Targeting Strategies for Tissue-Specific Drug Delivery

Off-target effects of systemically administered drugs have been a major hurdle in designing therapies with desired efficacy and acceptable toxicity. Developing targeting strategies to enable site-specific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and thereby enhancing a drug’s therapeutic efficacy. Over the past three decades, a large body of literature has focused on understanding the biological barriers that hinder tissue-specific drug delivery and strategies to overcome them. These efforts have led to several targeting strategies that modulate drug delivery in both the preclinical and clinical settings, including small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Here, we discuss key advances and emerging concepts for tissue-specific drug delivery approaches and their clinical translation. Off-target effects of systemically administered drugs have been a major hurdle in designing therapies with desired efficacy and acceptable toxicity. Developing targeting strategies to enable site-specific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and thereby enhancing a drug’s therapeutic efficacy. Over the past three decades, a large body of literature has focused on understanding the biological barriers that hinder tissue-specific drug delivery and strategies to overcome them. These efforts have led to several targeting strategies that modulate drug delivery in both the preclinical and clinical settings, including small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Here, we discuss key advances and emerging concepts for tissue-specific drug delivery approaches and their clinical translation. Development of drugs or active pharmaceutical ingredients for specific disease pathologies, that is, the process of drug discovery, has been instrumental in generating new lead molecules for a plethora of disease conditions. While early drugs were sighted by serendipity, the discovery has been expedited by the introduction of novel discovery tools including structure-activity relationships, computer-aided drug design, high-throughput screening, combinatorial chemistry, and artificial intelligence (Macarron et al., 2011Macarron R. Banks M.N. Bojanic D. Burns D.J. Cirovic D.A. Garyantes T. Green D.V. Hertzberg R.P. Janzen W.P. Paslay J.W. et al.Impact of high-throughput screening in biomedical research.Nat. Rev. Drug Discov. 2011; 10: 188-195Crossref PubMed Scopus (577) Google Scholar, Ramström and Lehn, 2002Ramström O. Lehn J.M. Drug discovery by dynamic combinatorial libraries.Nat. Rev. Drug Discov. 2002; 1: 26-36Crossref PubMed Google Scholar, Topol, 2019Topol E.J. High-performance medicine: the convergence of human and artificial intelligence.Nat. Med. 2019; 25: 44-56Crossref PubMed Scopus (294) Google Scholar). Although the process of lead identification is robust, drugs often fail in later stages of development typically due to safety and efficacy concerns that fundamentally arise from high accumulation in off-target organs or poor accumulation in target organs, respectively. This has been a major bottleneck in the translation of potent drug candidates, which inherently possess excellent potential but fail to demonstrate significant clinical impact due to dose-related toxicities and/or dose-limited efficacies due to off-target effects. Drug delivery technologies hold the potential to address this limitation and have emerged in parallel to the drug discovery process. Over the years, drug delivery research has offered multiple approaches to target drugs, including local therapies such as topical formulations and physical devices (Gliadel wafers, drug-eluting stents, etc.). Local therapies offer the simplest means of targeting; however, they are not practical when the disease sites are hard-to-reach. Nanoparticles have also been developed to target therapies to specific tissues. Modulation of physicochemical properties such as size and charge could improve nanoparticles’ targeting to specific tissues (Maldonado et al., 2015Maldonado R.A. LaMothe R.A. Ferrari J.D. Zhang A.H. Rossi R.J. Kolte P.N. Griset A.P. O’Neil C. Altreuter D.H. Browning E. et al.Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance.Proc. Natl. Acad. Sci. USA. 2015; 112: E156-E165Crossref PubMed Scopus (0) Google Scholar, Williams et al., 2015Williams R.M. Shah J. Ng B.D. Minton D.R. Gudas L.J. Park C.Y. Heller D.A. Mesoscale nanoparticles selectively target the renal proximal tubule epithelium.Nano Lett. 2015; 15: 2358-2364Crossref PubMed Scopus (29) Google Scholar); however, nanoparticles also face biological barriers that impede their targeting capabilities (Blanco et al., 2015Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Google Scholar). The advent of nucleic acid-based therapies, gene therapies, and cell therapies has opened additional therapeutic opportunities, but has also introduced new delivery challenges. Several reviews exist on ligand-targeted drug delivery systems, some particularly dealing with the chemical and biochemical aspect of targeted constructs (Kapoor et al., 2019Kapoor D. Bhatt S. Kumar M. Maheshwari R. Tekade R.K. Ligands for Targeted Drug Delivery and Applications.in: Tekade R.K. Basic Fundamentals of Drug Delivery. Academic Press, 2019Crossref Scopus (1) Google Scholar, Srinivasarao and Low, 2017Srinivasarao M. Low P.S. Ligand-Targeted Drug Delivery.Chem. Rev. 2017; 117: 12133-12164Crossref PubMed Scopus (106) Google Scholar). In this review, we focus on the biological barriers that limit tissue-targeted therapy and categorize targeting strategies based on their length scales. We also overview the landscape of targeting moieties with an emphasis on the uniqueness of ligand biology, emerging concepts, and clinical advances, and provide the reader with an overview of targeted delivery strategies and guiding design principles to make an informed ligand selection. Our discussion is agnostic to the therapeutic modality, thereby providing a generalized discussion of targeting strategies (Figure 1). In general, we will discuss small molecules, aptamers, peptides, antibodies, and cell-based targeting strategies with a focus on clinical developments. We focus our discussion on targeting strategies for intravascularly administered therapeutics. Intravascularly administered therapeutics experience biological barriers serially before reaching the target sites (Figure 2), and the complexity of these barriers depends on the properties of the therapeutics and their formulations. Here, we discuss key biological barriers encountered by therapeutics. Because the nature of the biological barriers is substantially different for nanoparticle therapeutics, we also highlight the barriers faced by nanoscale therapeutics. Comprehensive reviews of biological barriers have been elegant, as discussed in other reviews (Blanco et al., 2015Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Google Scholar, Rosenblum et al., 2018Rosenblum D. Joshi N. Tao W. Karp J.M. Peer D. Progress and challenges towards targeted delivery of cancer therapeutics.Nat. Commun. 2018; 9: 1410Crossref PubMed Scopus (297) Google Scholar). Upon intravascular administration, therapeutics encounters several intravascular barriers (Figure 2). Intravascular enzymes, such as proteases and nucleases, degrade the active ingredients, forming the first intravascular barrier (Juliano et al., 2009Juliano R. Bauman J. Kang H. Ming X. Biological barriers to therapy with antisense and siRNA oligonucleotides.Mol. Pharm. 2009; 6: 686-695Crossref PubMed Scopus (207) Google Scholar). In addition, small molecule therapeutics and large molecule therapeutics of certain size (<6 nm) can be cleared via renal filtration (Longmire et al., 2008Longmire M. Choyke P.L. Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats.Nanomedicine (Lond.). 2008; 3: 703-717Crossref PubMed Scopus (1048) Google Scholar). Nanoparticle therapeutics experience additional intravascular barriers, including sequestration by the mononuclear phagocyte system (MPS), consisting of a system of phagocytes, mainly resident macrophages lining the vascular wall in the liver (Kupffer cells) and spleen (splenic macrophages) and monocytes in the bone marrow (Gustafson et al., 2015Gustafson H.H. Holt-Casper D. Grainger D.W. Ghandehari H. Nanoparticle uptake: The phagocyte problem.Nano Today. 