Nanoparticles in Drug Delivery: From History to Therapeutic Applications PDF

nanomaterials Review Nanoparticles in Drug Delivery: From History to Therapeutic Applications Obaid Afzal 1 , Abdulmalik S. A. Altamimi 1 , Muhammad Shahid Nadeem 2, * , Sami I. Alzarea 3 , Waleed Hassan Almalki 4 , Aqsa Tariq 5 , Bismillah Mubeen 5 , Bibi Nazia Murtaza 6 , Saima Iftikhar 7 , Naeem...

nanomaterials Review Nanoparticles in Drug Delivery: From History to Therapeutic Applications Obaid Afzal 1 , Abdulmalik S. A. Altamimi 1 , Muhammad Shahid Nadeem 2, * , Sami I. Alzarea 3 , Waleed Hassan Almalki 4 , Aqsa Tariq 5 , Bismillah Mubeen 5 , Bibi Nazia Murtaza 6 , Saima Iftikhar 7 , Naeem Riaz 8 and Imran Kazmi 2, * 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia 2 Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia 3 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia 4 Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia 5 Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore, Lahore 54000, Pakistan 6 Department of Zoology, Abbottabad University of Science and Technology (AUST), Abbottabad 22310, Pakistan 7 School of Biological Sciences, University of Punjab, Lahore 54000, Pakistan 8 Department of Pharmacy, COMSATS University, Abbottabad 22020, Pakistan * Correspondence: [email protected] (M.S.N.); [email protected] (I.K.) Abstract: Current research into the role of engineered nanoparticles in drug delivery systems (DDSs) for medical purposes has developed numerous fascinating nanocarriers. This paper reviews the various conventionally used and current used carriage system to deliver drugs. Due to numerous drawbacks of conventional DDSs, nanocarriers have gained immense interest. Nanocarriers like polymeric nanopar- ticles, mesoporous nanoparticles, nanomaterials, carbon nanotubes, dendrimers, liposomes, metallic Citation: Afzal, O.; Altamimi, A.S.A.; nanoparticles, nanomedicine, and engineered nanomaterials are used as carriage systems for targeted Nadeem, M.S.; Alzarea, S.I.; Almalki, delivery at specific sites of affected areas in the body. Nanomedicine has rapidly grown to treat certain W.H.; Tariq, A.; Mubeen, B.; Murtaza, diseases like brain cancer, lung cancer, breast cancer, cardiovascular diseases, and many others. These B.N.; Iftikhar, S.; Riaz, N.; et al. nanomedicines can improve drug bioavailability and drug absorption time, reduce release time, elimi- Nanoparticles in Drug Delivery: nate drug aggregation, and enhance drug solubility in the blood. Nanomedicine has introduced a new From History to Therapeutic Applications. Nanomaterials 2022, 12, era for drug carriage by refining the therapeutic directories of the energetic pharmaceutical elements 4494. https://doi.org/10.3390/ engineered within nanoparticles. In this context, the vital information on engineered nanoparticles was nano12244494 reviewed and conferred towards the role in drug carriage systems to treat many ailments. All these nanocarriers were tested in vitro and in vivo. In the coming years, nanomedicines can improve human Academic Editors: Di Zhang and health more effectively by adding more advanced techniques into the drug delivery system. Zeru Tian Received: 11 November 2022 Keywords: drug delivery; nanomedicine; therapeutics; nanoparticles; personalized medicine Accepted: 14 December 2022 Published: 19 December 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- Drug delivery systems (DDSs) have been used in past eras to treat numerous ailments. iations. All medicines rely on pharmacologic active metabolites (drugs) to treat diseases. Some of the drugs are designed as the inactive precursor, but they become active when transformed in the body. Their effectiveness depends on the route of administration. In conventional drug delivery systems (CDDSs), drugs were delivered usually via oral, nasal, inhaled, Copyright: © 2022 by the authors. mucosal, and shot methods. The conventionally delivered drugs were absorbed less, Licensee MDPI, Basel, Switzerland. distributed randomly, damaged unaffected areas, were excreted early, and took a prolonged This article is an open access article time to cure the disease. They were less effective due to many hurdles like their distributed under the terms and enzymatic degradation or disparity in pH, many mucosal barriers, and off-the-mark effects, conditions of the Creative Commons and their immediate release enhanced toxicity in blood. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Due to all such reasons, the controlled-release drug delivery system was developed. 4.0/). Such evolution in the DDS enhances drug effectiveness in many ways. DDSs have been Nanomaterials 2022, 12, 4494. https://doi.org/10.3390/nano12244494 https://www.mdpi.com/journal/nanomaterials Nanomaterials 2022, 12, 4494 2 of 27 engineered in recent years to control drug release. Such engineered DDSs used various novel strategies for controlled drug release into the diseased areas. These strategies were erodible material, degradable material, matrix, hydrogel, osmotic pump, and reservoir. They all provided a medium for the medicines to deliver at the desired sites like tissues, cells, or organs. In these approaches, drugs are often available for many diseases. Such strategies were unsuccessful due to lower distribution, less solubility, higher drug aggregation, less target selection, and poor effects for disease treatment. Moreover, drug development is the most expensive, intricate, and time-consuming process. The innovative drug findings involved the identification of new chemical entities (NCEs), having the