Polymer-drug conjugates: recent progress on administration routes.

Review

Polymer-drug conjugates: recent progress on administration routes

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Maastricht on 06/10/14 For personal use only.

Xin Pang, Xiaoye Yang & Guangxi Zhai† †

Shandong University, College of Pharmacy, Department of Pharmaceutics, Jinan, China

1.

Introduction

2.

Mechanism of action of polymer-drug conjugates

3.

Injectable drug delivery system

4.

Oral drug delivery system

5.

Transdermal drug delivery system

6.

Ocular drug delivery system

7.

Expert opinion

Introduction: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration. Areas covered: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems. Expert opinion: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions. Keywords: intravenous route, ocular administration, oral route, polymer-drug conjugates, pulmonary administration, routes of administration, transdermal route Expert Opin. Drug Deliv. [Early Online]

1.

Introduction

The use of polymers in medical therapy is not new, and undoubtedly conjugating macromolecular polymers with drugs have been applied as a promising platform for drug delivery. Polymer-drug conjugates belong to the area of polymer therapeutics. Its common feature is that therapeutic agent is not encapsulated but chemically linked to a polymeric macromolecular carrier [1]. This approach was suggested over 50 years ago. Jatzkewitz pioneered attachment of mescaline to water-soluble poly (vinyl prrolidone) via a dipeptide spacer in 1955 [2]. Subsequently, numerous polymer-drug conjugates were designed and synthesized [3,4]. Until the mid1970s, a clear analysis of a complete polymer-conjugated drug delivery system was first proposed by Ringsdorf [5]. According to the proposed mode, an ideal polymer-drug conjugate is characterized by a hydrophilic polymer backbone as a vehicle and bioactive agent(s) usually bound to the polymeric scaffold via a biological response linker. Sometimes, a targeting moiety or a solubilizer may also be introduced into the conjugate to improve the therapeutic efficiency. In general, the behaviors of the drugs will be changed deeply after conjugation. Compared with the pristine drug, the main advantages of polymer-drug conjugates are: i) an increased water solubility of the hydrophobic drugs; ii) controlled drug release manner under certain conditions (pH or enzymes); iii) protection of drugs 10.1517/17425247.2014.912779 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as a versatile platform for drug delivery. In the case of polymer-drug conjugates, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration. Injectable drug delivery system as the preferred administration route is well used, and the vast majority of polymer-drug conjugates undergoing market and clinical trials are injectable administration. Emerging drug delivery systems, such as oral, transdermal, pulmonary and ocular administrations, have been under intensive investigation. Poly(amidoamine) and hyaluronic acid as drug carriers provide a promising platform for drug delivery.

This box summarizes key points contained in the article.

against degradation; iv) a prolonged plasma half-life and improved bioavailability; and v) altered biodistribution and specific accumulation in sites by targeting agents or the known ‘enhanced permeability and retention (EPR) effect’ [6]. However, the task of acquiring an ideal polymer-drug conjugate seems intricate. Various factors should be considered, including selection of polymeric carrier (e.g., molecular weight, architecture, polydispersity, size and surface charged), desired target (intracellular, lymphatic system, etc.), type of conjugation (direct or indirect) and linker chemistry [7]. Moreover, when designing polymer-drug conjugates, physicochemical properties of drug molecules itself are also in need of attention. In the process of conjugation, they may suffer from some specific environments like pH, temperature and certain catalyst. Therefore, it seems that not every drug molecule is suitable for polymer-drug platform and the preparation techniques of conjugates must enable that drug molecules would not be degraded and destroyed. In addition, it should not be ignored that the design of a successful polymer-drug conjugate is also strongly influenced by its proposed route of administration. Drugs are introduced into human body by numerous routes such as enteral (oral, rectal and sublingual administrations), parenteral (injection and inhalation administration), or topical (skin and mucosal membranes). Each route has specific purposes, advantages and disadvantages [8]. Clearly, no drug delivery system can ever be described as ‘optimal’ or ‘ideal’ without comment on the proposed polymer-drug conjugates. Fundamentally, the route of administration has a serious impact on the accessibility of drug molecules to their respective target site and medical therapy. In the case of polymer-drug conjugate, the molecule is necessary to remain the form of conjugate in transit environment. While on arrival within disease cells, it should be enzymatically or chemically cleaved to release drug at the desired rate. Thus, the speed 2