2015; 10: 487-510Crossref PubMed Scopus (294) Google Scholar). Upon entering circulation, plasma proteins immediately adsorb onto the surface of nanoparticles forming a protein corona (referred to as “opsonization”). Opsonized nanoparticles are recognized by MPS via specific receptor binding and are subsequently internalized by phagocytes. The endothelial barrier prevents therapeutics from extravasating into the target tissues (Figure 2). Endothelial cells line the vascular lumen and adhere to the underlying basement membrane and extracellular matrix tightly via integrins (Juliano et al., 2009Juliano R. Bauman J. Kang H. Ming X. Biological barriers to therapy with antisense and siRNA oligonucleotides.Mol. Pharm. 2009; 6: 686-695Crossref PubMed Scopus (207) Google Scholar). The integrity of the endothelial barrier varies depending on specific tissues and their pathological conditions. The endothelial barrier between the blood and the brain (blood-brain barrier) is extremely restrictive because of a high density of endothelial cells and tight junctions between them (Banks, 2016Banks W.A. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery.Nat. Rev. Drug Discov. 2016; 15: 275-292Crossref PubMed Scopus (253) Google Scholar). In certain disease conditions, such as tissue injury, cancer, and infection, the vascular endothelium undergoes dysfunction and fenestration, leading to the formation of a relatively leaky vessel, a phenomenon referred to as the enhanced permeation and retention (EPR) effect. The EPR effect is particularly significant to cancer due to its aggressive angiogenic nature (Blanco et al., 2015Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Google Scholar, Rosenblum et al., 2018Rosenblum D. Joshi N. Tao W. Karp J.M. Peer D. Progress and challenges towards targeted delivery of cancer therapeutics.Nat. Commun. 2018; 9: 1410Crossref PubMed Scopus (297) Google Scholar), creating an opportunity to deliver therapeutics, especially nanoparticle therapeutics, to tumors. In cases of inflammation, extravasation through leaky vasculature and inflammatory cell-mediated sequestration (ELVIS) can help in targeting drugs to inflammation sites (Yuan et al., 2012Yuan F. Quan L.D. Cui L. Goldring S.R. Wang D. Development of macromolecular prodrug for rheumatoid arthritis.Adv. Drug Deliv. Rev. 2012; 64: 1205-1219Crossref PubMed Scopus (82) Google Scholar). Upon successful extravasation across the endothelial barrier, therapeutics must penetrate through the extracellular matrix (ECM) to reach cells of the target tissues (Figure 2). Small molecules can easily diffuse through, but large molecules, including nanoparticles, experience resistance in the ECM. In certain disease conditions, the ECM environment can be significantly altered, creating additional biological barriers. For example, tumors often have poor lymphatic drainage, a dense ECM, and widespread fibrosis. These factors, together with the disrupted vasculature, lead to a high interstitial fluid pressure in tumors, which drastically compromises the osmotic and hydrostatic pressures, thereby impeding the transport of small molecules across the vessels, and reduces the extravasation of large molecules and nanoparticles to the target cells (Blanco et al., 2015Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Google Scholar, Heldin et al., 2004Heldin C.H. Rubin K. Pietras K. Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy.Nat. Rev. Cancer. 2004; 4: 806-813Crossref PubMed Scopus (1187) Google Scholar). Upon reaching the target tissue, therapeutics with intracellular targets have to cross the plasma membrane to reach their targets in the cytosol or nucleus of the cell. The plasma membrane is relatively permeable to hydrophobic small molecules. However, the transport of macromolecules and nanoparticles requires an active uptake mechanism, which requires their efficient interactions with the plasma membrane and subsequent endocytosis processes, such as phagocytic-, clathrin-, and caveolae-mediated endocytosis (Blanco et al., 2015Blanco E. Shen H. Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery.Nat. Biotechnol. 2015; 33: 941-951Crossref PubMed Google Scholar, Zhao et al., 2019bZhao Z. Ukidve A. Krishnan V. Mitragotri S. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers.Adv. Drug Deliv. Rev. 2019; 143: 3-21Crossref PubMed Scopus (19) Google Scholar). Endocytosed macromolecules and nanoparticles are translocated to intracellular vesicles including endosomes, phagosomes, and lysosomes. These endosomal compartments have a harsh environment including acidic pH and enzymes that facilitate the degradation of active therapeutics (Zhao et al., 2019bZhao Z. Ukidve A. Krishnan V. Mitragotri S. Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers.Adv. Drug Deliv. Rev. 2019; 143: 3-21Crossref PubMed Scopus (19) Google Scholar). This creates an additional biological barrier. Entrapped therapeutics need to escape from the endosomal compartments to reach their intracellular targets. Better understanding of the abovementioned biological barriers has facilitated the development of many effective targeting strategies for tissue-specific drug delivery. In general, the engagement of targeting ligands with their receptors requires a close molecular contact, which can only be mediated by non-specific transport processes including blood circulation, diffusion, and lymph draining, except for the use of live cells as ligands. Based on their length scale, we categorize major targeting strategies to small molecule-based, nucleic acid-based, peptide- and antibody-based, and cell-based strategies, and discuss each strategy in detail in the following context. Small molecule targeting ligands are entities used for targeted delivery that have an average molecular weight less than 1 kDa, corresponding to a Stokes-Einstein radius of 1 nm (Kapoor et al., 2019Kapoor D. Bhatt S. Kumar M. Maheshwari R. Tekade R.K. Ligands for Targeted Drug Delivery and Applications.in: Tekade R.K. Basic Fundamentals of Drug Delivery. Academic Press, 2019Crossref Scopus (1) Google Scholar). Several previous reviews have focused on small molecule targeting ligands (Kapoor et al., 2019Kapoor D. Bhatt S. Kumar M. Maheshwari R. Tekade R.K. Ligands for Targeted Drug Delivery and Applications.in: Tekade R.K. Basic Fundamentals of Drug Delivery. Academic Press, 2019Crossref Scopus (1) Google Scholar, Muro, 2012Muro S. Challenges in design and characterization of ligand-targeted drug delivery systems.J. Control. Release. 2012; 164: 125-137Crossref PubMed Scopus (135) Google Scholar, Srinivasarao and Low, 2017Srinivasarao M. Low P.S. Ligand-Targeted Drug Delivery.Chem. Rev. 2017; 117: 12133-12164Crossref PubMed Scopus (106) Google Scholar), with an emphasis on the chemical design aspect of small molecule-based targeting constructs. Several small molecule ligands have advanced to the clinic (Table 1). We focus on their biology and provide the current landscape and challenges faced using this approach. Small molecules were among the first targeting ligands to be explored because of the simplicity of the chemistry of their conjugation to therapeutic cargoes. In addition, small molecules also generally have ease of manufacturability that further bolsters their utility. As a generalization, small molecule ligands have weak interactions with their targets (Srinivasarao and Low, 2017Srinivasarao M. Low P.S. Ligand-Targeted Drug Delivery.Chem. Rev. 2017; 117: 12133-12164Crossref PubMed Scopus (106) Google Scholar); therefore these ligands need to interact with receptors having deep topographies to ensure good target engagement. Some strategies are represented in the schematic (Figure 3).Table 1Representative Clinical Trials for Small Molecule-Based Targeting StrategiesTargeting AgentTargeted Modality EmployedClinical IndicationIdentifierClinical StatusFolic acidvintafolide (EC145) + etrafolide (EC 20)ovarian cancer, endometrial cancerNCT00507741phase II (completed)vintafolide (EC145) + etarfolatide (EC 20)adenocarcinoma of lungsNCT00511485phase II (completed)vintafolide (EC145)recurrent or refractory solid tumorsNCT00308269phase II (completed)vintafolide (EC145)platinum resistant ovarian cancerNCT00722592phase II (completed)vintafolide (EC145)solid tumorsNCT01002924phase I (completed)vintafolide (EC145) + etarfolatide (EC 20)triple negative breast cancerNCT01953536phase II (withdrawn)vintafolide (EC145)FR (++) second line non-small cell lung cancerNCT01577654phase II (completed)etarfolatide (EC20)–NCT01748864phase I (completed)EC0489 + EC20refractory or metastatic tumorsNCT00852189phase I (completed)EC0225 + EC20refractory or metastatic tumorsNCT00441870phase I (completed)EC1456 + 99 mTc-etarfolatideovary cancerNCT03011320phase I (completed)EC1456 and EC20solid tumors, non-small cell lung carcinomaNCT01999738phase I (completed)Glucoseglufosfamidesecond line metastatic pancreatic cancerNCT01954992phase III (recruiting)glufosfamidepancreatic cancerNCT00099294phase III (completed)glufosfamideneoplasms, pancreatic neoplasmsNCT00102752phase I/II (completed)glufosfamidebrain and CNS system tumorsNCT00014300phase II (completed)glufosfamidepancreatic cancerNCT00005053phase II (completed)glufosfamidelung cancerNCT00005055phase II (completed)glufosfamidesoft tissue sarcomaNCT00441467phase II (completed)GalactoseALN-AS1acute hepatic porphyriasNCT03338816FDA-approvedAPOC-III-L-Rxelevated triglycerides (TG)NCT02900027phase I (completed)IONIS FXI-LRx–NCT03582462phase I (completed)DCR-PHXCprimary hyperoxaluria type 1 (PH1), primary hyperoxaluria type 2 (PH2), kidney diseases, urologic diseases, genetic diseaseNCT04042402phase III (enrolling by invitation)DCR-PHXCprimary hyperoxaluria type 1 (PH1), primary hyperoxaluria type 2 (PH2), kidney diseases, urologic diseases, genetic diseaseNCT03847909phase II (recruiting)revusirantransthyretin (TTR)-mediated amyloidosis, familial amyloidotic polyneuropathy (FAP), ATTR amyloidosis, familial amyloid neuropathiesNCT02595983phase II (completed)revusiran (ALN-TTRSC)TTR-mediated amyloidosisNCT02292186phase II (completed)ALN-TTRSC (revusiran) for subcutaneous administrationTTR-mediated amyloidosisNCT01981837phase II (completed)ALN-TTRSC (revusiran)TTR-mediated amyloidosisNCT01814839phase I (completed)revusiran (ALN-TTRSC)transthyretin (TTR) mediated familial amyloidotic cardiomyopathy (FAC), amyloidosis, hereditary amyloid neuropathies, familial amyloid neuropathies amyloidosis, hereditary, transthyretin-related familial transthyretin cardiac amyloidosisNCT02319005phase III (completed)ALN-TTRSC02transthyretin-mediated amyloidosis (ATTR amyloidosis)NCT02797847phase I (completed)givosiran (ALN-AS1)acute intermittent porphyriaNCT02949830phase I/II (active/not recruiting)givosiran (ALN-AS1)acute intermittent porphyriaNCT02452372phase I (completed)givosiran (ALN-AS1)acute hepatic porphyria, acute intermittent porphyria, porphyria, acute intermittent acute porphyria, hereditary coproporphyria (HCP), variegate porphyria (VP), ALA dehydratase deficient porphyria (ADP)NCT03338816phase III (active, recruiting)givosiranacute intermittent porphyria (AIP), acute hepatic porphyria (AHP), porphyria, acute intermittent acute porphyriaNCT03505853phase I (completed)fitusiranhemophilia A, hemophilia BNCT03417245phase III (recruiting) Open table in a new tab Folic acid (FA) is the most widely used small molecule targeting agent (Ledermann et al., 2015Ledermann J.A. Canevari S. Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments.Ann. Oncol. 2015; 26: 2034-2043Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Low et al., 2008Low P.S. Henne W.A. Doorneweerd D.D. Discovery and development of folic-acid-based receptor targeting for imaging and therapy of cancer and inflammatory diseases.Acc. Chem. Res. 2008; 41: 120-129Crossref PubMed Scopus (799) Google Scholar). It is a vitamin that is used by all cells for nucleotide synthesis. Folic acid receptors (FRs) are expressed in different cells, which can be selectively targeted. For instance, FR α is expressed on more than 40% of human cancers, including ovarian and CNS-related cancers (Ledermann et al., 2015Ledermann J.A. Canevari S. Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments.Ann. Oncol. 2015; 26: 2034-2043Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), while FR β is expressed on activated macrophages (Salazar and Ratnam, 2007Salazar M.D. Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics?.Cancer Metastasis Rev. 2007; 26: 141-152Crossref PubMed Scopus (254) Google Scholar). These targets are suitable for oncology and auto-immune applications, respectively. FA has a high affinity for FR (Kd = 10−7 mM), thus making FA a versatile targeting strategy for various therapeutic modalities (Ledermann et al., 2015Ledermann J.A. Canevari S. Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments.Ann. Oncol. 2015; 26: 2034-2043Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, Srinivasarao and Low, 2017Srinivasarao M. Low P.S. Ligand-Targeted Drug Delivery.Chem. Rev. 2017; 117: 12133-12164Crossref PubMed Scopus (106) Google Scholar). FA enables efficient intracellular delivery as well, following FR-mediated endocytosis, provided the linker is capable of endosomal escape (Zheng et al., 2019Zheng Z. Li Z. Xu C. Guo B. Guo P. Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping.J. Control. Release. 2019; 311–312: 43-49Crossref PubMed Scopus (3) Google Scholar). FA-desacetylvinblastine hydrazide conjugate (vintafolide) showed a high safety profile as a single agent in phase I and II clinical trials (ClinicalTrials.gov: NCT00308269 and NCT00722592) compared to its untargeted counterpart. Its imaging counterpart, etarfolatide, which is FA-targeted 99Tc, is also listed in clinical trials as a biomarker diagnostic for FR targeted therapy (ClinicalTrials.gov: NCT00507741, NCT01748864, and NCT01953536). However, vintafolide failed in phase III clinical trials in combination with PEGylated doxorubicin for treatment of ovarian cancer due to inability of the combination to improve progression-free survival (ClinicalTrials.gov: NCT01170650). It was used for treating non-small cell lung cancer (NSCLC) in combination with docetaxel (ClinicalTrials.gov: NCT01577654) and has successfully completed phase IIb. Monosaccharides, such as glucose, mannose, and galactose, represent another class of excellent targeting ligands. Glucose, for instance, targets GLUT1 receptor that is overexpressed at the blood-brain barrier. Glucose and its derivative-modified therapeutic modalities and nanocarriers have been investigated for treating glioma (Jiang et al., 2014Jiang X. Xin H. Ren Q. Gu J. Zhu L. Du F. Feng C. Xie Y. Sha X. Fang X. Nanoparticles of 2-deoxy-D-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment.Biomaterials. 2014; 35: 518-529Crossref PubMed Scopus (81) Google Scholar). Glucose is also a major energy substrate for all living cells. Glufosfamide is a chemotherapeutic agent modified by D-glucose and uses the Warburg effect to target cells undergoing aerobic glycolysis. Clinically, it had failed phase II trial for treatment of pancreatic cancer, glioblastoma multiforme, and soft tissue sarcomas due to severe off-target toxicities (ClinicalTrials.gov: NCT00099294, NCT00014300, NCT00005053, and NCT00441467) but was advanced to clinical phase III for metastatic pancreatic cancer in combination with gemcitabine and eventually failed to demonstrate significant efficacy (ClinicalTrials.gov: NCT00099294). Similarly, mannose-6-phosphate receptor represents a transmembrane glycoprotein target in many tissues like lung and brain and immune cells in particular (Irache et al., 2008Irache J.M. Salman H.H. Gamazo C. Espuelas S. Mannose-targeted systems for the delivery of therapeutics.Expert Opin. Drug Deliv. 2008; 5: 703-724Crossref PubMed Scopus (171) Google Scholar). Mannosylated nanocarriers have been utilized in preclinical models to demonstrate efficient targeting resulting in improved efficacy in rodent models of tumor and inflammation (Sahu et al., 2015Sahu P.K. Mishra D.K. Jain N. Rajoriya V. Jain A.K. Mannosylated solid lipid nanoparticles for lung-targeted delivery of Paclitaxel.Drug Dev. Ind. Pharm. 2015; 41: 640-649Crossref PubMed Scopus (20) Google Scholar). Lectin-like receptors, such as mannose-6-phosphate receptor, are protein receptors that are responsive to carbohydrates. C-type lectin receptors are particularly used as targets for glycosylated modalities (Kapoor et al., 2019Kapoor D. Bhatt S. Kumar M. Maheshwari R. Tekade R.K. Ligands for Targeted Drug Delivery and Applications.in: Tekade R.K. Basic Fundamentals of Drug Delivery. Academic Press, 2019Crossref Scopus (1) Google Scholar). Galactose-modified delivery systems have been utilized in preclinical models, targeting galectin-3, for colorectal cancer applications (Minko, 2004Minko T. Drug targeting to the colon with lectins and neoglycoconjugates.Adv. Drug Deliv. Rev. 2004; 56: 491-509Crossref PubMed Scopus (160) Google Scholar). Galactose has also been used in hepatocellular carcinoma preclinical models and clinical settings due to its ability to target asialoglycoprotein (ASGP) receptors, and recently, galactosamine-modified small interfering RNA (siRNA) received approval from the Food and Drug Administration (FDA) for the drug, Givlaari, for the treatment of acute hepatic porphyria (Chen and Huang, 2019Chen F. Huang G. Application of glycosylation in targeted drug delivery.Eur. J. Med. Chem. 2019; 182: 111612Crossref PubMed Scopus (6) Google Scholar). Urea derivatives have been explored for targeting prostate-specific membrane antigen (PSMA). The receptor itself is known to internalize via clathrin-mediated endocytosis, deliver attached ligand, and recover back to the surface quickly. Its natural ligands, glutamate urea, are used for targeting PSMA. Particularly, (2-[3-(1,3-dicarboxypropyl)-ureido] pentanedioic acid (DUPA) is known to have very high affinity for PSMA (Ki ~14 nM) (Lv et al., 2018Lv Q. Yang J. Zhang R. Yang Z. Yang Z. Wang Y. Xu Y. He Z. Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA-Paclitaxel Conjugate.Mol. Pharm. 2018; 15: 1842-1852Crossref PubMed Scopus (4) Google Scholar). DUPA-modified liposomal docetaxel passed phase I and phase II clinical trials for the treatment of prostate cancer (ClinicalTrials.gov: NCT01300533 and NCT01812746), while DUPA modified tubulysin was used in the recently concluded phase I clinical trial for the treatment of castration-resistant prostate cancer (ClinicalTrials.gov: NCT02202447). Glutamate urea has also been used for single-photon emission computerized tomography (SPECT) imaging for PSMA marker diagnosis (Eiber et al., 2017Eiber M. Fendler W.P. Rowe S.P. Calais J. Hofman M.S. Maurer T. Schwarzenboeck S.M. Kratowchil C. Herrmann K. Giesel F.L. Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy.J. Nucl. Med. 2017; 58: 67S-76SCrossref PubMed Scopus (71) Google Scholar). In addition to the ones listed above, several other small molecules have been used for tissue-specific targeting. For example, drugs modified with glycyrrhetinic acid (GA) derivatives were used for several preclinical hepatocellular applications due to presence of GA receptors and variabilities and immunogenicity associated with FR-targeted and epidermal growth factor (EGF)-R targeted therapies, respectively (Singh et al., 2018Singh H. Kim S.J. Kang D.H. Kim H.R. Sharma A. Kim W.Y. Kang C. Kim J.S. Glycyrrhetinic acid as a hepatocyte targeting unit for an anticancer drug delivery system with enhanced cell type selectivity.Chem. Commun. (Camb.). 2018; 54: 12353-12356Crossref PubMed Google Scholar). Sulfonamide derivatives can be used to target solid tumors expressing carbonic anhydrase IX (Krall et al., 2014Krall N. Pretto F. Decurtins W. Bernardes G.J. Supuran C.T. Neri D. A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors.Angew. Chem. Int. Engl. 2014; 53: 4231-4235Crossref PubMed Scopus (0) Google Scholar). Benzamides, such as anisamide, can be specifically targeted to sigma-1 receptors (Huo et al., 2017Huo M. Zhao Y. Satterlee A.B. Wang Y. Xu Y. Huang L. Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remo