are preferred candidates for transdermal delivery [19]. However, when passing through the stratum corneum, molecules reach the more hydrophilic lower epidermal layers (viable epidermis), and in the capillaries of the epidermal–dermal junction, they can be cleared, entering the systemic circulation [29]. Thus, high lipophilicity hinders the clearance. Ideally, the permeant should possess moderate hydrophilic–lipophilic properties, expressed as a logarithm partition coefficient (log Pwater/octanol) in the range 1–3 [20][33].
Unfortunately, not all anticancer medications possess this desired hydrophilic–lipophilic balance. For example, 5-fluorouracil, approved for actinic keratosis (AK) and superficial basal cell carcinoma (sBCC), is a highly hydrophilic molecule (log P: −0.89) [36]. This hydrophilicity restricts penetration through the hydrophobic stratum corneum and is reflected in low treatment efficacy for deeper laying lesions [36]. Furthermore, the insufficient skin penetration of 5-FU requires frequent and higher administration doses, which leads to side effects such as skin inflammation [37][38][39]. The situation with imiquimod, used for the treatment of BCC, is similar. Due to its low water solubility, permeability within the hydrophilic dermis media is difficult. Moreover, there is an interaction between the amine groups of the drug molecule with the anionic components of the skin, limiting additional imiquimod permeation, and resulting in reduced therapeutic effect [40][41].
Another factor that influences skin penetration is the molecular weight of a permeant as the transport of molecules via the skin happens by passive diffusion under a concentration gradient, following Fick’s law. According to the Stokes–Einstein equation, the diffusion coefficient of a molecule increases with the increase in its approximate radius. Therefore, a higher molecular weight is related to a higher approximate radius, so that the diffusion coefficient is generally smaller and thus the diffusion is hindered. For transdermal delivery, the drug’s molecular weight (MW) should be less than 500 Da [19][20], making the penetration of anticancer drugs with higher molecular weight difficult.
Another problem arising in cancer therapy is multidrug resistance (MDR). The interaction between the drug and the tumor media is a complex phenomenon and cancers can exhibit significant resistance to various molecules. Multidrug resistance can be defined as the decrease in the efficacy and potency of a drug to produce a therapeutic effect and is a major problem that reduces the chemotherapies’ effectiveness [22][42]. Drug resistance in skin cancers can be primary (intrinsic) or acquired. Primary resistance appears without prior exposure to anticancer agents, and thus the initial response to treatment is poor [43]. Acquired resistance is developed during the application of the cytostatic drug, and it is associated with devastating results after initially good ones [42][44].
Different mechanisms are associated with intrinsic resistance, such as changes in drug transport and efflux pump, alteration in enzyme activation and DNA repair, modulation of the apoptotic pathway, etc. [44][45][46][47]. Acquired drug resistance is affected mainly by genetic or environmental factors that enable the progress of drug-resistant cancer cell lines or induce enzyme mutations [42][43][48]. Therefore, understanding the modifications in molecular processes involved in drug resistance can trigger the development of new therapeutic strategies against skin cancers.
One of the potential factors leading to the sensitivity of drugs is the limited amount of drug reaching the tumor cells. This is why the determination of the “maximum tolerated dose” (MTD)—the highest single dose of an agent that does not cause significant or intolerable toxicity effects—is of great importance [42][49]. Therefore, any methods for increasing the penetration of the anticancer drug through the skin, and thus increasing the amount reaching the tumor cells, can lead to improved therapeutic outcomes.

4. Opportunities for Increasing Skin Penetration

Considering all the issues discussed and the factors involved in managing the transport of anticancer drugs through the skin, the most important challenge of therapy is the improvement in the drug uptake, allowing the drug to pass through the deeper layers of skin, inside cancerous cells [20].
One of the techniques to augment penetration is the utilization of “penetration enhancers” [20][50], such as ethanol, Azones, fatty alcohols, glycols, and DMSO. These substances mainly disrupt the lipid bilayer packing, interacting with intercellular proteins [19]. It is important to know that water possesses enhancer properties, as the drug diffusion is higher through hydrated skin; thus, occlusion is necessary for improved therapy [50].
