INTRODUCTION:

A wide range of illnesses, including cancer, are caused by the unchecked proliferation of cancerous cells, which can invade and spread to other bodily areas¹. It is estimated that over 10 million new cases of cancer-related deaths occur annually. The development of new drugs is difficult. Clinical trials cannot use the successful administration of recent medications due to their poor effective performance. Chemotherapy is the most successful and efficient therapeutic procedure in clinical practice, and it has been utilized extensively².

One cutting-edge technique that improves cancer therapeutic and diagnostic research is nanoformulation. Nanomedicine offers several benefits because there are many obstacles to overcome, such as low bioavailability, unstable circulation, and harmful consequences³. In the past five years, the death rate has dropped as a result of improved understanding as well as knowledge of the biology of tumors and enhanced diagnostic tools and procedures. Chemotherapy, radiation therapy, intervention, or a mix of these are available as cancer treatment options nowadays. The fact that agents are not selective and can harm both healthy and normal tissue can result in a number of undesirable and unwanted side effects, such as nausea, loss of appetite, and severe adverse effects on healthy organs and tissue caused by chemotherapeutic drugs. These side effects are a major contributing factor to the high death rate among cancer patients⁴. These medications require high doses, have relatively poor bioaccessibility to tumor tissues, and cause increased toxicity in normal cells. and raise the likelihood of developing multiple medication resistance. Therefore, it's imperative to create chemotherapeutics that can target malignant cells either actively or passively, minimize side effects, and increase the effectiveness of treatment⁵.

Polymer utilized in the co-delivery system preparation:

1) Conjugated block co-polymers

2) Polymers that are thermosensitive

3) Polymers responsive to pH

4) Polymers susceptible to redox

2.Various carriers for the Delivery of Drugs:

2.1. Nanocarriers:

Different nanocarriers for the delivery of therapeutic and imaging substances for the treatment and diagnosis of cancer are constantly being developed by researchers.

Fig. No.1

It is often categorized as follows:

i. Organic NPs

ii. Inorganic NPs

iii. Hybrid NPs

2.2. Organic nanopraticles:

Table No. 1:

Sr. No.	Types of nanocarriers	Size	Properties	Drugs used	Comments come outcomes	Reference
1.	Paclitaxel liposomal (ES-SSL-PTX)	135.93 nm	Long-acting, sterically stabilized liposome that responds to estrogen	Paclitaxel	Prevents the growth of cancer cells by halting cell division, which leads to cell death.	6
2.	Polymorphism (PLAD-MLP)	110 nm	Several medications in liposome form with preferred pharmacological properties	Together with alendronate	Procarcinogens can be activated or inactivated by xenobiotic-metabolizing enzymes, but for this to happen, they need to work in tandem with other substances.	6,7
3.	PLGA-PEG PNPs (GEM+BA)	195.93 ± 6.83 nm	Co-encapsulating biodegradable polymer for enhanced anti-tumor efficaciousness	Betulinic acid plus gemcitabine	Medications in an efficient manner and produce the desired increased permeability and retention (EPR) effect.	8,9,10
4.	GAD 7	350 nm	Encourage the death of Neuroblastoma cell lines	Gallic substance	They can be injected into the region of the tumor while reducing non-specific dispersion.	11,12

Table No. 2: Inorganic Nanopraticles:

7.	Au-SMCC-DOX nanoparticle Au	-	increased lethality against cancer cells	Doxorubicin	Target ligands to increase therapeutic impact while reducing off-target adverse effects by drug penetration and adsorption.	13,14
8.	(DTX-CNTP-Tf) carbon nanotube	Length: 241-483 nm	When coupled with transferrin, it exhibits reduced ROS production, increased cytotoxicity, and a low hazardous profile.	Acetazolazol	permitting targeted release of anticancer medications to increase therapeutic efficacy and lessen side effects on healthy tissues.	15,16,17
9.	Silica nanoparticles	4 nm	In the artificial environment, cell internalization increased.	Doxorubicin	Vast surface area, pore volumes, homogeneous pore size adjustment, and large-scale production.	18,19,20
10.	Ferroelectric nanoparticles (FeO NPs) covered in silica	8–12 nm	Targeted tumor cell death is increased when heat treatment is used.	Antibodies (anti-integrin αvβ6)	Cause the death of tumor cells, which will enhance the tumor's release of neo-antigens.	21,22,23 24,25,26

Table No.3: Hybrid Nanopraticles:

11.	Blend of Inorganic and Organic (LB-MSNP-PTX-GEM)	101 nm	The addition of PTX inhibits the GEM-inhibiting enzyme CDA and reduces tumor stroma.	Paclitaxel with Gemcitabine	May be able to easily penetrate tissues and reach tumors	26,27,28,29,
12.	combination of organic and inorganic materials (PSi NPs-Giant Liposome)	About 170 nm	Sufficient treatment for cancer, adaptable therapeutic ratio, and controlled release of medication	Erlotinib 17 AAG Doxorubicin	Elevated level of selectivity and sensitivity	30,31,32
13.	NPs coated with cell membrane (DOX/MSN@CaCO3)	100nm	biocompatible, straightforward construction that causes cell death on mesoporous silica and is capped with CaCO3.	Doxorubicin	Attain blood circulation that is prolonged and, in addition, stimulate immunity against cancer.	33,34
14.	NPs covered with cell membrane (DOX-CuS@RBC-B16 NPs)	200 nm	Extended duration of circulation and improved uniform targeting performance	Doxorubicin	Efficiently administer medication and accomplish the increased permeability and retention (EPR) result.	35,36,37
15.	Anti-CEA hAb lipid polymer hybrid nanoparticle	83-95 nm	Increased cytotoxicity	Paclitaxel	Increased cancer chemo-sensitization.	38,39,40

2.3. Micelle:

Fig. No.2

Characteristics of hydrophilic polymers frequently seen in polymeric micelles:

Table No.4

Polymer	Advantages	Disadvantages	Comments come outcomes	Reference
PEG	Clinically cleared for clandestine conduct	Unexpected modifications to PK's behavior Not biodegradable	excellent cellular absorption due to their nanosized range, low toxicity, high drug encapsulation and loading capacity, and ease of removal from the biological environment	41
Polysacchrides	Safe and biodegradable Discreet actions promoting mucoadhesion	its high-temperature (above-melting-point) deterioration (oxidation) properties,	reduced negative effects from systemic toxicity, more targeted delivery to certain tissues	42
pHPMA	Not hazardous not immunogenic biocompatible. Pendant formations were easily constructed	Few soluble drug conjugates have been tested in humans. complex synthesis.	Continuous blood stability	43
Poly(acrylic acid)	Mucoadhesive and pH-sensitive Degradable in nature biocompatible	Poor mechanical qualities; its structures must be changed in order to be used	improve the bioavailability and solubility of medications that are poorly soluble.	44

The LBL method, layer by layer:

Studies that are presented on liposomal systems coated with LbL and intended for medication delivery:

Table No.5

Liposome Structure	Polycations	Polyanions	Capsule Agents	Properties	Comments come outcomes	Reference
11.5 mg of cholesterol, 2 mg of stearyl amine (SA), and soy lecithin (24.5 mg)	The chitosan	Acid PAA, or polyacrylic	PTX, or Paclitaxel	Prolonged release with a 3-hour latency compared to PTX-liposome	may improve cancer treatments by targeting programmed cell death	49
DPPC/Chol/DDAB	The chitosan	The alginate	BSA, or bovine serum albumin	prolonged linear release of BSA,	lessening detrimental effects on organ health	50
DPPC/Chol/DDAB	The chitosan	The alginate	Remington's human osteogenic protein-1	Localized limitation of its consequence	enhancing the medicinal compounds' stability and bioavailability	51
DMPC and DLPA	Chitosan	Deoxyribonucleic acid (DNA) or dextran sulfate (DXS)	Alendronate, glucose	DNA denaturation enables temperature-driven release.	reducing negative effects,	52

3. REFERENCE:

1. Tran S, De Giovanni PJ, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clinical and Translational Medicine. 2017 Dec; 6: 1-21.

2. Bahrami B, Hojjat -Farsangi M, Mohammadi H, Anvari E, Ghalamfarsa G, Yousefi M, Jadidi –Niaragh F. Nanoparticles and targeted drug delivery in cancer therapy. Immunology Letters. 2017 Oct 1; 190: 64-83.

3. Bahrami B, Hojjat-Farsangi M, Mohammadi H, Anvari E, Ghalamfarsa G, Yousefi M, Jadidi-Niaragh F. Nanoparticles and targeted drug delivery in cancer therapy. Immunology letters. 2017 Oct 1; 190: 64-83.

4. Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. European Journal of Pharmaceutics and Biopharmaceutics. 2015 Jun 1; 93: 52-79.

5. Avramović N, Ignjatović N, Savić A. Platinum and ruthenium complexes as promising molecules in cancer therapy. Srpski Arhiv Za Celokupno Lekarstvo. 2019; 147(1-2): 105-9.

6. Quintero Escobar M, Maschietto M, Krepischi AC, Avramovic N, Tasic L. Insights into the chemical biology of childhood embryonal solid tumors by NMR-based metabolomics. Biomolecules. 2019 Dec 8; 9(12): 843.

7. Radic T, Coric V, Bukumiric Z, Pljesa-Ercegovac M, Djukic T, Avramovic N, Matic M, Mihailovic S, Dragicevic D, Dzamic Z, Simic T. GSTO1* CC Genotype (rs4925) predicts shorter survival in clear cell renal cell carcinoma male patients. Cancers. 2019 Dec 17; 11(12): 2038.

8. (https://druginfo.medlineplus.gov/meds/a61303.html).

9. (See more about Venetoclax Oral at https://www.webmd.com/drugs/2/drug-171572/).

10. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Advances in Enzyme Regulation. 2001 May 1; 41(1): 189-207.

11. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Advances in Enzyme Regulation. 2001 May 1; 41(1): 189-207.

12. National Comprehensive Cancer Network. American Cancer Society.(2005). Nausea and vomiting: Treatment Guidelines for Patients With Cancer. 2007.

13. Friedman R, Boye K, Flatmark K. Molecular modelling and simulations in cancer research. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2013 Aug 1;1836(1):1-4.

14. Han B, Yang Y, Chen J, Tang H, Sun Y, Zhang Z, Wang Z, Li Y, Li Y, Luan X, Li Q. Preparation, characterization, and pharmacokinetic study of a novel long-acting targeted paclitaxel liposome with antitumor activity. International Journal of Nanomedicine. 2020 Jan 24:553-71.

15. Gabizon A, Ohana P, Amitay Y, Gorin J, Tzemach D, Mak L, Shmeeda H. Liposome co-encapsulation of anti-cancer agents for pharmacological optimization of nanomedicine-based combination chemotherapy. Cancer Drug Resistance. 2021 Jun 19;4(2):463.

16. Saneja A, Kumar R, Mintoo MJ, Dubey RD, Sangwan PL, Mondhe DM, Panda AK, Gupta PN. Gemcitabine and betulinic acid co-encapsulated PLGA− PEG polymer nanoparticles for improved efficacy of cancer chemotherapy. Materials Science and Engineering: C. 2019 May 1;98:764-71.

17. Zhou Q, Zhang L, Yang T, Wu H. Stimuli-responsive polymeric micelles for drug delivery and cancer therapy. International Journal of Nanomedicine. 2018 May 18:2921-42.

18. Nguyen TT, Nguyen CK, Nguyen TH, Tran NQ. Highly lipophilic pluronics-conjugated polyamidoamine dendrimer nanocarriers as potential delivery system for hydrophobic drugs. Materials Science and Engineering: C. 2017 Jan 1;70:992-9.

19. Alfei S, Marengo B, Zuccari G, Turrini F, Domenicotti C. Dendrimer nanodevices and gallic acid as novel strategies to fight chemoresistance in neuroblastoma cells. Nanomaterials. 2020 Jun 26;10(6):1243.

20. Cheng J, Gu YJ, Cheng SH, Wong WT. Surface functionalized gold nanoparticles for drug delivery. Journal of Biomedical Nanotechnology. 2013 Aug 1;9(8):1362-9.

21. Singh RP, Sharma G, Singh S, Patne SC, Pandey BL, Koch B, Muthu MS. Effects of transferrin conjugated multi-walled carbon nanotubes in lung cancer delivery. Materials Science and Engineering: C. 2016 Oct 1;67:313-25.

22. Rivero-Buceta E, Bernal-Gómez A, Vidaurre-Agut C, Moncholi EL, Benlloch JM, Manzano VM, Donoso CD, Botella P. Prostate cancer chemotherapy by intratumoral administration of Docetaxel-Mesoporous silica nanomedicines. International Journal of Pharmaceutics. 2024 Oct 25;664:124623.

23. Legge CJ, Colley HE, Lawson MA, Rawlings AE. Targeted magnetic nanoparticle hyperthermia for the treatment of oral cancer. Journal of Oral Pathology and Medicine. 2019 Oct;48(9):803-9.

24. Hu CM, Kaushal S, Cao HS, Aryal S, Sartor M, Esener S, Bouvet M, Zhang L. Half-antibody functionalized lipid− polymer hybrid nanoparticles for targeted drug delivery to carcinoembryonic antigen presenting pancreatic cancer cells. Molecular Pharmaceutics. 2010 Jun 7;7(3):914-20.

25. Bellapu KK, Joga R, Kannan BR, Yerram S, Varpe P, Mergu T, Vasu PY, Srivastava S, Kumar S. Lipid-based mesoporous silica nanoparticles: a paradigm shift in management of pancreatic cancer. Pharmaceutical Patent Analyst. 2023 Nov 1;12(6):261-73.

26. Reinsalu O, Ernits M, Linko V. Liposome-based hybrid drug delivery systems with DNA nanostructures and metallic nanoparticles. Expert Opinion on Drug Delivery. 2024 Jun 2;21(6):905-20.

27. Chen G-B, Chen H-H, Liu C-M, et al. Mesoporous silica nanoparticles enveloped in cancer cell membranes that contain a pH-sensitive gatekeeper for cancer therapy. Biointerfaces Colloids Surf B. 2019;175:477–4886.

28. Huai Y, Hossen MN, Wilhelm S, Bhattacharya R, Mukherjee P. Nanoparticle interactions with the tumor microenvironment. Bioconjugate Chemistry. 2019 Aug 13;30(9):2247-63.

29. Domingues C, Santos A, Alvarez-Lorenzo C, Concheiro A, Jarak I, Veiga F, Barbosa I, Dourado M, Figueiras A. Where is nano today and where is it headed? A review of nanomedicine and the dilemma of nanotoxicology. ACS Nano. 2022 Jun 22;16(7):9994-10041.

30. Knop K, Hoogenboom R, Fischer D, Schubert US. Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angewandte Chemie International Edition. 2010 Aug 23;49(36):6288-308.

31. Zhang F, Liu MR, Wan HT. Discussion about several potential drawbacks of PEGylated therapeutic proteins. Biological and Pharmaceutical Bulletin. 2014 Mar 1;37(3):335-9.

32. Zhang N, Wardwell PR, Bader RA. Polysaccharide-based micelles for drug delivery. Pharmaceutics. 2013 May 27;5(2):329-52.

33. Thanou M, Verhoef JC, Junginger HE. Chitosan and its derivatives as intestinal absorption enhancers. Advanced Drug Delivery Reviews. 2001 Oct 1;50:S91-101.

34. Patra JK, Das G, Fraceto LF, Campos EV, Rodriguez-Torres MD, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S. Nano based drug delivery systems: recent developments and future prospects. Journal of Nanobiotechnology. 2018 Dec;16:1-33.

35. Pertici G. Introduction to bioresorbable polymers for biomedical applications. InBioresorbable Polymers for Biomedical Applications 2017 Jan 1 (pp. 3-29). Woodhead Publishing.

36. Poole-Warren LA, Patton AJ. Introduction to biomedical polymers and biocompatibility. InBiosynthetic Polymers for Medical Applications 2016 Jan 1 (pp. 3-31). Woodhead Publishing.

37. Luo K, Yang J, Kopečková P, Kopeček J. Biodegradable multiblock poly [N-(2-hydroxypropyl) methacrylamide] via reversible addition− fragmentation chain transfer polymerization and click chemistry. Macromolecules. 2011 Apr 26;44(8):2481-8.

38. Alfurhood JA, Sun H, Kabb CP, Tucker BS, Matthews JH, Luesch H, Sumerlin BS. Poly (N-(2-hydroxypropyl) methacrylamide)–valproic acid conjugates as block copolymer nanocarriers. Polymer Chemistry. 2017;8(34):4983-7.

39. Kopeček J, Kopečková P, Minko T, Lu ZR. HPMA copolymer–anticancer drug conjugates: design, activity, and mechanism of action. European Journal of Pharmaceutics and Biopharmaceutics. 2000 Jul 3;50(1):61-81.

40. Tucker BS, Sumerlin BS. Poly (N-(2-hydroxypropyl) methacrylamide)-based nanotherapeutics. Polymer Chemistry. 2014;5(5):1566-72.

41. Ulbrich K, Hola K, Subr V, Bakandritsos A, Tucek J, Zboril R. Targeted drug delivery with polymers and magnetic nanoparticles: covalent and noncovalent approaches, release control, and clinical studies. Chemical Reviews. 2016 May 11;116(9):5338-431.

42. Soni V, Pandey V, Tiwari R, Asati S, Tekade RK. Design and evaluation of ophthalmic delivery formulations. InBasic fundamentals of Drug Delivery 2019 Jan 1 (pp. 473-538). Academic Press.

43. Liu H, Chen H, Cao F, Peng D, Chen W, Zhang C. Amphiphilic block copolymer poly (acrylic acid)-b-polycaprolactone as a novel pH-sensitive nanocarrier for anti-cancer drugs delivery: In-Vitro and in-vivo evaluation. Polymers. 2019 May;11(5):820.

44. Xu H, Yao Q, Cai C, Gou J, Zhang Y, Zhong H, Tang X. Amphiphilic poly (amino acid) based micelles applied to drug delivery: The in vitro and in vivo challenges and the corresponding potential strategies. Journal of Controlled Release. 2015 Feb 10;199:84-97.

45. van der Koog L, Gandek TB, Nagelkerke A. Liposomes and extracellular vesicles as drug delivery systems: a comparison of composition, pharmacokinetics, and functionalization. Advanced Healthcare Materials. 2022 Mar;11(5):2100639.

46. Cao Y, Ma Y, Tao Y, Lin W, Wang P. Intra-articular drug delivery for osteoarthritis treatment. Pharmaceutics. 2021 Dec;13(12):2166.

47. Borges J, Mano JF. Molecular interactions driving the layer-by-layer assembly of multilayers. Chemical Reviews. 2014 Sep 24;114(18):8883-942.

48. Correa S, Boehnke N, Deiss-Yehiely E, Hammond PT. Solution conditions tune and optimize loading of therapeutic polyelectrolytes into layer-by-layer functionalized liposomes. ACS Nano. 2019 Apr 15;13(5):5623-34.

49. Fan J., Feliu N., Gogotsi Y., Caruso F., Dähne L., Decher G., De Geest B.G., Zhao S., Hammond P.T., Hersam M.C., et al. The Future of Layer-by-Layer Assembly: A Tribute to ACS Nano Associate Editor Helmuth Möhwald. 2019;13:6151–6169 in ACS Nano. 10.1021/acsnano.9b03326 is the DOI.

50. Chen MX, Li BK, Yin DK, Liang J, Li SS, Peng DY. Layer-by-layer assembly of chitosan stabilized multilayered liposomes for paclitaxel delivery. Carbohydrate Polymers. 2014 Oct 13;111:298-304.

51. Hardik Patel, Shraddha Parmar, Bhavna Patel, Int. J. Pharm. Sci. Rev. Res., 21(1), Jul – Aug 2013. 223-235.

52. Ashishmasih, Amarkumar, Shivamsingh, Ajay Kumar Tiwari Fast Dissolving Tablet- A Review International Journal Of Current Pharmaceutical Research. 2017; 2(2).