In vivo distribution of surface-modified PLGA nanoparticles following intravaginal delivery.

Intravaginal (ivag) delivery, which is a proven way to confer local protection against STDs contracted via the reproductive tract, is complicated by the mucus gel barrier, the hormone cycle, and the harsh mucosal environment that leads to low residence-time for administered agents. Polymer delivery vehicles may be useful in overcoming these barriers. In this study, we explored the fate of nanoparticles (NP) made from poly(lactide-co-glycolide) (PLGA) in the mouse reproductive tract after ivag delivery. The nanoparticles were modified to display avidin (Avid-NP) or 2 kDa PEG (PEG-NP) on their surface. Vaginal retention fractions for both muco-adhesive Avid-NP and stealthy PEG-NP were 5× higher than unmodified PLGA particles (NP). The amount of particles associated with mucus differed across formulations (Avid-NP>NP>PEG-NP). PEG-NP was found at higher concentration in the tissue than Avid-NP and NP up to 6h after delivery, and particles were found within epithelial cells, the underlying submucosal stromal and fibroblast cells of the vaginal tissue. Our results demonstrate that surface properties of nanoparticles can impact their fates following ivag delivery. Moreover, we show that the muco-evasive PEG-modified nanoparticles are the most effective among the delivery vehicles tested for this application.

[1]  P. Cresswell,et al.  Enhanced and prolonged cross‐presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles , 2006, Immunology.

[2]  A. Woolfson,et al.  Drug delivery by the intravaginal route. , 2000, Critical reviews in therapeutic drug carrier systems.

[3]  N. Mishra,et al.  Plasmid DNA loaded chitosan nanoparticles for nasal mucosal immunization against hepatitis B. , 2008, International journal of pharmaceutics.

[4]  Y. Ikada,et al.  Size effect on systemic and mucosal immune responses induced by oral administration of biodegradable microspheres. , 1996, Vaccine.

[5]  P. Wakeley,et al.  Mucosal or systemic administration of rE2 glycoprotein antigen loaded PLGA microspheres. , 2009, International journal of pharmaceutics.

[6]  A. I. Yudin,et al.  Diffusion of macromolecules and virus-like particles in human cervical mucus. , 2001, Biophysical journal.

[7]  Lynn Morris,et al.  Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women , 2010, Science.

[8]  A. Tiwary,et al.  Mucoadhesive Microspheres for Gastroretentive Delivery of Acyclovir: In Vitro and In Vivo Evaluation , 2008, The AAPS Journal.

[9]  V. Lee.  Enzymatic barriers to peptide and protein absorption. , 1988, Critical reviews in therapeutic drug carrier systems.

[10]  K. Whaley,et al.  Residence half-life of IgG administered topically to the mouse vagina. , 1996, Biology of reproduction.

[11]  P. Ogra.  Handbook of mucosal immunology , 1994 .

[12]  A. Vila,et al.  Transport of PLA-PEG particles across the nasal mucosa: effect of particle size and PEG coating density. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[13]  J. Mestecky,et al.  Immunologic Uniqueness of the Genital Tract: Challenge for Vaccine Development , 2005, American journal of reproductive immunology.

[14]  B. Chatterton,et al.  Retention and distribution of two 99mTc-DTPA labelled vaginal dosage forms. , 2004, International journal of pharmaceutics.

[15]  M. Qiao,et al.  Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[16]  R. Cone,et al.  Barrier properties of mucus. , 2009, Advanced drug delivery reviews.

[17]  Y. Kawashima,et al.  Effectiveness of submicron-sized, chitosan-coated liposomes in oral administration of peptide drugs. , 2005, International journal of pharmaceutics.

[18]  Shohei Sugimoto,et al.  Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[19]  W. Saltzman,et al.  Vaccine delivery by polymeric vehicles in the mouse reproductive tract induces sustained local and systemic immunity. , 2010, Molecular pharmaceutics.

[20]  H. Okada,et al.  Effects of menstrual cycle on gene transfection through mouse vagina for DNA vaccine. , 2008, International journal of pharmaceutics.

[21]  Tejraj M Aminabhavi,et al.  Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Jung Soo Suk,et al.  Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that "slip" through the human mucus barrier. , 2008, Angewandte Chemie.

[23]  W. Jiskoot,et al.  Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[24]  M. Sakaguchi,et al.  The biological fate of sodium prasterone sulfate after vaginal administration. I. Absorption and excretion in rats. , 1992, Journal of pharmacobio-dynamics.

[25]  Maria José Alonso,et al.  Comparative Uptake Studies of Bioadhesive and Non-Bioadhesive Nanoparticles in Human Intestinal Cell Lines and Rats: The Effect of Mucus on Particle Adsorption and Transport , 2002, Pharmaceutical Research.

[26]  Yen Cu,et al.  Controlled surface modification with poly(ethylene)glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. , 2009, Molecular pharmaceutics.

[27]  Justin Hanes,et al.  Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus , 2007, Proceedings of the National Academy of Sciences.

[28]  R. Walker,et al.  New strategies for using mucosal vaccination to achieve more effective immunization. , 1994, Vaccine.

[29]  Fakhrul Ahsan,et al.  Influence of surface charge of PLGA particles of recombinant hepatitis B surface antigen in enhancing systemic and mucosal immune responses. , 2009, International journal of pharmaceutics.

[30]  W. Mark Saltzman,et al.  Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA , 2009, Nature materials.

[31]  A. Iwasaki.  Mucosal dendritic cells. , 2007, Annual review of immunology.

[32]  F. Ahsan,et al.  The vagina as a route for systemic drug delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[33]  Kazuya Matsumoto,et al.  Synthesis of novel iodinated derivatives of nonoxynol-9 and their bioavailability in rats. , 2002, Nuclear medicine and biology.