Many dosage forms are used for topical delivery of skin anticancer medication, such as powders, aerosols, emulsions, and creams. However, hydrogels have superior properties [20][51]. Their structure allows them to be controlled at a molecular scale, which can be used to modify the properties such as degradation rate, long-time release, tunable pore size, and chemical and biological response to stimuli such as pH, enzymes, and temperature, in accordance to desired values [52]. Moreover, hydrogel-based drug dosage forms exhibit improved chemotherapy outcomes by increasing drug half-life, enabling controlled drug release, and reducing nontargeted exposure [53][54][55].
The combination of gel formation technology and nanotechnology leads to the creation of advanced drug delivery systems such as nanogels, liposomes, ethosomes, niosomes, and transferosomes, improving the skin penetration and bioavailability, and can be potentially used for topical skin cancer therapy [28][37][56].

References

  1. Linares, M.A.; Zakaria, A.; Nizran, P. Skin Cancer. Prim. Care Clin. Off. Pract. 2015, 42, 645–659.
  2. Craythorne, E.; Al-Niami, F. Skin Cancer. Medicine 2017, 45, 431–434.
  3. Peris, K.; Fargnoli, M.C.; Garbe, C.; Kaufmann, R.; Bastholt, L.; Seguin, N.B.; Bataille, V.; del Marmol, V.; Dummer, R.; Harwood, C.A.; et al. Diagnosis and Treatment of Basal Cell Carcinoma: European Consensus–Based Interdisciplinary Guidelines. Eur. J. Cancer 2019, 118, 10–34.
  4. Nawaz, A.; Ullah, S.; Alnuwaiser, M.A.; Rehman, F.U.; Selim, S.; Al Jaouni, S.K.; Farid, A. Formulation and Evaluation of Chitosan-Gelatin Thermosensitive Hydrogels Containing 5FU-Alginate Nanoparticles for Skin Delivery. Gels 2022, 8, 537.
  5. Barrera, M.V.; Herrera, E. Topical Chemotherapy for Actinic Keratosis and Nonmelanoma Skin Cancer: Current Options and Future Perspectives. Actas Dermo-Sifiliográficas Engl. Ed. 2007, 98, 556–562.
  6. Safwat, M.A.; Soliman, G.M.; Sayed, D.; Attia, M.A. Fluorouracil-Loaded Gold Nanoparticles for the Treatment of Skin Cancer: Development, in Vitro Characterization, and in Vivo Evaluation in a Mouse Skin Cancer Xenograft Model. Mol. Pharm. 2018, 15, 2194–2205.
  7. Ghezzi, M.; Pescina, S.; Delledonne, A.; Ferraboschi, I.; Sissa, C.; Terenziani, F.; De Freitas Rosa Remiro, P.; Santi, P.; Nicoli, S. Improvement of Imiquimod Solubilization and Skin Retention via Tpgs Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid. Pharmaceutics 2021, 13, 1476.
  8. Lapteva, M.; Mignot, M.; Mondon, K.; Möller, M.; Gurny, R.; Kalia, Y.N. Self-Assembled MPEG-HexPLA Polymeric Nanocarriers for the Targeted Cutaneous Delivery of Imiquimod. Eur. J. Pharm. Biopharm. 2019, 142, 553–562.
  9. Capanema, N.S.V.; Mansur, A.A.P.; Carvalho, S.M.; Carvalho, I.C.; Chagas, P.; de Oliveira, L.C.A.; Mansur, H.S. Bioengineered Carboxymethyl Cellulose-Doxorubicin Prodrug Hydrogels for Topical Chemotherapy of Melanoma Skin Cancer. Carbohydr. Polym. 2018, 195, 401–412.
  10. Gamal, F.A.; Sayed, O.M.; El-Ela, F.I.A.; Kharshoum, R.M.; Salem, H.F. Treatment of Basal Cell Carcinoma Via Binary Ethosomes of Vismodegib: In Vitro and In Vivo Studies. AAPS PharmSciTech 2020, 21, 51.
  11. Dummer, R.; Ascierto, P.A.; Basset-Seguin, N.; Dréno, B.; Garbe, C.; Gutzmer, R.; Hauschild, A.; Krattinger, R.; Lear, J.T.; Malvehy, J.; et al. Sonidegib and Vismodegib in the Treatment of Patients with Locally Advanced Basal Cell Carcinoma: A Joint Expert Opinion. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 1944–1956.