and the efficiency with drug action are strongly dependent on the route of administration. Based on the different physiological environment of cells or organism, various deliveries will produce diverse effects on drug release kinetics, which is crucial to a successful polymer-drug conjugate, and the rate at which a drug reached its target site of action must be significantly influenced by its absorption and distribution profiles. Importantly, the toxicity and biocompatibility of conjugates also correlate distinctly with the route of administration. Initially, the routes of administration were not taken seriously on the design consideration of polymer-drug conjugates. Afterwards, as the most well-known synthetic polymers, PEG has been widely investigated in the field of drug conjugation and delivery known as a famous strategy named PEGylation. Preclinical studies showed some PEGprotein conjugates could induce intracellular vacuolation, which notably enhance the awareness of the potential problems and risk of any nonbiodegradable polymer-based drug conjugates in respect of their route of, and frequency of administration, and dose [9]. However, even with the biodegradable polymer carrier, the route of administration must be highly emphasized as well. This is essential to be sure that polymer/conjugate will be degradable within an acceptable time frame following administration, and the degradation products should be nontoxic and nonimmunogenic [10]. Recently, many published reviews discussed different aspects of the growing field of polymer-drug conjugates [11-13]. Lengthy discussion of every aspect of polymer-drug conjugates are beyond the scope of this article. In the review, we mainly focus on the recent advances in diverse routes of administration using polymer-drug conjugates. The mechanism of action and further perspective will also be presented. This emerging approach affords a new vision of pharmaceutical science research and opens novel and promising avenues to find desirable polymer-drug conjugates.

Mechanism of action of polymer-drug conjugates

2.

The major rationale for the design consideration of administration route of polymer-drug conjugates is based on the mechanism of action. This complex mechanism has been reviewed in [14] and shown in Figure 1. In the field of polymer-drug conjugates, conjugated-drugs following ocular administration are commonly suggested to retain in intraocular tissues to treat some ophthalmic diseases, instead of exposure to systemic circulation. Apart from intravenous (i.v.) administration that conjugates could immediately enter the blood circulation, there are several barriers, in other drug delivery systems, needing to be overcome before accessing bloodstream, such as unfavorable gastrointestinal (GI) environment, hepatic first-pass elimination, penetrating intact skin and alveolar-vascular permeable barrier. Generally, the designed linker between polymer and drug is expected to be stable in bloodstream and interstitial space. Owing to

Expert Opin. Drug Deliv. (2014) ()

Polymer-drug conjugates

Tumor tissue

A.

B.

b c d

b H+ a


e

Endosome

f

H+ Nucleus Kidney Normal vessel Drug

g

Enzyme Lysosome h

Tumor vessel

Targeting moiety

Ploymer-drug conjugate

Receptor

Figure 1. The mechanism of action of polymer-drug conjugates following intravenous administration. A. Whole organism level. B. Tumor cellular level. a. Minimum extravasation into normal tissues; b. Increased tumor targeting due to enhanced permeability and retention effect; c. Uptake by fluid-phase pinocytosis; d. Uptake by receptor-mediated endocytosis; e. Macromolecular drugs escape into cytosol; f. Exocytosis and receptor recycling; g. Drug release triggered by pH or lysosomal enzymes and access to therapeutic target; h. Exocytosis of nondegradable polymer carrier.

retention in the vascular compartment, minimum conjugate molecules extravasate into normal tissues. Even if a few conjugates access healthy cells and/or tissue (including sites of potential toxicity), it does not seem easy to release drug via the linker cleaved by biological environments. Reversely, the known ‘EPR effect’ allows increased conjugates to accumulate in tumor tissues specifically and perform alterative biodistribution However, this passive targeting is not always very efficient, because of certain tumors without the EPR effect, different permeability of vessels throughout a single tumor, as well as inefficient diffusion and inhomogeneous distribution of drugs in the tumor resulting from high interstitial fluid pressure of solid tumors [15,16]. Through the introduction of cell-specific recognition ligands, it is available to bring about the added benefit of receptor-mediated targeting of disease cells. On arrival in the tumor interstitium, polymer-drug conjugate will be internalized into disease cells through either receptor-mediated endocytosis (targeted polymer-conjugated drug) or fluid-phase pinocytosis (nontargered polymerconjugated drug). Because endosomes and lysosomes can offer a specific enzyme environment (e.g., cathepsin B) and lower pH (~ 5.5), the designed linker is susceptible to be cleaved to release drug intracellularly. Afterwards, the drugs, no matter passive or active transport, diffuse out of these vesicular compartments and access to their therapeutic targets. Generally, polymeric carriers can be divided in two groups according to desired lifetimes in vivo: biostable and biodegradable. Biostable polymers are simply inert in the host and maintain their mechanical properties without degradation

over decades, like PEG. By contrast, for a biodegradable polymer, its macromolecular structure can be degraded at least partially by a biological system but no proof of elimination from the body. In the field of biodegradable polymer-drug conjugates, the bioresorbable polymer carriers are the most common, such chitosan, hyaluronic acid (HA) and polyglutamic acid. Those polymer carriers will undergo bond cleavage in the molecular backbone, either hydrolytically or enzymatically, to generate degradation products (e.g., amino acids and saccharides) that can be excreted or absorbed in the biochemical pathways of the body. And for the biopersistent conjugate platforms, the polymer carriers will eventually be eliminated from the cell by exocytosis. In general, few polymeric carriers appear in the cytosol. Besides, the polymer carriers could also get out of the cell following cellular death. Then, these biostable polymers return to the bloodstream via the lymphatic circulation and are eliminated through kidney glomeruli (molecular weight [MW] below glomerular threshold) or the hepatic bile duct system (MW above glomerular threshold), like PEG and poly(amidoamine) (PAMAM) [9,11]. Suffice it to say, understanding the mechanism of action is important before designing the route of administration; in the following, various kinds of administration routes based on polymer-drug conjugates are discussed in detail. 3.