vital distinguishing characteristics of drug capacity and pharmaceutical chemistry. This methodology, however, was confirmed to be less effective in terms of the overall attainment percentage , as 40% of drug development was botched due to its changeable responses and unpredicted noxiousness in humans. From past decades until now, drug development and its delivery are shifting from the micro to the nano level to prolong life expectancy by revolutionizing drug delivery systems (Figure 1). Figure 1. Illustration of how traditional medications were administered without the use of nanocarri- ers and harm was done to healthy organs or cells. In contrast, modern procedures use nanomedicines to transport medications to specific parts of the body. In 1959, Feynman was the first physicist to introduce the notion of nanotechnology in the lecture entitled “There’s Plenty of oom at the Bottom”. This concept initiated remarkable developments in the arena of nanotechnology. Nanotechnology is the study of extremely tiny things and is basically the hub of all science disciplines including physics, chemistry, biology, engineering, information technology, electronics, and material science. The structures measured with nanotechnology range from 1–100 nm at the nanoscale level. Nanoparticles have different material characteristics because of submicroscopic size and also provide practical implementations in a wide range of fields including engineering, drug delivery, nanomedicine, environmental indemnification, and catalysis, as well as target diseases such as melanoma and cardiovascular diseases (CVD), skin diseases, liver diseases, and many others. Therefore, medicines linked with nanotechnology can enhance efficiency of medicines and their bioavailability. The relation of nanoparticles to biomedicine was demon- strated in late the 1970s, and over 10,000 publications have referred to this association with the term “nanomedicine”. Almost thirty papers on this term were accessible by 2005. After 10 to 12 years, Web of Science published more than 1000 nanomedicine articles in 2015 and most of the articles relating nanoparticles (NPs) for biomedical usage. Nanomaterials 2022, 12, 4494 3 of 27 Nanocarriers such as dendrimers, liposomes, peptide-based nanoparticles, carbon nano tubes, quantum dots, polymer-based nanoparticles, inorganic vectors, lipid-based nanopar- ticles, hybrid NPs, and metal nanoparticles are the advanced forms of NPs. Nanoparti- cles are nowadays a growing arena for drug delivery, microfluidics, biosensors, microarrays, and tissue micro-engineering for the specialized treatment of diseases [23–25]. Nanoparticles are less effective and can treat cancer by selectively killing all cancerous cells. In 2015, the Food and Drug Administration (FDA) approved the clinical trials of onivyde nanomedicine in the treatment of cancer. The characteristic properties of nanocarriers are physicochemical properties, supporting the drugs by improving solubility, degradation, clearance, targeting, theranostics, and combination therapy. Studies on nanomedicine based on protein used for drug delivery in which various protein subunits combine to deliver medicine on site to a specific tumor have been reported. Many altered kinds and forms of nanocarriers arranged to carry medicine are protein-based podiums, counting several protein coops, nanoparticles, hydrogels, films, microspheres, tiny rods, and minipellets. All proteins, including ferritin–protein coop, the small heat shock protein (sHsp) cage, plant-derived viral capsids, albumin, soy and whey protein, collagen, and gelatin-implemented proteins are characterized for drug carriage. The nanomedicines are escorted in a new-fangled epoch, meant for drug carriage by refining the therapeutic directories of the energetic pharmacological elements engineered inside nanoparticles. In this epoch, nanomedicine-based targeted-design structures can deliver multipurpose freight with favorable pharmacokinetics and capitalized so as to enhance drug specificity, usefulness, and safety, as shown in (Figure 2). The failure of chemotherapeutic approaches has increased the recurrence chances of disease, which enhances the complexity of lethal diseases. Figure 2. Aids of using nanomedicine platform for delivering drugs to the tumor complex. Figure 2. Aids of using nanomedicine platform for delivering drugs to the tumor complex. 2. History Petros and his colleague reported a study about mid-19th century work on nan- otechnology. As they reported, polymers and drugs were conjugated in 1955 , the first controlled-release polymer device appeared in 1964, the liposome was discovered by Bangham in 1965, albumin-based NPs were reported in 1972, liposome-based drugs were formulated in 1973, the first micelle was formulated and approved in 1983, the FDA approved the first controlled formulation in 1989, and first polyethylene glycol (PEG) conjugated with protein entered the market in 1990. Further studies have produced incredibly encouraging results for treating a variety of disorders (Table 1). Nanomaterials 2022, 12, 4494 4 of 27 Table 1. Evolution of nanoparticles from 1991 to 2022 in detail discussed here. Year Types of NPs Drug Delivery Approaches Diseases Applications Characterization References Poly-alkyl-cyanoacrylate Cancer chemotherapy and intracellular Scanning electron microscope 1991 Carrier that delivers drug to target specific site. Cancer [37,38] nanoparticles antibiotherapy. (SEM) Calcium hydroxyapatite Drug gentamicin placed in the porous blocks of Chronic osteomyelitis The bactericidal activity