  12. Mousa, I.A.; Hammady, T.M.; Gad, S.; Zaitone, S.A.; El-Sherbiny, M.; Sayed, O.M. Formulation and Characterization of Metformin-Loaded Ethosomes for Topical Application to Experimentally Induced Skin Cancer in Mice. Pharmaceuticals 2022, 15, 657.
  13. Kollipara, R.K.; Tallapaneni, V.; Sanapalli, B.K.R.; Kumar, G.V.; Karri, V.V.S.R. Curcumin Loaded Ethosomal Vesicular Drug Delivery System for the Treatment of Melanoma Skin Cancer. Res. J. Pharm. Technol. 2019, 12, 1783–1792.
  14. Priya, P.; Raj, R.M.; Vasanthakumar, V.; Raj, V. Curcumin-Loaded Layer-by-Layer Folic Acid and Casein Coated Carboxymethyl Cellulose/Casein Nanogels for Treatment of Skin Cancer. Arab. J. Chem. 2020, 13, 694–708.
  15. Alhakamy, N.A.; Aldawsari, H.M.; Ali, J.; Gupta, D.K.; Warsi, M.H.; Bilgrami, A.L.; Asfour, H.Z.; Noor, A.O.; Md, S. Brucine-Loaded Transliposomes Nanogel for Topical Delivery in Skin Cancer: Statistical Optimization, in Vitro and Dermatokinetic Evaluation. 3 Biotech 2021, 11, 288.
  16. Iqbal, B.; Ali, J.; Ganguli, M.; Mishra, S.; Baboota, S. Silymarin-Loaded Nanostructured Lipid Carrier Gel for the Treatment of Skin Cancer. Nanomedicine 2019, 14, 1077–1093.
  17. Nagaraja, S.; Basavarajappa, G.M.; Attimarad, M.; Pund, S. Topical Nanoemulgel for the Treatment of Skin Cancer: Proof-of-Technology. Pharmaceutics 2021, 13, 902.
  18. Kaplan, A.; Cetin, M.; Orgul, D.; Taghizadehghalehjoughi, A.; Hacimuftuoglu, A.; Hekimoglu, S. Formulation and in Vitro Evaluation of Topical Nanoemulsion and Nanoemulsion-Based Gels Containing Daidzein. J. Drug Deliv. Sci. Technol. 2019, 52, 189–203.
  19. Taylor, K.M.G. Aulton’s Pharmaceutics: The Design and Manufacture of Medicines, 4th ed.; Elsevier: Amsterdam, The Netherlands, 2013.
  20. Shende, P.; Vaidya, J.; Gaud, R.S. Pharmacotherapeutic Approaches for Transportation of Anticancer Agents via Skin. Artif. Cells Nanomed. Biotechnol. 2018, 46, S423–S433.
  21. Depieri, L.V.; Praça, F.S.G.; Campos, P.M.; Bentley, M.V.L.B. Advances in the Bioanalytical Study of Drug Delivery across the Skin. Ther. Deliv. 2015, 6, 571–594.
  22. Khan, N.H.; Mir, M.; Qian, L.; Baloch, M.; Khan, M.F.A.; Rehman, A.; Ngowi, E.E.; Wu, D.-D.; Ji, X.-Y. Skin Cancer Biology and Barriers to Treatment: Recent Applications of Polymeric Micro/Nanostructures. J. Adv. Res. 2022, 36, 223–247.
  23. Bolzinger, M.-A.; Briançon, S.; Pelletier, J.; Chevalier, Y. Penetration of Drugs through Skin, a Complex Rate-Controlling Membrane. Curr. Opin. Colloid Interface Sci. 2012, 17, 156–165.
  24. Prausnitz, M.R.; Mitragotri, S.; Langer, R. Current Status and Future Potential of Transdermal Drug Delivery. Nat. Rev. Drug Discov. 2004, 3, 115–124.
  25. Matsui, T.; Amagai, M. Dissecting the Formation, Structure and Barrier Function of the Stratum Corneum. Int. Immunol. 2015, 27, 269–280.
  26. Sahu, P.; Kashaw, S.K.; Jain, S.; Sau, S.; Iyer, A.K. Assessment of Penetration Potential of PH Responsive Double Walled Biodegradable Nanogels Coated with Eucalyptus Oil for the Controlled Delivery of 5-Fluorouracil: In Vitro and Ex Vivo Studies. J. Control. Release 2017, 253, 122–136.