Injectable drug delivery system

Nowadays, the preferred route for the delivery of drugs using polymers is the injectable administration. As macromolecular


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drugs are not much bioavailable orally, the vast majority of them are frequently provided to patients as parenteral formulation. In general, polymer-protein conjugates are typically administered subcutaneously or intramuscularly, whereas polymer-drug conjugates are given intravenously. The i.v. route is the most straightforward one, and its advantages are obvious. As it shows the ability to be directed to the blood circulation and distributed throughout the body within seconds, i.v. administration is able to address the variable absorption patterns of the GI tract, resulting in immediate and complete bioavailability and thereby, accurate dosage. Currently, several formulations in the market are designed as subcutaneous (s.c.) and intramuscular (i.m.) administrations (Table 1). These delivery systems can act to slowly release the drug from the injection site to the bloodstream, hence, less frequent administration are required. Following evaluation of the biological fate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers injected via different routes, Seymour et al. found that after both intraperitoneal (i.p.) and s.c. administrations, long-term body (rats) distribution of HPMA copolymers displayed molecularweight-dependent accumulation in the organs of reticuloendothelial system, whereas the circulating blood volume available to the copolymers following i.v. administration was barely affected by MW [17]. Subsequently, studies focus on poly(vinyl alcohol) and PEG with various MWs. Afteri.p., s.c. or i.m. administration, the elimination rate of both polymers from the injection sites increased in the order of i.p.>s.c.>i.m. For the last two injections, with a decrease in the molecular weight, polymers were eliminated sooner. Interestingly, the injection site is the very important factor that affects the concentration profile of polymers in the blood circulation [18]. A desirable polymeric carrier suitable for injectable administration must be nontoxic and nonimmunogenic. Another critically important characteristic to emphasize (especially if a conjugate is to be i.v.-administered) is whether or not the polymer backbone has good hematocompatibility, and even drugs are routinely evaluated for hemolytic properties. What is more, the carrier should exhibit an inherent body distribution that will confine the specific targeting therapy, ideally, avoid exposure to collateral normal tissues to create toxicity. If at all possible, the polymeric carrier should be preferably biodegradable within an acceptable time frame. It is essential to avoid polymer used at high doses and/or repeatedly to accumulate progressively. Furthermore, nontoxic and nonimmunogenic degradation products are also important for an ideal polymer/conjugate [7]. Meanwhile, other parameters, such as MW, surface charge and architecture, have significant influence on injectable administration. Compared with linear polymers, the branched are eliminated through renal filtration more slowly and perform better therapeutic effect. Among the polymers with different surface charge, blood half-life is highest for neutral polymers. Cationic polymer carriers tend to be cleared most quickly from the blood and cause several complications such as hemolysis and platelet aggregation. Besides, 4

these positively charged polymers are taken up at a faster rate owing to a slight negative charge of the cell membrane and electrostatic attractions driving cell uptake and are preferentially accumulated in the liver. Usually, polymers with higher MWs will have less blood clearance, eventually resulting in their accumulation in tumor tissues. Currently, those polymer-drug conjugates that are under clinical trials bear MWs between 25 and 50 kDa, whereas the importance of MW of conjugates still remains unclear due to limited clinical data [19,20]. However, a great many polymers under developed can not be degraded properly by the body. Although tailor-making MW is available to maximize the chance of elimination via glomerular filtration, their nonbiodegradability still renders a great potential to accumulate in the lysosomes and increase the osmotic pressure with a high risk of ‘lysosomal storage disease’ syndrome. Therefore, it should be carefully consider when nondegradable polymers following high dose and or repeated administration are used to treat diseases where chronic parenteral therapy is required [21,22]. Even widely used natural polymers, such as poly(amino acids) or polysaccharides, may not be degraded into small fragments able to cross the lysosomal membrane. And the larger fragments are likely to accumulate intracellularly with a potentially negative impact on biocompatibility, which is a serous issue for injectable administration [10]. For instance, as plasma expander, dextran (a-1,6 polyglucose) are slowly degraded by mammalian enzymes. Further chain modification with pendant groups up to 5 mol% will seriously harness the degradation of dextran backbone. Even worse, it can cause an IgM response. On the contrary, dextran, a-1,4 poly(glucose), is a biocompatible polymer and easily degraded when exposure to a-amylase present in extracellular fluids and plasma. It has been widely used as carrier for injectable drug delivery [23]. Interestingly, just as seemingly safe platform, such as oxidized dextran-doxorubicin (AD-70), caused serious toxicity in Phase I clinical trial after infusion administration, which may be ascribed to uptake by liver reticuloendothelial cells [24]. Another carboxymethyl dextran-exatecan conjugate (DE-310) given by infusion also failed in Phase I clinical due to doselimiting toxicities including thrombocytopenia, neutropenia and reversible hepatotoxicity [25]. It is revealed that modifying pendant groups of polymers to enable drug conjugation probably impedes the host’s ability to effectively enzymatically degrade the polymeric carrier, thus inducing unsuccessful clinical trials [14]. Thereby, besides the concern of the toxicity, biodistribution and retention or excretion features of the polymeric carrier, conjugation itself is also of paramount importance in the early screening. Actually, the injection administration methods are prone to a number of problems. Some of the problems related to drug delivery are irrelevant for the formulation, such as hypersensitivity, microbiological contamination, particulate matter and poor injection technique or burred needles. Others are inherent drawbacks. The majority of side effects of injection



Table 1. Polymer-drug conjugates via injectable drug delivery system present in market and clinical trials. Conjugates

Trade name


Polymer-protein conjugates SMANCS Zinostain Stimaler PEG-adenosine Adagen deaminase PEG-asparaginase Oncospar

Route of administration Subcutaneous injection Intramuscular

PEG-IF-a-2a

PEGASYS

Intravenous intramuscular Subcutaneous

PEG-IF-a-2b

PEGINTRON

Subcutaneous

PEG-human GCSF

Neulasta

Subcutaneous

PEG-hGH antagonist PEG-antiTNF Fab

Somavert

Subcutaneous

Cimzia

Subcutaneous

Polymer-drug conjugates PEG-irinotecan NKTR-102

Intravenous

PEG-SN38

EZN-2208

Intravenous

PEG-docetaxel

NKTR-105

Intravenous

PHPMAdoxorubicin PHPMA- doxorubicin-galactosamine PHPMA-platinum PHPMA-DACHoxaliplatin

PK1 (FCE28068)

Intravenous

PK2 (FCE28069)

Intravenous

AP5280 ProLindac (AP5346)

Intravenous Intravenous

Fleximercamptothecin

XMT1001

Intravenous

Carboxymethyl dextran-T2513 Cyclodextrincamptothecin

Delimotecan

Infusion

CRLX101

Intravenous

Xyotax, Opaxio, CT-2103 CT-2106

Intravenous

Polyglutamic acidpaclitaxel Polyglutamic acidcamptothecin

Intravenous

Effects

Status

Individualized hepatocellular carcinoma therapy

Market

Low arginine concentrations of < 2 µM in all patients; sometimes in combination with 5-fluorouracil Decreased hypersensitivity reactions; partial response in non-Hodgkin lymphoma patients Chronic hepatitis C; a mean half-life of 160 h that allows once weekly injections Chronic hepatitis C; a reduced dosing frequency (generally injected once weekly) Febrile neutropenia; less frequent administration (a single injection on day 2 of each chemotherapy cycle) Acromegaly; decreased antagonistic activity and clearance; a mean half-life of ~ 6 days Crohn’s disease, arthritis; increased elimination half-life of ~ 2 weeks, permitting every 2 or 4 weeks dosing

Market

High confirmed objective response rate on advanced breast cancer; manageable toxicity (dose-limiting) Significant activity in triple-negative breast cancer patients; good tolerability A prolonged half-life of 60 days; an increased MTD of 40 mg/kg; great activity in colon and lung cancer xenograft models. 6/62 partial responses with side effects; obvious tumor accumulation in two metastatic breast cancers Half the MTD value of PK1; effective liver targeting; acute and cardiovascular toxicities Minimal renal toxicity and myelosuppression Two partial responses in metastatic melanoma and ovarian cancer; CA-125 normalization in a suspected ovarian cancer patient A favorable PK profile; prolonged stable disease ‡ 12 weeks in nine patients at doses below the MTD A long terminal half-life of 109 h; high exposures; doselimiting Stable disease in 28 patients (64%) and a PFS of 3.7 months at the MTD, 16 (73%) and 4.4 months for the subset of NSCLC patients, respectively An orphan drug to treat glioblastoma multiforme combined with radiotherapy A manageable toxicity profile; a MTD of 25 mg/m2 weekly given 3 of 4 weeks

Market Market Market Market Market Market

Phase III/II Phase II Phase I

Phase II Phase II Phase II Phase II

Phase I

Phase I Phase IIa

Phase III

Phase II

DACH: Diaminocyclohexane; GCSF: Granulocyte colony-stimulating factor; hGH: Human growth hormone; MTD: Maximum-tolerated dose; PHPMA: Poly[N-(2-hydroxypropyl) methacrylamide]; SMANCS: Styrene maleic anhydride-neocarzinostatin; SN-38: 7-ethyl-10-hydroxy-camptothecin; T-2513: An active camptothecin derivative.

administration that result from the formulation are hemolysis, phlebitis, precipitation and pain [26]. Additionally, high concentration of the drug may be delivered to health cells and/ or tissue and some chemotherapy regimens are designed to afford the maximal-tolerated dose of drug to kill diseased cells in a short period of therapy followed by several weeks without injection administration [27-29]. Hence, when designing a

conjugate intended for long-term therapy, a more safe and convenient route of administration should be considered. 4.

Oral drug delivery system

Oral administration is the best route in terms of patient adherence. It makes patients feel less sick and reduce their


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medical cost. Importantly, from a convenient point of view, the oral therapy is appealing because of its ease of administration and does not require a clinic or hospitalization visit, nursing and palliative treatment. Likewise, high efficacy/safety ratio is one of the main significant advantages of oral drug delivery. Nevertheless, an orally administration drug has to undergo several rigorous challenges on its way to systemic circulation, including exposure to the confounding enzymes and bacterial population in the GI tract, highly acidic environment of the stomach, extensive hepatic first-pass elimination, the P-glycoprotein (P-gp) efflux pumps and the CYP450-mediated metabolism in the intestinal wall. All these barriers associated with poor physicochemical properties (solubility and permeability) of drugs may seriously impair the bioavailability of the drug. In the field of oral drug delivery, covalent conjugation to polymeric materials can be used to: i) enhance the stability of the drug by avoiding degradation in the GI tract; ii) facilitate the drug absorption in intestine via dramatically increased aqueous solubility; iii) overcome hepatic firstpass effect; iv) improve therapeutic index and decrease toxicity; and v) protect the drug from resistance mechanisms by altering the route of drug absorption from transcellular to paracellular or transcytosis pathways [11,30,31]. Up to now, polymer-drug conjugates are of particular interest, but for little, the conjugates are designed for the oral administration. Oral delivery of polymer-drug conjugates is limited owing to their large size, poor polydispersity and high hydrophilicity, as well as the premature drug liberation in GI tract. Furthermore, different MW, shape and surface charge also seriously influence the pharmacokinetic profile of a conjugate. Unlike other administration routes, a special challenge incurred in oral drug delivery system is the highly acidic environment in the stomach. Herein, it should be noted that some acid-labile linkers like ester and hydrazone are preferred to avoid when designing oral delivery system, and polymer carriers sensitive to acidity are also less favored. Recently, PEG, chitosans and dendrimers are widely used as oral drug carriers. The classical approach for polymer-drug conjugates can be broadly categorized as PEGylation. Unequivocally, the appealing inhibitory response of PEGs on the P-gp efflux and its solubilization potential contributes significantly in increasing the oral bioavailability of drugs [11]. As a good illustration, NKTR-118, a PEGylated form of naloxol (PEG-naloxol conjugate), is currently under Phase III clinical trails as an oral, once-daily tablet for the treatment of debilitating conditions such as opioid-induced bowel dysfunction and opioid-induced constipation [32]. Phase II clinical trial indicated that oral NKTR-118 attenuated GI-related side effects by increasing the frequency of spontaneous bowel movements in patients with opioid-induced constipation, while simultaneously no apparent reversal of opioid-mediated analgesia. Similarly, using PEG-based oligomers to regulate the amphiphilic properties and manipulate the location of attachment could provide a promising platform for oral delivery of therapeutic peptides 6

and proteins like insulin (hexyl-insulin monoconjugate-2) and calcitonin [33,34]. In addition, the bioconjugation of branched 20 kDa PEG with lactoferrin caused decreased binding affinity to its receptor and eventually achieved an approximate 10-fold enhancement of intestinal absorption relative to native lactoferrin after oral administration [35]. Chitosan, not good substrates for the mammalian enzymes after parenteral administration, is frequently used to enhance oral delivery of drugs. The mucoadhesive property of chitosan can greatly enhance the drug retention in the GI tract after oral administration. Additionally, its high capacity to capture a large volume of water molecules is also favorable to oral absorption. For example, directly combining atorvastatin with chitosan to form nano-sized conjugate could achieve 100-fold increase in water solubility compared with free atorvastatin and significantly protect drug from acidic degradation [36]. After oral administration to rats, the nanoconjugate showed bioavailability enhancement of nearly fivefold relative to atorvastain suspension. Compared to high-MW chitosan, low-MW chitosan (LMWC) showed higher water solubility and lower toxicity. One of the most significant advantages of it is to open the tight junctions between Caco-2 cells to boost paracellular transport, which is a highly useful property for oral drug delivery. Recently, the novel oral delivery systems for LMWC-conjugated paclitaxel or its synthetic analogue (docetaxel) successfully prolonged the retention of the conjugate in the GI tract owing to improved mucoadhesive properties and bypassed the P-gp effux pumps and CYP450-mediated metabolism in the intestinal wall, resulting in remarkably enhanced bioavailability, decreased sub-acute toxicity and improved antitumor efficacy in vivo to that of i.v.-administered drugs [37,38]. Further, conjugation to LWMC also allows the challenging molecule (insulin) for effective oral delivery [39]. Suffice it to say, permeability is known to have an important impact on transepithelial transport. Meanwhile, drug absorption in the GI tract after oral administration heavily depends on permeability. Many dendrimer-based drug conjugates (Figure 2) can easily penetrate through intestinal membranes like the epithelial barrier, increasing their oral absorption. Importantly, instead of in the large intestine, the uptake of dendrimers via the lymphoid tissue always occurs in the small intestine [40]. In the case of anionic PAMAM dendrimers, which possess rapid serosal transfer rates and low tissue deposition, generations 2.5 and 3.5 revealed a highly efficient transcytotic transport pathway [41]. Meanwhile, cationic PAMAM dendrimers, as intestinal penetration enhancers, could increase the permeability of hydrophobic small molecules through the small intestine, especially for generations 0.0 -- 3.0 that performed reversible plasma membrane damage at high concentrations (0.5% w/v) [42]. Besides generation size and surface charge mentioned above, the penetration of dendrimers across epithelial barrier depends on other important features, such as concentration, incubation time, efflux transport, surface charge and modification [43].



Terminal groups for conjugation

Linker

Central core G0 G1


G2 Drug

Figure 2. Schematic presentation for dendritic polymer-drug conjugate. Central core is composed of an atom or a molecule with at least two identical chemical functions; G denotes generation. The organized repetition of branches in a geometrical progression results in a series of radially concentric layers called ‘generations’; Terminal functional groups located at the surface of dendrimer are used to conjugate with drug molecules.

5.

Transdermal drug delivery system

Very selective transdermal drug delivery system (TDDS) is a noninvasive route of administration via the skin for both local and systemic therapies. In contrast to injectable and oral administrations, it presents several major beneficial in reducing the frequency of dose, achieving target therapy and bypassing the hepatic first-pass elimination. Likewise, the sustained drug release profile allows steady absorption of drug over hours or days, thus avoiding the potential toxicity. Moreover, the simple dosage schedule and high flexibility are appealing to many patients [44]. Although TDDS is an attractive alternative to oral and hypodermic administrations, the outermost layer of the epidermis -- stratum corneum (SC) as a protective barrier against exogenous molecules -- performs a great challenge for numerous drug molecules [45]. Particularly, the SC is a prominent barrier against those compounds with MW over 500 Da and/or those with 1-octanol/ phosphate buffered saline partition coefficients < 1 or > 3 [44,46,47]. For this reason, polymers bearing the property of enhancing transdermal penetration have been extensively favored, such as polyesters, dendrimers, chitosan and HA. The other properties, which are utmost importance, are that of biodegradability and biocompatibility. Especially for biocompatibility, it is indispensable to TDDS because the application of a transdermal formulation onto the surface of the skin can be for several days [48]. Again, the ester linkage is also desirable in TDDS given that viable skin is typically abundant in esterase activity, facilitating the hydrolysis process to release drug [49].

In the field of TDDS based on polymer-drug conjugates, surface functional groups on polymer carriers or drug molecules are another key determinant that can affect the permeation efficiency. Because mammalian skin has a net negative charge under normal physiological conditions, it will attract positively charged molecules and repulse negatively charged molecules. On the one hand, the presence of ionized functional groups on the drug molecule could be repulsed by oppositely charged groups on SC components. On the other hand, polymer carriers interact with skin layers also depend on their surface groups as well as size. To the best of our knowledge, regardless of the various dendrimer categories, only one type of dendrimer (PAMAM) has been employed to covalently conjugate with drugs in TDDS. In the presence of PAMAM dendrimers, the drugs (like transretinal, pyridoxal and pyridoxal phosphate) were able to permeate the skin effectively and the bioconjugates did modify the diffusion of free drugs [50]. Furthermore, it has been proved that with the decrease of PAMAM dendrimers size, the penetration absorption will be gradually improved [51,52]. Compared with the generation 2 (G2) PAMAM dendrimers, the G4 PAMAM showed less efficient permeability and were limited to the SC of pig skin after topical application. After surface modification, the enhancement in drug permeability coefficient was in the following order: G4-NH2 > G4-OH > G3.5-COOH. However, the G2 PAMAM dendrimers exhibited different permeation enhancement effects. Because of the concentration gradient across the skin and possibly charge repulsions between the dendrimers and the negatively charged cell membrane, those surface-modified with neutral (G2-COCH3) or negatively charged groups (G2-COOH) would go through the skin layers to dermal layer easily via an extracellular pathway that could be faster than the transcellular pathway taken by positively charged G2-NH2 which could only penetrate to viable epidermis. The other attractive polymer proposed as a conjugated carrier for drug in TDDS is HA. Widely distributing in synovial and extracellular matrix, HA is known to be a ligand that can recognize CD44 and the receptor for HA-mediated motility, therefore conjugation of it with drugs is supposed to increase cellular uptake and realize drug-targeted delivery by receptormediated endocytosis. Furthermore, its excellent biodegradability and biocompatibility also impel HA as a promising candidate for polymer-drug conjugates for successful transdermal delivery of bioactive molecules [53]. As a great example, HAhGH conjugates as receptor-mediated transdermal delivery system of protein drugs achieved dramatically enhanced penetration and evenly distributed in the skin tissue, even be delivered effectively to the dermis (Figure 3) [54]. Interestingly, owing to HA-receptor-mediated penetration and the hydration of SC by hygroscopic HA, HA-hGH conjugate seemed to be dramatically delivered through the skin into the bloodstream. After conjugation with HA, the bioavailability of hGH was highly enhanced, by as much as 10-fold, following transdermal administration in comparison with parent hGH (1.53%).


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Hydration

Stratum corneum Active targeting Epidermis

Keratinocyte Stem-cell like cell


Basal layer IGF Dermis Fibroblast HA-hGH conjugate

HA receptor

hGH receptor

Figure 3. Schematic illustration of the hyaluronic acid (HA)-hGH conjugates across the skin tissue. The receptors of HA and hGH are widely distributed in the skin tissue. Through hydration and receptor-mediated active targeting, HA-hGH conjugates could penetrate the stratum corneum and be effectively delivered even to the dermis. In this process, the HA-hGH conjugates first bind to HA receptors on keratinocytes in the epidermis and then combine with hGH receptors located in fibroblasts to promote cell proliferation and the synthesis of IGF-1 in the dermis.

Pulmonary drug delivery system As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung, of course, is an attractive target for drug delivery. Compared with other approaches like oral delivery or injection, pulmonary drug delivery has many advantages. The lung provides a high solute permeability, a limited proteolytic activity and a huge surface area for local drug action and systemic absorption of drug. Moreover, pulmonary delivery is noninvasive. Drug can be targeted to the site of action, which potentially decreases the overall dose and the incidence of side effects that result from high concentration of systemic drug exposure. Alternatively, targeted drug delivery to the alveolar region can be absorbed through the thin layer of epithelial cells and into the systemic circulation, rendering a systemic drug delivery. It is desirable to avoid the first-pass metabolism and deliver some bioagents that can not be administered orally and thus have to accept parenteral delivery. Meanwhile, pulmonary administration allows targeted drug delivery to special lung cells like alveolar macrophages, for treatment of diseases such as lung cancer [55-57]. Currently, only HA and PAMAM have been used for pulmonary drug delivery in the field of polymer-drug conjugates. Compared with i.v. administration, pulmonary delivery could effectively improve drug deposition and retention in the lung. For instance, conjugation of cisplatin (CDDP) with HA was able to achieve 5.7-fold increase of total platinum level in the lung after lung instillation at 24 h relative to the HACDDP i.v. group [58]. Meanwhile, judged by IC50 values, 5.1

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the HA-CDDP conjugates fully preserved the antitumor activity of CDDP. Promisingly, the drug accumulation in the brain, heart and kidney was significantly reduced following lung instillation of HA-CDDP conjugates, which is an indication of reduced side effects. Moreover, PAMAM as the other macromolecular drug carrier that attracts considerable concern has been shown to enhance pulmonary absorption of drug [59]. In a pulmonary inflammatory murine model at the dose of 5 mg/kg, the G4-OH PAMAMconjugated methylprednisolone (MP) dramatically improved the airway delivery following a 11-fold enhancement of eosinophil lung accumulation after five daily inhalation exposures of sensitized mice to allergen ovalbumin, which revealed that PAMAM-MP conjugates could promote the ability of MP to decrease allergen-induced inflammation, probably resulting from the improved drug residence time in the lung. Indeed, it was supported that only 24% of a single dose of conjugates transported to the peripheral lung is lost over a 3-day period. As a major port of entry, the lung has evolved to show protective barrier against unwanted airborne particles entering into the body. It should be noted that humidity, airway geometry, mucociliary clearance and alveolar macrophages can have a significant impact on maintaining the sterility of the lung. As a consequence, they also act as barriers to the therapeutic effect of inhaled medications. Moreover, the efficacy of drugs is likely to be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat [60]. In addition, to provide an effective and efficient




pulmonary drug delivery, some parameters must be considered. Particles of larger 5 µm aerodynamic diameter (dae) result in oropharyngeal deposition and are more likely to be swallowed than to reach the lung. Smaller particles (dae = 1 -- 5 µm) generally reach the deeper parts of the lung, the more smaller particles in the alveolar region, the larger more in the bronchial airways. Those very small particles (dae < 1 µm) will likely be exhaled. Particles < 150 nm are able to experience delayed lung clearance, increased protein interactions and more transepithelial transport relative to larger particles. Surface charge is another important factor to consider in rational design. Low surface energy is needed to avoid particle agglomeration. Oppositely charged particles are also possible to induce electrostatic interactions with the alveolar wall. Moreover, the MWs of macromolecules < 40 kDa (< 5 -- 6 nm in diameter) will rapidly appear in the blood following inhalation into the airways [61-63]. Although there are limited reports on the use of polymer-drug conjugates in pulmonary administration, it may be a promising platform for targeted drug delivery with high therapeutic effect and low systemic toxicity. 6.

Ocular drug delivery system

Ocular drug delivery has remained as one of the most challenges for scientists. Drug delivery to the eye can be broadly classified into two segments: anterior and posterior. Because of the high sensitivity to ocular tissues like retina and the presence of tissue barriers to drug penetration, such as the lipophilic corneal epithelium, the hydrophilic corneal and the conjunctival lymphatics, scleral stroma, choroidal vasculature and the blood--retinal barrier (BRB), few amounts of administrated drugs can get across the ocular barriers to reach disease sites, and most of the topically applied drugs are washed off from the eye by various mechanisms (lacrimation, tear dilution and turnover), resulting in accumulation of drugs in unwanted eye tissues and low ocular bioavailability of drugs [64]. Up to now, treatment of posterior segment diseases is still a formidable task. The tight junctions of BRB restrict the systematic administration of ophthalmic drugs by oral or i.v. routes to arrive the retina. High virtual drug level is necessary to treat posterior segment diseases. It can be made possible only with the local administration, such as periocular injection, intravitreal injection or implant [65]. Owing to great bioadhesion, sustained drug release and eye penetration enhancement, dendrimers as a drug carrier have recently received much more attention in local ocular administration [66]. Perhaps, the most remarkable advantage of dendrimers is their potential for targeted drug release in the posterior segment of the eye. Conjugation of hydroxylterminated G4 PAMAM with fluocinolone acetonide (FA), upon intravitreal administration, could induce in vivo efficacy against retinal degeneration in the Royal College of Surgeons rat model, and arrest of retinal degeneration was fully observed for an entire month [67]. Indeed, the conjugate had

an intrinsic ability to selectively localize within activated outer retinal microglia, but not in the retina of health controls. Promisingly, it could release FA for a sustained period over 90 days for the treatment of retinal neuroinflammation. Additionally, carboxyl-terminated G3.5 PAMAM-conjugated glucosamine or glucosamine-6-sulfate both be proved to exhibit potent activities in a validated and clinically relevant wound healing glaucoma model in rabbit following subconjunctival injection [68]. As one of the two main structural components of the vitreous in the eye along with collagen, HA shows its powerful vitality in ocular drug delivery. Historically, it was found that HA-based conjugates could increase the residence time of drug (like methylprednisolone) in the tear fluid [69]. Recently, anti-VEGF receptor 1 (Flt 1) peptide of GNQWFI was chemically attached to tetra-n-butyl ammoniummodified HA to effectively inhibit retinal choroidal neovascularization after intravitreal injection [70]. Moreover, the retinal vascular permeability and the deformation of retinal vascular structure were significantly diminished in diabetic retinopathy model rats through intravitreally injection treatment with HA-GNQWFI conjugate. It was also confirmed that antiFlt 1 peptide after conjugation with HA remarkably increased the mean residence time over 2 weeks. 7.

Expert opinion

Use of polymeric materials and their implications in delivering bioactive agents seems to be crucial in therapeutics. It is well accepted that the choice of the route of administration remains the utmost challenge regarding dosing, frequency of administration, dose volume, number of treatments and so on. Importantly, meanwhile, it should be designed both from the nature of the drug and the proposed disease but should combine with the patient’s use. Likewise, in the case of polymer carrier, its physicochemical and biological properties also strongly affect the selection of the route of administration. Although enormous progress has been achieved in the past decades, a great many polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection). Most importantly, the translation of polymer-drug conjugates into market has been too slow due to many serious challenges. Inherent defects of polymer-drug conjugates on the one hand that are impeding further development include polymer-related toxicity (e.g., cytotoxicity, hematotoxicity, carcinogenicity, teratogenicity, complement activation and cellular and humoral immunogenicity); limited drug loading or unsuitable choice of drug (usually unstable and bioactivity too low) and inappropriate linker design that fail to release drug at the desired rate until conjugates arrive in therapeutic targets. On the other hand, some technical and methodological factors also delay this translation, such as accessible industrial-scale manufacture;


9


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an urgent need for validated analytical techniques required to confirm conjugate identity/purity; appropriate clinical trial design; systemic studies on pharmaceutical formulation to realize rapid solubilization of particle-free solutions for safe administration and great shelf-life stability at a defined storage temperature and pharmacoeconomic considerations. However, some appealing polymer carriers still offer several promising platforms to drug delivery. For instance, existing widely in most of body fluids and secretory fluids HA is suitable for a large variety of administration routes (e.g., i.v., transdermal, pulmonary and ocular drug delivery) due to its great biodegradability and biocompatibility. In addition, unlike other polymers, dendrimers showed well-controlled sizes (3 -- 10 nm), narrow dispersibility (~ 1.0), ease of functionalization, defined chemical structure and good biocompatibility. Recently, these dendrimers, especially PAMAM, are being considered as additives in several routes of administration (as detailed above). Meanwhile, some modern polymerization techniques, including reversible additionfragmentation chain transfer polymerization, atom-transfer radical polymerization, small-angle neutron scattering and pulse-field gradient nuclear magnetic resonance, have already shown to be valuable tools for controlling and indentifying macromolecular impurities and physicochemical characterization, which greatly influence biological behavior and determine whether or not a polymer-drug conjugate can progress towards market. In the further, many efforts are desirable to understand the ADME (absorption, distribution, metabolism and excretion) of polymer-drug conjugates, obtaining a rational and Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Acknowledgement This work is supported by the Natural Science Foundation of Shandong Province, China (No.ZR2011HM026).

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. This work is supported by the Nature Science Foundation of Shandong Province, China (No. ZR2011HM026). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation Xin Pang1, Xiaoye Yang1 & Guangxi Zhai†2 PhD † Author for correspondence 1 Shandong University, College of Pharmacy, Department of Pharmaceutics, 44 Wenhua Xilu, Jinan 250012, China 2 Professor, Shandong University, College of Pharmacy, Department of Pharmaceutics, 44 Wenhua Xilu, Jinan 250012, China Tel: +86 531 88382015; E-mail: [email protected]

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