was retained and drug No 1992 [39,40] ceramic (CHC) calcium hydroxyapatite antibiotics (CHA). (animal model) shows effective results. in vivo experiments performed In vitro, Micro-particulate system used for the Enhance oral immune system 1993 Nano and micro particles self-diffusion, liberation due to erosion, pulsed In vitro experiments performed [41,42] administration of the drug. (immunization) delivery due to oscillating field. Acrylic acid, acrylic amide, acrylic-butyl ester, Help opsonin to reach specific target site and also 1994 Acrylic acid copolymer NPs and methacrylic methyl ester used as No Small angle X-ray scattering [43,44] enhance reticuloendothelial system. copolymer in drug delivery. Ofloxacin (OFX) and perfloxacine entrapped in Freeze fracture electron Poly-alkyl-cyanoacrylate The fluoro-quinolone-loaded nanoparticles 1995 PECA nanoparticles. OFX system more efficient Bacterial diseases microscopy, physicochemical [45,46] (PECA) nanoparticles enhance antimicrobial activity of the drug. than PFX system. characterization Monoclonal antibodies, recombinant proteins Avidin conjugate with BBB vector to transport all Protein and peptides-based No characterization of 1996 transported to BBB by chimeric Alzheimer’s disease proteins across BBB. Vasoactive intestinal peptide [47,48] NPs physiologic-based strategy peptide approach. cures brain diseases. Nanoparticles as carrier to deliver drug to Easily penetrate into the arterial wall and without Restenosis (arterial 1997 Nanoparticle intra-arterial localization system. Cather causing injury. Biocompatible and effective for No [49,50] reobstruction) based delivery restenosis treatment. Help to sustain drug rate. Solubilize, release, and Diblock copolymer Micelles and nanosphere carry genes and 1998 No protect drugs. Enhance retention time in No [51,52] nanoparticles hydrophobic drugs to target site. the blood. Zeta potential, laser doppler Potential of chitosan nanoparticles to improve MicroAB assay used to determine insulin loading anemometry, 1999 Chitosan nanoparticles Diabetes [53,54] absorption of insulin through nasal cavity. and release. photon correlation spectroscopy Liposome with hyperthermia Increased drug delivery to tumor. 2000 Ovarian carcinoma Helpful in human cancer treatment. Experiments performed [55,56] as nanoparticles Hyperthermia helps liposome to work properly. Long retention time in blood as compared to PEGylated poly-cyano-acrylate Efficient drug carrier to deliver therapeutic non-PEGylated nanoparticles. Brain and spleen 2001 Prion Diseases Experiments performed [57,58] nanoparticles molecules in prion disease test. target tissues show uptake higher in scrapie-infected animals. Cancer Transferrin receptor interceded iron uptake; Transferrin mediated receptor Transferrin and transferrin receptor in drug and 2002 and regulation of transferrin receptor expression, No [59,60] endocytosis in gene transference via the BBB. Brain diseases anticancer drugs site-specific to tumor cells. Hepatitis B virus infects liver hepatocyte cells. Intravenous injection of L-particles loaded with I-Hepatitis B L-nanoparticles deliver drugs or genes efficiently 2003 L-nanoparticles green dye shows hepatocellular carcinoma in II-Hepatocellular carcinoma No [61,62] and specifically to the targeted hepatocyte cells in humans. III-Hemophilia a mouse xenograft model. TEM, dynamic light scatter, Colloidal gold nanoparticles used as vector to The designed vector PT-cAu-TNF bound on the and differential centrifugal 2004 Colloidal gold nanoparticles carry tumor necrosis factor (TNF) towards MC-38 carcinoma tumor surface of the gold NPs. Intravenous injection [63,64] sedimentation, specific part of tumor in mice. shows effective results in MC-38 carcinoma tumor. zeta potential Folate-associated, lipid-based nanoparticles Vitamin Folic acid placed inside cationic transport DNA with high transfection efficacy and liposomes and conjugate liposomes to folate Cancer (human constraining tumor progress with intratumoral 2005 Liposomes, nanoparticles ligand act as carrier and chemotherapeutics nasopharyngeal and prostate No [65,66] shot into human nasopharyngeal and prostate agents, and DNA attaches to the tumor) malignancy using an HSV-tk/GCV receptor-bearing cancer cells in vitro. treatment system. Nanomaterials 2022, 12, 4494 5 of 27 Table 1. Cont. Year Types of NPs Drug Delivery Approaches Diseases Applications Characterization References Folate changed with PEG coupled to the In vitro, FA-PEG/StNP targeted on liver cells AFM and zeta potential, Folate-conjugated starch exterior of starch NPs to attain the BEL7404. It reduced DOX toxicity. This UV Spectro-photometer 2006 Liver cancer [67,68] nanoparticles (StNP’s) FA-PEG/StNPs. Doxorubicin loaded on combination can be suitable for cancer targeting characterize particle size FA-PEG/StNP. drug haulers in future. determination Drug and gene delivery approach to deliver Properties of drug transfer like reduced toxicity, Gold nanoparticles drugs and genes by using gold nanoparticles. Human treating acute diseases, uptake and release rate Fluorescence and bright-field 2007 [69,70] (AuNPs) The transfection efficacy for beta galactosidase nasopharyngeal carcinoma using fluorophore AuNPs provide added insight microscopy with various MMPCs. in future. The diversity in medicine released in vitro in TEM and image analysis, Very effective drug transfers with AuNPs’ two-phase solution system. In vivo in DLS measurement, 2008 PEGylated gold nanoparticles vector for in vivo photodynamic treatment Cancer cancer-bearing mice shows that the way of drug [71,72] UV-vis, and fluorescent in cancer. carriage is enormously well-planned, and spectrophotometer submissive targeting prefers the tumor area. Nanoparticles of alginate/chitosan polymers Optimization of Alg/Chi NPs and preparation are Zeta potential, photon Alginate/ were arranged by pre-gel preparation method areas of this research. Some parameters like ratio correlation spectroscopy, 2009 Chitosan (Alg/Chi) via drop-wise addition of several concentrations No [73,74] of Alg/Chi, ratio of CaCl2 /Alginate and N/P can scattering particle size analyzer, nanoparticles of CaCl2 to a definite concentration of sodium disturb size and loading ability of these particles. FTIR analysis, DSC analysis alginate. (a) Choice of adaptable surface functionalization; Targeted carriage of chemotherapeutic mediator (b) High level of cell specificity and effective methotrexate (MTX) to Mesoporous silica cellular uptake; Scanning electron microscope 2010 tumor cells by means of poly (ethylene Cancer [75,76] nanoparticles (c) A slight grade of early seepage and the (SEM) mine)-functionalized mesoporous silica measured release of the medicine; (d) Low small units as vectors for drug delivery. cytotoxicity of the transporter. Well-organized delivery of oligonucleotide by a cationic nano-diamond nanoparticle: Nano diamonds have ability to transport small Nano diamond (ND) or Ewing Sarcoma (i) Suitably robust adsorption of the FT-IR confirm the absorption of interfering RNA into sarcoma (Ewing) cells. 2011 diamond Cells biomolecule on the particle surface across the cell PAH on nano-diamonds and [77,78] Was examined with evaluation of the route of nanoparticles (Cancer) membrane deprived of damage of material; (ii) zeta potential in vivo anticancer nucleic acid drug transfer. The severance of the compound on the time-scale of a cell division cycle. This method was to design stable silver NP The leaf potage of Annona squamosa used as an Ultraviolet spectrophotometry, Malaria, Dengue fever, 2012 Silver nanoparticles vector to make larvicides of mosquitos to active capping and reducing mediator for the X-Ray diffraction, [79,80] Filariasis destroy mosquitos’ life with drugs. fusion of silver nanoparticles. FT-IR, SEM Nanoparticles of noble metal show potential as Good consistency to nucleases, hybridization UV-spectrophotometer, photo-activated vectors for drug delivery. SNPs amplified action upon photo release, and effective 2013 Silver nanoparticle Photo-activated gene silencing fluorescent confocal [81,82] conjugated with thiol-terminated photo-liable cellular uptake as associated to commercial microscopy DNA oligonucleotides. transfection vectors. Medically active plant and earth eco-friendly. Silver nanoparticles as Silver nanoparticles synthesized from plant Larvicidal action of silver nanoparticles and leaf UV-visible absorption 2014 Dengue [83,84] drug-loading vector Pongamia pinnata by green method. extract contrary to Aedes aegypti showed spectrum, TEM, XRD, FTIR positive results. Polyamidoamine nanoparticles work as Fluorescence-assisted cell Union of doxorubicin and polymers increases nanocarrier and deliver anti-malarial drug to sorting, transmission electron 2015 Polyamidoamine nanoparticles Malaria drug solubility, enhances its blood half-life, [85,86] the targeted sites. It also works microscopy, confocal decreases toxicity, and enhances targeting. as nanomedicine. immunofluorescence Nanomaterials 2022, 12, 4494 6 of 27 Table 1. Cont. Year Types of NPs Drug Delivery Approaches Diseases Applications Characterization References Electroporation and nanocarrier used to deliver Confocal laser scanning drugs. In this study, SLNP laden with cyanine Solid Lipid Drug transfer potential of therapeutics microscopy (CLMS) for the 2016 type IR-780, flavonoid derivatives, Colon cancer [87,88] nanoparticles (SLNP) compressed with electroporation. estimation of photosensitizer through solvent F-actin AFM and DLS diffusion method. Filamentous bacteriophage used in the making of Delivery of drug and gene through phage mark medicine transfer as virus-based delivery Filamentous bacteriophage particles. Phage can be chemically altered or system. The bacteriophage uncovered with 2017 and phage-mimetic Bacterial and viral diseases No [89,90] genetically designed to load drugs and transfer mark-definite peptides or antibodies can be bound nanoparticles foreign genes. with other carriers (such as liposomes, inorganic NPs) to make a unique transfer scheme. Transmission electron The practice of non-viral vectors can solve most of Mesoporous silica Through electrostatic absorption, MSNs loaded microscopy, dynamic light these problems like short time, noxiousness while 2018 nanoparticles with surface-hyper-branching polymerized poly No scattering (DLS), and zeta [91,92] inorganic, and non-viral vectors, like MSNs, are (MSNs) (ethylene- mine) for loading siRNA. potential involved in particle also very affordable and vigorous. size determination Ocular drug delivery, vaccine delivery, perioral delivery, vaccine transfer, Drug loaded on chitosan nanoparticles to mucosal and nasal drug transfer, gene carriage, 2019 Chitosan nanoparticles deliver to targeting sites. All types of drug No No [93,94] pulmonary drug delivery, delivery sites involved. buccal medicine distribution, vaccine transfer, and cancer treatment. The hyper-branched polymer HBP encapsulates This approach is pH subtle drug delivery XRD, TEM, HNMR spectra, Mesoporous silica NPs with the drug particles in the mesopores as a lid, which system built on folic-acid-targeted HBP to SEM, UV-analysis, 2020 folic acid Cancer progresses the permanency of the carrier material [95,96] re-form/reshape the mesoporous Thermogravimetric (MSN COOH-Tet-HBP-FA) and permits the drug to attain “zero pre-release” silica nanoparticles. analysis (TGA) within 20 h in a usual physiological atmosphere. The nucleic acid vaccines comprise cell-mediated and humoral immunity activation, affluence of In this approach, DNA or messenger RNA strategy, quick malleability to altering pathogen (mRNA) sequences are transported to the body 2021 Novel silver nanoparticles SARS-CoV-2 strains, and customizable multi-antigen vaccines. No to produce proteins, which copy disease To fight the SARS-CoV-2 epidemic and many antigens to arouse the immune response. other ailments, nucleic acid vaccines seem to be a hopeful way. It helped in the COVID-19 treatment vaccines, These nanoparticles have crucial role in the such as Doxil and Onpattro, and has a good COVID-19 success rate. success rate. 1-Lipid based nanoparticles Metals such as Au, Ag, Zn, Cu have potential in COVID-19 No Such NPs have been used in prevention like face 2021 2-Metal and metal oxide NPs controlling coronavirus due to their SARS-Cov-2 viral disease COVID-19 mono and [98–100] masks, various immune sensors, and coatings on 3-Resveratrol-zinc NPs discrete features. COVID-19 adjuvant therapy various things. It is a drug delivered via carrier. It gives Resveratrol-zinc nanoparticles possess a chief immuno-anti-inflammatory viral retort. pharmacokinetic gain for COVID-19. A nanoprobe was synthesized for in vivo fluorescence tomography of microRNA and Nanoprobe helped in vivo in healing studies and No coactive photothermal dealings of lump. continuously killed the lump growth. Nanocarriers are biocompatible, 1-Iridium oxide NPs Cancer 2022 It is a biotic macromolecule-based medicine Theses neuroprotective mediators are merged into biodegradable, [101,102] 2-Chitosan nanoparticles Nervous breakdown transfer system to advance the curative the structure of NGCs and delivered into brain via non-immunogenic, constant, potential of non-natural neural NPs. and hold tunable properties control networks. Nanomaterials 2022, 12, 4494 7 of 27 3. Recent Approaches Used in Drug Carriage System for Treatment of Various Diseases 3.1. Brain Drug Delivery System and Its Types Under the most pathological circumstances of diseases such as strokes, seizures, mul- tiple sclerosis, AIDS, diabetes, glioma, Alzheimer’s disease, and Parkinson’s disease, the blood–brain barrier (BBB) is disrupted. An important reason for the breakdown of the blood–brain barrier is the remodeling of the protein complex in intra-endothelial junctions under the pathological conditions. Normally, the blood–brain barrier acts to maintain blood–brain homeostasis by preventing entry of macromolecules and micro- molecules from the blood. If a drug crosses the BBB, it restricts accumulation of the drug in the intracerebral region of brain, and bioavailability is reduced, due to which brain diseases cannot be treated. Therefore, the optimal drug delivery system (DDS) is a cell membrane DDS, virus-based DDS, or exosome-based DDS designed for BBB pene- trability, lesion-targeting ability, and standard safety. For the cure of brain diseases, the nanocarrier-assisted intranasal drug carriage system is widely used. Now, at the advanced level, drugs poorly distributed to the brain can be loaded into a nanocarrier-based system, which would interact well with the endothelial micro vessel cells at the BBB and nasal mucosa to increase drug absorption time and the olfactory nerve fibers to stimulate straight nose-to-brain delivery , thus greater drug absorption in brain parenchyma through the secondary nose-to-blood-to-brain pathway. The current strategies used are viral vectors, nanoparticles, exosomes, brain permeability enhancers, delivery through active transporters in the BBB, alteration of administration route, nanoparticles for the brain, and imaging/diagnostics under diseased conditions. 3.1.1. Role of Nanocarriers in Alzheimer’s Disease Alzheimer’s disease is one of the fastest growing neurodegenerative diseases in the elderly population. Clinically, it is categorized by abstraction, damage to verbal access, and diminishing in spatial skills and reasoning. Furthermore, engrossment of amyloid (A ) aggregation and anxiety in the brain have significant parts. The treatment of different diseases with nanotechnology-based drug delivery uses nanotechnology-based approaches. In Alzheimer’s diseases, polymeric nanoparticles, liposomes, solid lipid nanoparticles, nano-emulsions, micro-emulsions, and liquid-crystals are used for treatment. Polymeric Nanoparticles I. The drug Tacrine was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced the concentration of tacrine inside the brain and also reduced the whole-dose quantity. II. Rivastigmine drug was loaded on polymeric nanoparticles and administered through an intravenous route. It enhanced learning and memory capacities. Solid Lipid Nanoparticles (SLNPs) SLNPs enhanced drug retention in the brain area, raising absorption across the BBB. Some of the drug’s effects are listed below. I. Piperine drug is loaded on solid lipid nanoparticles through an intraperitoneal route inside the brain to decrease plaques and masses and to increase AChE enzyme activity. II. Huperzine A improved cognitive functions. No main irritation was detected in rat skin when the drug was loaded on SLNPs in an in vitro study. In recent reports, the coating of SLNPs with polysorbate enhances drug bioavailabil- ity [120,121]. Some of the coated NPs are listed below. I. The drug clozapine was loaded on a Dynasan 116 [Tripalmitin] lipid matrix coated with surfactant Poloxamer 188, Epikuron 200 to unload the drug safely into the brain microenvironment [122,123]. Nanomaterials 2022, 12, 4494 8 of 27 II. Vitamin A was loaded on a lipid matrix Glyceryl behenate with coated surfactant hydroxypropyl distarch to unload the drug safely across the BBB [124,125]. III. Diminazine was loaded on a stearic acid matrix coated with polysorbate 80 to deliver to an infected area safely [126,127]. IV. Doxorubicin was loaded on stearic acid SLNs coated with Taurodeoxycholate surfac- tant to deliver the drug without reducing its effectiveness [128,129]. Liposomes Liposomes have gained attention as auspicious tactics for brain-targeted drug deliv- ery. The recorded beneficial features of liposomes are their capacity to integrate and carry a large quantity of drugs and their likelihood to adorn their exterior with diverse ligands [131,132]. Curcumin–PEG derivative was loaded on liposomes and showed high affinity on senile plaques in an ex vivo experiment. Furthermore, in vitro it demonstrated the ability for A aggregation and was taken inside by the BBB in a rat model. Folic acid was loaded on liposomes, administered through an intranasal route and absorbed through the nasal cavity. Nanoemulsions I. Beta-Asarone was loaded on nanoemulsions, administered through an intranasal route, and enhanced bioavailability. Micro Emulsion I. Tacrine was loaded on a microemulsion and improved memory. Such nanoparticles absorbed rapidly via the nose to the brain through an intranasal route. Liquid Crystals I. T. divaricate was loaded on liquid crystals and injected through a transdermal route. It increased permanency of the drug in designs and also increased skin infusion and retention. 3.1.2. Role of Nanocarriers in Parkinson’s Disease (PD) Parkinson’s disease is considered the second most common neurological ailment, and it faces problems in reliable drug delivery for treatment and diagnosis. The conventional anti-Parkinson’s drug is Levodopa, but it experiences low bioavailability and deprived transfer to the brain; this is the most thought-provoking problem. To solve this problem, nanotechnology comes to the fore with insightful solutions to solve this problem. Various nanoparticles like metal nanoparticles, quantum dots, cerium oxide nanoparticles, organic nanoparticles, liposomes, and gene therapy are used in PD treatment. All these nanoparticles enable drugs to enter through numerous ways across the blood–brain barrier (BBB). In the current study, Bhattamisra et al. reported Rotigotine drug loaded on chitosan NPs in human SH-SY5Y neuroblastoma cells and delivered from the nose to the brain in rat model of Parkinson’s disease. A study of the pharmacokinetic data proposed that the intranasal route is the best path for a straight channel of rotigotine to the brain. Ropinirole (RP) Ropinirole (RP) is a dopamine agonist used for Parkinson’s treatment. RP-loaded solid lipid nanoparticles (RP-SLNs) with nanostructured lipid carriers (RP-NLCs) comprising hydrogel (RP-SLN-C and RP-NLC-C) formulations are better for oral and topical distribu- tion. Generally, the results confirmed that lipid nanoparticles and consistent hydrogel formulations can be measured as another carriage methodology for the upgraded oral and topical delivery of RP for the active treatment of PD. Neurodegenerative pathologies Nanomaterials 2022, 12, 4494 9 of 27 such as AD and PD can be treated with solid lipid nanoparticles, as this permits the drug to cross the BBB and reach the damaged area of the central nervous system. 3.2. Mechanism of Nanoparticles’ Brain Drug Delivery (across BBB) The NPs are commonly administered via intranasal, intraventricular, intraparenchy- mal routes. All these routes enabled nanoparticles to cross the BBB due to their small size. When nanoparticles reach the BBB, several mechanisms are used, like receptor-mediated mechanisms, active transport, and passive transport to deliver nanoparticles into the brain. Nanoparticles are small in size, can diffuse passively across the endothelial cells of the BBB, and can interact favorably with brain receptors and recognize ligands for interaction (Figure 3). Figure 3. Diagram showing the mechanism of targeted drug delivery across BBB in brain microenvi- ronment. Piperine loaded on SLNPs is injected intraperitonially, across BBB efferently to stop plaque formation. Polymeric nanoparticles are used for Tacrine delivery inside the brain, folic acid are loaded on the liposomes crossing blood–brain barrier to treat Alzheimer’s disease, while nanoemul- sions and SLNP are loaded with drugs used to deliver medicines inside the targeted brain area to cure Parkinson’s disease. 3.3. Advantages and Disadvantages of Nanomedicines When employed for brain illnesses, nanomedicines have both benefits and drawbacks (Table 2). Nanomaterials 2022, 12, 4494 10 of 27 Table 2. Advantages and disadvantages of nanomedicine. Nanomedicine Names Advantages Disadvantages Ref. NPs are reserved in the brain for long time, biocompatible, low in Slowly degradable, Tacrine-loaded polymeric NPs cost, control drug release, and targeted conjugation with ligands sometimes uncertain toxicity They increase drug concentration in the brain, avoid phagocytosis Rivastigmine-loaded polymeric NPs Increase oxidative stress, toxicity by RES Widely examined, fewer side effects of drugs, improved therapeutic Low loading capacity, easily cleared by Piperine-loaded SLNPs effects and drug solubility reticuloendothelial system Highly biocompatible and biodegradable, Difficulty in binding with lipids, low stability and drug Folic-acid-loaded liposomes High stability and bioavailability, carriage rate active surface targeted Improved bioavailability, capability to hydrolyze hydrophobic and Thermodynamically unstable, Beta-Asarone-loaded nanoemulsions hydrophilic drugs instant drug release Nanomaterials 2022, 12, 4494 11 of 27 4. Nanocarriers Role in Major Cancers 4.1. Brain Cancer Brain malignancy is the most critical disease in the sense of treatment. Malig- nancies of the brain are most difficult to treat due to limits imposed by the blood–brain barrier. The brain microvascular endothelium is present in the BBB and creates barri- ers that distinguish blood from the neural tissues of the brain. The BBB prevents the entry of harmful toxins, xenobiotic and other metabolites from entering the brain. The majority of brain cancers include glioma and glioblastoma. Both of these are among the most lethal forms of brain cancer. The annual occurrence is 5.26 per 100,000 people or 17,000 new diagnoses each year. The most common treatment is radiation surgery and chemotherapy, usually implemented with with temozolomide (TMZ). Nanoparticles have a high potential to treat brain cancer because of their small size in nm, tissue-specific targeting properties, and ease in crossing the BBB (Table 3). 4.2. Breast Cancer Cancer causes major deaths all over the world. Tumors spread due to the proliferation of cells , which invade through the lymphatic system to various parts of the body if they becomes malignant. According to WHO, the ratio of deaths globally due to cancer is assessed to be 13%, attributing 8.2 million deaths every year. Breast cancer is the most recorded type of melanoma present in only females, and its severity leads to mortality more often than lung cancer. In 2012, estimated female breast cancer cases were 1.7 million, with 25% of deaths all over the world. In a recent study, a report published in the name of Global Cancer Statistics 2020: GLOBOCAN estimates the incidence and mortality worldwide for 36 cancers in 185 countries and provides an update on cancer internationally. A reported estimate is 19.3 million new cancer cases (18.1 million excluding non-melanoma skin cancer) and almost 10 million cancer deaths (9.9 million without non-melanoma skin cancer) occurring in 2020 worldwide. Female breast cancer has exceeded lung cancer as the most frequently diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), prostate (7.3%), colorectal (10%), and stomach (5.6%) cancers. For the effective treatment of breast cancer, surgery, chemotherapy, radiation therapy, hormonal therapy, and targeted therapy are performed. However, nowadays, nanotechnology has gained interest for breast cancer treatment. Various organic and inorganic nanocarriers are used to deliver drugs to the specific target site. Nanocarriers enhance the hydrophobicity of the anticancer drugs and promote specific target drug delivery. Organic nanocarriers include polymeric nanocarriers, liposome nanocarriers, and solid lipid nanocarriers, while inorganic nanocarriers include magnetic nanocarriers, quantum dots, and carbon nanotubes (CNTs); both categories show great results towards treatment of heart diseases (Table 4). The mechanism of drug delivery in breast cancer is shown in Figure 4. Nanomaterials 2022, 12, 4494 12 of 27 Table 3. Various nanoparticles involved in brain cancer treatment in recent era. NP Name NP Types Drug Loaded on NPs Cancer Type Model Action Ref. Endocytosis occurs. Cytotoxic Glioma and glioma activity increased both on DOX-SL-GG AuNPs Gold nanoparticles Doxorubicin In vitro [157,158] stem cell lines LN-229 glioma cells and HNGC-2 glioma stem cells. Constrain movement, invasion Lapatinib-loaded human Albumin-bound Murine model Lapatinib Brain metastasis and adhesion of high [159,160] serum albumin nanoparticle in vitro brain-metastatic 4T1 cells. Both LTNPs (10 mg kg 1 ) and Lapatinib-incorporated Lipoprotein-like LTNPs (30 mg kg 1 ) significantly Lapatinib Glioma In vivo murine model [161,162] lipoprotein like NPs nanoparticles constrain the progress of U87 xenografts. Comparatively greater Gold–iron oxide Curcumin–lipoic Cytotoxicity and cytotoxicity against cancerous Glutathione Brain cancer [163,164] nanocomposites acid conjugate apoptosis assay U87MG cells than standard astrocyte cells. Synergistic influence of Tocopherol polyethylene Fabricated synergistic Enhance cellular uptake nanoparticles has increased the Docetaxel Brain cancer [165,166] glycol chitosan nanoparticles bioadhesive nanoparticles and cytotoxicity delivery of docetaxel into brain melanoma cells. Methotrexate-loaded Nanoparticles show cytotoxicity Chitosan or glycol chitosan chitosan and glycol Cytotoxicity assay and against C6 cells line and are able Methotrexate (MTX) C6 glioma cells [167,168] (GCS) nanoparticles (NPs) chitosan-based cell lines to control MDCKII-MDR1 nanoparticles cell hindrance. The effectiveness of 5-FU to In vitro cytotoxic activity Lipid–drug-conjugated 5-FU (fluo- Brain cancer medicate the brain malignancy is Fluorouracil and human glioma cell lines [169,170] (LDC) nanoparticle rouracil)nanoparticles glioma cells improved when it is designed in vivo with LDC nanoparticles. Nanomaterials 2022, 12, 4494 13 of 27 Table 4. Nanoparticles’ role in treatment of breast cancer. Nanomaterial Material Used Drug Loaded with NPs Animal Model Disease Description Ref. (Organic Nanomaterial) Lactate dehydrogenase (LDH) and 3-(4, 5-Dimethylthiazol-2-yl)-2, In-vitro Solid lipid Folic-acid-receptor-targeted Letrozol (LTZ) 5-diphenyltetrazolium bromide (MTT) MCF-7 cancer Breast cancer [182,183] nanoparticles (SLNPs) solid lipid nanoparticles Folic acid assays to check cell membrane damage. cell lines Caspase-3 activity and TUNEL assays were performed to confirm induced apoptosis. Curcumin-loaded SLNs 5–10 folds more CURC-loaded SLNs and Curcumin–Solid Lipid effectively than curcumin in free form, doxorubicin Doxorubicin (DOX) In-vitro Breast cancer [184,185] nanoparticles (CURC-SLNs) increasing toxicity in Pgp-expressing triple p-glycoprotein (Pgp) negative breast cancer. Anti-HER2-conjugated O-succinyl chitosan HER2-over- Copolymer-magnetite doxorubicin–core-shell graft pluronic F127 copolymer Doxorubicin (DOX) In-vitro express in [186,187] nanoparticles chitosan nanoparticles nanoparticles are effective for the making breast cancer of anticancer drug carriers. Combination remedy by DMMA-P-DOX/LAP nanoparticles PEGylated "-poly-l-lysine doxorubicin and MCF-7 breast Polymeric nanoparticles In-vitro constrains the solid tumors to shrink or [188,189] polymeric nanoparticle lapatinib cancer cell disappear completely in the MCF-7 tumor model. Nanomaterial Material Used Drug Loaded on NPs Animal Model Disease Description Ref. (Inorganic Nanomaterial) Gemcitabine-hydrochloride In vitro Human breast Gemcitabine-hydrochloride-loaded gold Colloidal gold nanoparticles (GEM)-loaded colloidal Gemcitabine (MDA-MB-231) cancer nanoparticles developed using gum acacia [190,191] Iron-based metal network gold nanoparticles cell line adenocarcinoma as a polysaccharides-based system. CCMNPs were targeted precisely, amassed L-carnosine-coated magnetic In vitro in lump, showing noteworthy decrease in Magnetic nanoparticles L-carnosine Breast cancer [192,193] nanoparticles (CCMNPs) In vivo lump mass size with no general harmfulness. Nanomaterials 2022, 12, 4494 14 of 27 Figure 4. Schematic Figure Schematicrepresentation of mechanism representation of drug of mechanism of letrozol loaded on drug letrozol solid lipid loaded nanoparticles on solid lipid nanoparti- (SLNs) and folic acid coupled to SLNs. The whole carrier was delivered inside the animal rat model to treat effects on breast cancer cell lines. Inside cytoplasm, biodegradation occurred, as well as drug release and caspases’ activation inside nucleus, causing apoptosis. 4.3. Lung Cancer Lungs are basically responsible for inhalation. The lung is composed airways (conveying the air inside and outside of the lungs) and alveoli (gas exchange zones). In fact, airways are comparatively tough barriers for particles to enter through, while the barrier along the alveolar wall and the capillaries is relatively fragile in the gas exchange component. The huge exterior area of the alveoli and deep air blood exchange cause the alveoli to be less healthy when affected by environmental injuries. Such injuries may be the reason for some pulmonary illnesses, including lung malignancy. Several nanoparticles are now being established for respiratory applications that aim at eliminating the restrictions of orthodox drugs (Table 5). Nanoparticles aid the cure of many lung diseases, such as asthma, tuberculosis, emphysema, cystic fibrosis, and cancer. Nanomaterials 2022, 12, 4494 15 of 27 Table 5. Recent discovered nanoparticle’s role in lung cancer treatment. Nanoparticles Exposure Method Animal Model Description Used for Reference Poly (L-aspartic acid co lactic Mouse DPPE co-polymer NPs laden with acid)/DPPE Intraperitoneal injection Lung melanoma [200,201] xenograft model doxorubicin (DOX) copolymer nanoparticles PBAE polymers that self-assemble with DNA Poly ( -amino ester) Mouse Intratumoral injection and evaluated for transfection effectiveness in Small cell lung cancer [202,203] nanoparticle (PBAE) xenograft model the p53 mutant H446 SCLC cell line The receptor factor (EGF) was co-designed with Lipid polymeric nanoparticles Intraperitoneal injection Mice Lung carcinoma cisplatin plus doxorubicin Methoxy poly -poly Doxorubicin and cisplatin (CDDP) (ethylenimine)-poly(l-glutamate) copolymers Metastatic lung Pulmonary administration Mouse model [205,206] co-loaded nanoparticles were manufactured as a transporter for the melanoma codelivery of DOX and CDDP PAA-ss-OA-modified Erlotinib (ETB)-loaded Redox-responsive plus Mouse lipid nanoparticles (PAA-ETB-NPs) were made Non-small cell lung Subcutaneous injection pH-sensitive nanoparticles xenograft model using the emulsification and solvent melanoma (NSCLC) evaporation method MSC as lung-melanoma-targeted drug transfer transporters by loading nanoparticles (NPs) Nanoparticles/mesenchymal stem Injected by loading on NPs Rabbit, mice, and monkey with anticancer medicine. MSC demonstrated a Lung melanoma [208,209] cell (MSC) inside the body greater medicine ingestion ability than fibroblasts Assessment of the capacity of hyaluronic-acid-based nanostructured lipid Hyaluronic-acid-based Dialysis techniques used in No carriers (NLCs) to improve apigenin (APG) Lung cancer lipid nanoparticle in vitro study efficacy as Nrf2 inhibitor, in immediate administration with DTX in A549 NSCLC Cancer-definite hybrid theranostics MAGE-A3 NIR insistent nanomaterials MAGE-A3 NIR insistent glow Non-small cell lung In vitro activity In vivo mouse model luminescence nanoparticles nanoparticles coupled to Afatinib for in situ carcinoma conquest of lung adenocarcinoma Hyaluronic-acid- In vivo Mice used; Paclitaxel delivered via these NPs to cancerous