  27. Georgescu, S.R.; Tampa, M.; Mitran, C.I.; Mitran, M.I.; Caruntu, C.; Caruntu, A.; Lupu, M.; Matei, C.; Constantin, C.; Neagu, M. Tumour Microenvironment in Skin Carcinogenesis. Adv. Exp. Med. Biol. 2020, 1226, 123–142.
  28. Barua, S.; Mitragotri, S. Challenges Associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects. Nano Today 2014, 9, 223–243.
  29. McGrath, J.A.; Eady, R.A.J.; Pope, F.M. Anatomy and Organization of Human Skin. In Rook’s Textbook of Dermatology; Wiley: Hoboken, NJ, USA, 2004; Volume 1, Chapter 3; pp. 1–84.
  30. Taveira, S.F.; Lopez, R.F.V.; Taveira, S.F.; Lopez, R.F.V. Topical Administration of Anticancer Drugs for Skin Cancer Treatment; IntechOpen: London, UK, 2011; ISBN 978-953-307-722-2.
  31. Sahu, P.; Kashaw, S.K.; Sau, S.; Kushwah, V.; Jain, S.; Iyer, A.K. Discovering PH Triggered Charge Rebound Surface Modulated Topical Nanotherapy against Aggressive Skin Papilloma. Mater. Sci. Eng. C 2020, 107, 110263.
  32. Amasya, G.; Aksu, B.; Badilli, U.; Onay-Besikci, A.; Tarimci, N. QbD Guided Early Pharmaceutical Development Study: Production of Lipid Nanoparticles by High Pressure Homogenization for Skin Cancer Treatment. Int. J. Pharm. 2019, 563, 110–121.
  33. Williams, A. Transdermal and Topical Drug Delivery from Theory to Clinical Practice; Pharmaceutical Press: London, UK, 2003; ISBN 978-0-85369-489-2.
  34. National Research Council (US) Commission on Engineering and Technical Systems; Wartell, M.A.; Kleinman, M.T.; Huey, B.M. Strategies to Protect the Health of Deployed U.S. Forces: Force Protection and Decontamination. Washington (DC): National Academies Press (US); 1999. Appendix E, Percutaneous Absorption. Available online: https://www.ncbi.nlm.nih.gov/books/NBK225150/ (accessed on 1 March 2023).
  35. Touitou, E.; Barry, B.W. (Eds.) Enhancement in Drug Delivery; CRC Press: Boca Raton, FL, USA, 2006; ISBN 978-0-429-12231-6.
  36. Taylor, K.M.G.; Wenande, E.; Olesen, U.H.; Nielsen, M.M.B.; Janfelt, C.; Hansen, S.H.; Anderson, R.R.; Haedersdal, M. Fractional Laser-Assisted Topical Delivery Leads to Enhanced, Accelerated and Deeper Cutaneous 5-Fluorouracil Uptake: Expert Opinion on Drug Delivery: Volume 14, No 3. Available online: https://www.tandfonline.com/doi/abs/10.1080/17425247.2017.1260119 (accessed on 3 March 2023).
  37. De Oliveira, B.E.; Amorim, O.H.J.; Lima, L.L.; Rezende, R.A.; Mestnik, N.C.; Bagatin, E.; Leonardi, G.R. 5-Fluorouracil, Innovative Drug Delivery Systems to Enhance Bioavailability for Topical Use. J. Drug Deliv. Sci. Technol. 2021, 61, 102155.
  38. Diasio, R.B.; Harris, B.E. Clinical Pharmacology of 5-Fluorouracil. Clin. Pharmacokinet. 1989, 16, 215–237.
  39. Love, W.E.; Bernhard, J.D.; Bordeaux, J.S. Topical Imiquimod or Fluorouracil Therapy for Basal and Squamous Cell Carcinoma: A Systematic Review. Arch. Dermatol. 2009, 145, 1431–1438.
  40. Telò, I.; Pescina, S.; Padula, C.; Santi, P.; Nicoli, S. Mechanisms of Imiquimod Skin Penetration. Int. J. Pharm. 2016, 511, 516–523.
  41. Al-Mayahy, M.H.; Sabri, A.H.; Rutland, C.S.; Holmes, A.; McKenna, J.; Marlow, M.; Scurr, D.J. Insight into Imiquimod Skin Permeation and Increased Delivery Using Microneedle Pre-Treatment. Eur. J. Pharm. Biopharm. 2019, 139, 33–43.
  42. Nikolaou, M.; Pavlopoulou, A.; Georgakilas, A.G.; Kyrodimos, E. The Challenge of Drug Resistance in Cancer Treatment: A Current Overview. Clin. Exp. Metastasis 2018, 35, 309–318.
  43. Gottesman, M.M. Mechanisms of Cancer Drug Resistance. Annu. Rev. Med. 2002, 53, 615–627.
  44. Kalal, B.S.; Upadhya, D.; Pai, V.R. Chemotherapy Resistance Mechanisms in Advanced Skin Cancer. Oncol. Rev. 2017, 11, 326.
  45. Szakács, G.; Paterson, J.K.; Ludwig, J.A.; Booth-Genthe, C.; Gottesman, M.M. Targeting Multidrug Resistance in Cancer. Nat. Rev. Drug Discov. 2006, 5, 219–234.
  46. Ichihashi, N.; Kitajima, Y. Chemotherapy Induces or Increases Expression of Multidrug Resistance-Associated Protein in Malignant Melanoma Cells. Br. J. Dermatol. 2001, 144, 745–750.
  47. Mansoori, B.; Mohammadi, A.; Davudian, S.; Shirjang, S.; Baradaran, B. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv. Pharm. Bull. 2017, 7, 339.
  48. Grottke, C.; Mantwill, K.; Dietel, M.; Schadendorf, D.; Lage, H. Identification of Differentially Expressed Genes in Human Melanoma Cells with Acquired Resistance to Various Antineoplastic Drugs. Int. J. Cancer 2000, 88, 535–546.
  49. Marangolo, M.; Bengala, C.; Conte, P.F.; Danova, M.; Pronzato, P.; Rosti, G.; Sagrada, P. Dose and Outcome: The Hurdle of Neutropenia (Review). Oncol. Rep. 2006, 16, 233–248.
  50. Williams, A.C.; Barry, B.W. Penetration Enhancers. Adv. Drug Deliv. Rev. 2004, 56, 603–618.
  51. Vishnubhakthula, S.; Elupula, R.; Durán-Lara, E.F. Recent Advances in Hydrogel-Based Drug Delivery for Melanoma Cancer Therapy: A Mini Review. J. Drug Deliv. 2017, 2017, 7275985.
  52. Tsou, Y.-H.; Khoneisser, J.; Huang, P.-C.; Xu, X. Hydrogel as a Bioactive Material to Regulate Stem Cell Fate. Bioact. Mater. 2016, 1, 39–55.
  53. Ma, J.; Wang, Y.; Lu, R. Mechanism and Application of Chitosan and Its Derivatives in Promoting Permeation in Transdermal Drug Delivery Systems: A Review. Pharmaceuticals 2022, 15, 459.
  54. Collaud, S.; Peng, Q.; Gurny, R.; Lange, N. Thermosetting Gel for the Delivery of 5-Aminolevulinic Acid Esters to the Cervix. J. Pharm. Sci. 2008, 97, 2680–2690.
  55. Sepantafar, M.; Maheronnaghsh, R.; Mohammadi, H.; Radmanesh, F.; Hasani-Sadrabadi, M.M.; Ebrahimi, M.; Baharvand, H. Engineered Hydrogels in Cancer Therapy and Diagnosis. Trends Biotechnol. 2017, 35, 1074–1087.
  56. Gerecke, C.; Edlich, A.; Giulbudagian, M.; Schumacher, F.; Zhang, N.; Said, A.; Yealland, G.; Lohan, S.B.; Neumann, F.; Meinke, M.C.; et al. Biocompatibility and Characterization of Polyglycerol-Based Thermoresponsive Nanogels Designed as Novel Drug-Delivery Systems and Their Intracellular Localization in Keratinocytes. Nanotoxicology 2017, 11, 267–277.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Marta Slavkova
,
Borislav Tzankov
,
Teodora Popova
,
Christina Voycheva
View Times: 477
Revisions: 2 times (View History)
Update Date: 05 May 2023
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback